March 23rd, 2011
Fibrate Prescriptions: A Tale Of Two Countries
Larry Husten, PHD
During the past decade, fibrate use more than doubled in the U.S. but remained relatively stable in Canada, according to a study just published in JAMA.
In January 2002, fibrate use was similar in the two countries: 336 prescriptions per 100,000 population in the U.S. versus 402 per 100,000 in Canada. By December 2009, the number in the U.S. had skyrocketed to 730 per 100,000, while the number in Canada hit only 474 per 100,000 . Most of the change in the U.S. was attributed to an increase in the use of branded fenofibrate, whereas in Canada, fibrate use shifted from branded drugs to generic ones.
The study investigators (including senior author Harlan Krumholz, who is editor-in-chief of CardioExchange) concluded that “at a time when a less-is-more approach is being embraced by the medical community, this ever-increasing pattern of prescribing brand-name medications without evidence of clinical benefit warrants attention and close scrutiny to ensure that such medication use is optimized for clinical benefit, while avoiding unwarranted costs.” Here, lead author Cynthia Jackevicius answers questions about the study from CardioExchange editor Susan Cheng.
Q: Accumulating evidence suggests that fibrates have limited clinical utility, yet this study shows that fibrate use is increasing in the U.S. What do you think are some of the main reasons behind that observation?
CJ: We did not specifically study the reasons for the increase in fibrate prescriptions, but prescribing changes are usually a result of changes in evidence, policy, or marketing. During the past decade, there was not any new evidence — or any widespread policy changes — to support fibrate use, so the most likely influential factor was marketing.
Q: Is your group likely to pursue an analysis of outcomes associated with the observed prescribing patterns?
CJ: Whether the increasing use of fibrates in the U.S. over the last decade translates into improved patient outcomes is uncertain, so we would definitely like to explore this more. The main evidence to support clinical outcomes benefit is from placebo-controlled trials with the older fibrates gemfibrozil and clofibrate. These trials exert substantial influence in the meta-analyses that show that fibrates in aggregate significantly reduce cardiac events but not overall mortality. The relevance of this older evidence to contemporary practice is uncertain, particularly given the negative results of the ACCORD study, which is the only trial that has assessed fibrates in a population taking statins.
Q: How would you recommend that clinicians apply the main findings from this study? What about practice groups, health plans, and policy makers?
CJ: Our results should give clinicians pause about what is being accomplished with the increased use of fibrates. From a mechanistic perspective, lowering triglycerides should lower the risk for cardiac events and mortality, but the recent fenofibrate trials do not support this relationship. The increased use of fenofibrate that we observed indicates that the negative clinical outcomes results of these trials have been ignored. Continued caution is warranted in guideline and formulary recommendations for fibrates, particularly fenofibrate, as we await evidence of clinical outcomes benefits.
Questions to Dr. Cohen come from CardioExchange’s Dr. Richard A. Lange and Dr. L. David Hillis.
March 23rd, 2011
New Protocol Identifies Low-Risk Chest-Pain Patients
Larry Husten, PHD
Investigators in the Asia-Pacific region are proposing a “reliable, reproducible, and fast” 2-hour protocol to identify chest-pain patients in the emergency department who have a low short-term risk of having a major adverse cardiac event and who may therefore be suitable for early discharge. The accelerated diagnosis protocol (ADP) consists of the TIMI score, ECG, and a point-of-care biomarker panel of troponin, creatine kinase MB, and myoglobin.
In a paper published online in the Lancet, Martin Than and colleagues report their experience using the new protocol in 3582 consecutive chest-pain patients treated at 14 EDs in the Asian-Pacific region. Of the patients, 9.8% had negative results in all 3 tests and were therefore classified by the ADP as low risk. The rate of major adverse cardiac events was 11.8% in the entire population, compared to 0.9% in the low-risk group determined by the ADP. The investigators calculated that the ADP had a sensitivity of 99.3%, a negative predictive value of 99.1%, and a specificity of 11.0%.
The investigators pointed out that “the near 10% possible reduction in patients needing prolonged assessment in this large patient group could reduce overcrowding in hospitals and emergency departments and provide earlier reassurance and greater convenience for patients.”
In an accompanying comment, Richard Body writes that “ASPECT has successfully established that an accelerated diagnostic protocol incorporating triple-marker testing successfully identifies a group of patients at very low risk of major adverse cardiac events who could reasonably be considered for early discharge. The field must now ask whether the strategy defined is indeed optimal, whether more sensitive and specific assays might improve performance, and whether these promising data will stand up to subsequent analyses of cost-effectiveness and patients’ preference.”
March 22nd, 2011
Good News And Bad News About Physical And Sexual Activity and Cardiac Events
Larry Husten, PHD
The bad news is that physical and sexual activity can trigger acute cardiac events. The good news is that the immediate increase in risk becomes much smaller with more frequent activity, and the long-term overall benefits of activity remain unchallenged. These are the key findings of a meta-analysis by Issa Dahabreh and Jessica Paulus published in JAMA of 14 case-crossover studies.
The authors write that their “results are not incompatible with the well-established beneficial effect of regular physical activity on the risk of acute coronary events: active individuals are overall at a lower risk of such events compared with inactive individuals; however, during the short time period of acute exposure to physical or sexual activity, an individual’s risk of an event is increased compared with unexposed periods of time.”
Their findings, they write, suggest “that physicians counseling patients regarding their exercise habits may need to tailor their advice to the patients’ habitual activity levels: sedentary individuals should be counseled to increase the frequency and intensity of physical activity gradually.”
March 22nd, 2011
Study Explores Lowering the Troponin Diagnostic Threshold
Larry Husten, PHD
Lowering the troponin diagnostic threshold can significantly improve outcomes after MI, claim Scottish investigators in a report published in JAMA. More than 2,000 patients with suspected ACS were studied. Sixty-four percent of patients had troponin concentrations below 0.05 ng/mL, 8% had concentrations from 0.05 to 0.19 ng/mL, and 28% had concentrations 0.20 ng/mL or higher. By lowering the diagnostic threshold from 0.20 ng/mL to 0.05 ng/mL, the risk of death and recurrent MI was reduced from 39% to 21% in the group with troponin concentrations from 0.05 to 0.19 ng/mL during the validation phase of the study.
The authors write that “the appropriateness of continuing to lower the threshold of plasma troponin assay concentration to define increasing numbers of patients with MI may be questioned. This concern relates to the potential to reduce specificity and increase false-positive diagnoses of MI. Our study supports the contention that this is not the case, rather the concern relates to the potential for misclassification of high-risk patients through the use of outdated diagnostic thresholds.”
March 22nd, 2011
AHA Releases New Recommendations for Management of Acute VTE
Larry Husten, PHD
The AHA is offering new guidance for the management of patients with pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension. The scientific statement is published online in Circulation. In addition to advice about anticoagulant therapy, the statement offers extensive recommendations about the appropriate use of fibrinolytic agents, catheter-based and surgical interventions, and IVC filters.
“It is important for doctors to be able to identify the severity of these disorders and to select who might be eligible for more invasive therapies, such as clot-busting drugs, catheter-based treatments or surgery,” said M. Sean McMurtry, co-chair of the writing group, in an AHA press release. “Venous thromboembolism is very common, and frequently a complication of other ailments. While most patients need blood thinners only, patients with more severe forms of venous thromboembolism may benefit from more aggressive treatments.”
March 22nd, 2011
PROTECT Compares Unfractionated Heparin And Dalteparin In Critically Ill Patients
Larry Husten, PHD
ICU patients are at high risk to develop venous thromboembolism. Published in NEJM, PROTECT (the Prophylaxis for Thromboembolism in Critical Care Trial) compared the effects of the low-molecular-weight heparin dalteparin with unfractionated heparin (UFH) in 3746 critically ill patients.
There was no significant difference between the two groups in the primary outcome of the trial. Proximal leg deep-vein thrombosis occurred in 5.1% of dalteparin-treated patients and 5.8% of UFH-treated patients (dalteparin HR 0.92; CI 0.68-1.23, p=0.57). However, an important secondary endpoint, pulmonary embolism, was significantly lower in the dalteparin group than in the UFH group (1.3% versus 2.3%, HR 0.51, CI 0.30-0.88, p=0.01). There were no significant differences between the groups in the incidence of major bleeding or hospital deaths.
The authors discussed possible reasons for the positive finding for dalteparin in reducing pulmonary embolism: “Possible explanations include embolism from other sites (e.g., upper limbs, pelvis, or distal leg, for which we did not screen), an effect of dalteparin on the propensity of leg thrombi to embolize, new-onset thrombus formation in pulmonary arteries during critical illness, and insensitivity or nonspecificity of proximal ultrasonography in asymptomatic patients.”
March 18th, 2011
Dabigatran Dialogue: Two Experts Answer Our Questions and Yours
Samuel Goldhaber, MD and Elaine Marie Hylek, MD, MPH
In a series of blog posts on CardioExchange, Samuel Goldhaber, Director of the Venous Thromboembolism Research Group in the Cardiovascular Division at Brigham and Women’s Hospital, has been guiding us on best practices around dabigatran. Recently, he teamed up with Elaine Hylek, Director of the Thrombosis and Anticoagulation Service at Boston University School of Medicine, for a live interview on the topic. An edited transcript is below, and the podcast is available as well.
Q: Are there patients that you definitely would or would not put on dabigatran?
SG: For patients with new-onset atrial fibrillation and a CHADS2 score ≥2, where anticoagulation is unequivocally recommended, dabigatran is my default choice, barring end-stage renal disease with a creatinine clearance <15. For patients who are already on warfarin and doing fine, I see no reason to rock the boat.
EH: Every patient should be informed about exciting and new advances in the field. That said, this drug does require some changes, compared to what patients are accustomed to with warfarin. For example, dabigatran is a twice-daily drug, it does not require monitoring, and there may need to be some education around fluctuating renal status. Also, the drug loses its potency when it is removed from the original bottle, so patients should not remove the tablets to place into a pill organizer or pill box.
Q: Let’s shift to some cases now. If a 70-year-old woman with hypertension, prior heart failure, and no other major issues is newly diagnosed with chronic atrial fibrillation in your office, how would you counsel her regarding warfarin versus dabigatran?
SG: I would discuss both drugs with her, but I would tell her that dabigatran (150 mg twice daily) is my preferred choice based on a rigorous, pivotal clinical trial (RE-LY). In that study, patients who took dabigatran (150 mg twice daily) had a 30% lower risk for stroke and a 60% lower risk for intracranial bleeding than those who took warfarin. I would emphasize the importance of adherence to dabigatran and note that it should always be taken with food.
EH: I agree with Sam and would also counsel her about the slightly higher risk for GI bleeding with dabigatran versus warfarin.
Q: There’s no clear test of adherence to dabigatran. If a patient reports being on this drug consistently for at least 4 weeks prior to cardioversion, would you consider it safe to cardiovert without transesophageal echocardiogram to rule out intracardiac clot?
SG: Performing a TEE and not detecting an intracardiac thrombus does not give the patient immunity against stroke during the cardioversion procedure and can, in fact, lead to a false sense of security. My preference is always to give the patient anticoagulation for 4 weeks prior to cardioversion rather than do a TEE/cardioversion. I have always told my patients receiving anticoagulation that the risk for stroke during cardioversion is about 1 in 1000. However, a posthoc analysis of the RE-LY trial was just published, showing that, regardless of whether you give dabigatran at 150 mg twice a day or warfarin, the rate of stroke within 30 days after cardioversion is, to me, amazingly high: 3 to 6 events in every 1000 patients cardioverted. Based on that information, I am certainly going to change the conversation I have with my patients about the risks of cardioversion.
EH: The RE-LY trial clearly demonstrated that dabigatran is a potent anticoagulant, but some clinicians may be uncomfortable with the lack of monitoring and thus may be hesitant to trust the drug’s effects. My sense is that if you have put someone on dabigatran for 4 weeks before a cardioversion, then you believe in the medication, you believe in the mechanism and in the coagulation pathway, and you believe in the results of the RE-LY trial. To then subject the patient to a procedure like a TEE is not necessarily sound. If the patient is absolutely certain they have taken the medication, then you have done all you can to prevent stroke in this setting.
Q: How would you recommend managing patients on dabigatran before and after noncardiovascular surgical procedures?
SG: Unless the patient is at very high risk for a stroke or bleeding event, I simply omit the dabigatran dose the afternoon or evening before the procedure and then omit both doses on the day of.
EH: The package insert also provides details about specific procedures for which you would want to hold dabigatran for longer — for example, those that require absolute hemostasis. Obviously, it would behoove the surgeon and proceduralist to consult that resource.
Q: Given the dangers of not being in the therapeutic range because of nonadherence, do you think that more-intensive or more-frequent counseling will be required for patients taking dabigatran, and if so, what sort of initial counseling and frequency of follow-up would you recommend?
EH: Patients who alternate or skip doses of dabigatran won’t have the same buffer as they would on warfarin, because warfarin tends to remain in circulation for upwards of 36 to 40 hours. I would follow patients closely as they transition to dabigatran, especially if they have been on warfarin — at a minimum, I would see them once or twice in the first month and then maybe every 3 months for the next 6 months or so.
SG: We need the same type of collaborative engagement with patients on dabigatran as we have for patients on clopidogrel after coronary artery stent placement. Every clinician taking care of the patient — whether it be a cardiologist, primary care doctor, physician’s assistant, or nurse — needs to reminds him or her to take the dabigatran.
For more of our coverage on dabigatran, check out the Dabigatran Resource Round-Up.
March 18th, 2011
Cardiology Training Around the World — A Survey
John Ryan, MD, Andrew M. Kates, MD and James De Lemos, MD
A few months ago, we started a discussion on the Fellowship Training blog at CardioExchange about the differences in cardiology training around the world. Because the response we received was so enthusiastic, we decided to learn more about how different countries train their cardiologists. We have now created a short survey that we would like our international colleagues to complete. It is completely confidential and should take no more than a few moments to answer. We look forward to sharing the results with you soon!
March 17th, 2011
Meta-Analysis Suggests Worse Outcomes For Rosiglitazone Compared To Pioglitazone
Larry Husten, PHD
There are no long-term trials directly comparing rosiglitazone and pioglitazone. In an article published in BMJ, Yoon Kong Loke and colleagues performed a systematic review and meta-analysis of 16 observational studies with more than 800,000 thiazolidinedione users in an attempt to assess the relative cardiovascular effects of the two drugs.
When compared with pioglitazone, rosiglitazone was associated with
- a significant increase in MI (OR 1.16, CI 1.07-1.24; P<0.001),
- a significant increase in CHF (OR 1.22, CI 1.14-1.31; P<0.001), and
- a significant increase in death (OR 1.14, CI 1.09 to 1.20; P<0.001).
They calculated that for every 100,000 patients who received rosiglitazone rather than pioglitazone there would be 170 excess MIs, 649 excess cases of HF, and 431 excess deaths.
In an accompanying editorial, Victor Montori expresses concern over the continuing availability of rosiglitazone in the U.S., and writes that “research should be undertaken to understand what occurs when drugs are left on the market with strong warnings.” He also expresses concern that “regulators and prescribers do not seem to have learnt from the rosiglitazone saga,” noting that new diabetes drugs have been approved and rapidly adopted by prescribers in recent years.
Montori concludes:
“The rosiglitazone story says much about how healthcare has become less about promoting patients’ interests, alleviating illness, promoting function and independence, and curing disease, and much more about promoting other interests, including those of the drug industry. Has the corruption of healthcare advanced so far that it is unreasonable, even naive, to expect responsible drug companies, enlightened regulators, and thoughtful prescribers?”
March 17th, 2011
Small Study May Help Revive Hope for Stem Cell Therapy
Larry Husten, PHD
Stem cell therapy may help reverse long-term damage after MI, according to a small, preliminary study by a group led by Joshua Hare published in Circulation: Research. Eight patients with LV dysfunction after MI received injections of autologous bone marrow progenitor cells in the LV scar and surrounding area. At one year, as assessed by cardiac MRI, there was a significant decrease in end-diastolic volume (EDV), a trend towards decreased end-systolic volume (ESV), a significant reduction in infarct size, and improved regional function in the treated infarct zone.
Previous clinical studies found little effect on ejection fraction (EF). But the paper’s authors write that “a strong parallel decrease in both EDV and ESV” that they observed in their subjects means that “EF may not be a good outcome measure for studies of cell therapy for remodeled ventricles.”
The authors write that their study suggests that “human autologous bone marrow progenitor cells increase regional contractility of injected myocardial scar tissue within 3 months of treatment, and these functional changes are associated with later reverse remodeling.” They note that placebo-controlled trials with more patients are now underway.
“This therapy improved even old cardiac injuries,” said Hare, in an AHA press release. “Some of the patients had damage to their hearts from heart attacks as long as 11 years before treatment.”
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