March 22nd, 2013
Macrolide Antibiotic Linked to Increased CV Risk in Patients with Lung Conditions
Nicholas Downing, MD
Use of the macrolide clarithromycin in patients admitted with exacerbations of chronic obstructive pulmonary disease or community-acquired pneumonia is associated with increased risk for cardiovascular events, a BMJ study finds.
Researchers examined outcomes among nearly 3000 patients admitted to U.K. hospitals with either condition. During 1 year of follow-up, there were roughly 450 new admissions for a CV event.
After multivariable adjustment, patients who had received at least one dose of clarithromycin during their initial hospitalization were over 50% more likely to be admitted for a CV event during follow-up than those who didn’t receive a macrolide. In addition, among COPD patients, clarithromycin use was associated with increased risk for CV mortality at 1 year.
The researchers say their study is the first to show that clarithromycin use among such patients might be associated with an increased CV risk that persists well after treatment has stopped. Several potential mechanisms for this effect are proposed in the paper.
March 21st, 2013
FDA Panel Gives Tepid Endorsement to Abbott’s MitraClip
Larry Husten, PHD
The FDA’s Circulatory System Devices advisory panel gave a tepid endorsement to Abbott Laboratories’ MitraClip device on Wednesday. The panel met to evaluate use of the novel device in patients with significant symptomatic mitral regurgitation (MR) who have been determined by a cardiac surgeon to be too high risk for open mitral valve surgery and in whom existing comorbidities would not preclude the expected benefit from correcting the MR.
At the end of the day, after a long and torturous discussion, the panel voted 5-3 in favor of the device, saying that the benefits outweighed the risks. The panel agreed unanimously that the device was safe (8-0), but by a narrow margin said there was not a “reasonable assurance” that it was effective (5-4). The panel struggled over how to use the available data to identify patient groups that could benefit from the device.
In the end, many panel members appeared to be persuaded by the pleas of surgeons and patients asking for another option in the most difficult cases. Earlier in the week the FDA reviewers had recommended against approving the device.
“This was a unique panel with two schools of thought emerging, ” said John Carroll on Cardiosource. “On one hand, there was much discussion surrounding the importance of clinical judgment, access to new treatments for inoperable patients, and potential acceptability of solid and consistent observational data with imperfect comparators. On the other, there was concern regarding the lack of strong, well-executed randomized trial data of the target patient population. The patient testimonials were compelling and in line with the data showing enhanced quality of life. ”
Additional Reading:
- The Everest II Trial
- What Is Best for My Patient? (NEJM editorial)
- Abbott press release
March 21st, 2013
DIGging In: Three Reasons Why the Recent Digoxin Study Is Not Relevant to Readmission
Harlan M. Krumholz, MD, SM
Ali Ahmed of the University of Alabama presented an analysis of the DIG trial at the ACC (and simultaneously published in the American Journal of Medicine). In short, the researchers randomized some 3400 outpatients aged 65 years or older with chronic heart failure to receive digoxin or placebo. The primary outcome of all-cause hosptialization within 30 days occurred in 5.4% (92/1693) of digoxin-treated patients and 8.1% (139/1712) of placebo-recipients. The trial is being promoted as new information to decrease readmissions. Ahmed is quoted in MedPage Today as saying “If these findings can be replicated in contemporary older heart failure patients discharged from hospital after acute decompensation, digoxin may provide an inexpensive tool to reduce 30-day all-cause hospital readmission.”
Here are 3 reasons why this study is not relevant to efforts to reduce readmission.
- The study is not about readmissions. The DIG trial enrolled ambulatory patients and the study reports 30-day hospitalization rates. The relevance of hospitalization rates of ambulatory patients enrolled in a clinical trial to readmission rates is not known. Patients who are recently hospitalized have a dramatically elevated risk for a wide range of clinical outcomes. The admission rates of patients enrolled in a clinical trial are much lower and are not affected by a recent hospitalization.
- The research is dated. The DIG trial was conducted decades ago and practice has evolved considerably since then. The relevance of hospitalization rates for patients at that time for readmission rates now is not clear.
- The evidence is weak. The study is a post-hoc, retrospective analysis of a trial that reported lower admission rates, which was a secondary outcome. Moreover, the overall trial was negative for its primary endpoint – and a later analysis that our group conducted revealed that women experienced a higher mortality rate on digoxin – and that the therapeutic window for digoxin was quite narrow.
It would be wonderful if an inexpensive medication could dramatically reduce readmission risk for patients with heart failure. As far as I can see, however, this study has no relevance to that issue. Doctors should not start prescribing digoxin as a result of headlines reporting that this study supports that strategy.
March 20th, 2013
Controversial PFO Closure Trials Published in NEJM
Larry Husten, PHD
Two controversial trials testing PFO closure in patients with cryptogenic stroke, first presented last fall at the TCT meeting, have now been published in the New England Journal of Medicine. Both trials missed their primary endpoints but contained suggestions of possible benefit. The results appear unlikely to resolve the ongoing controversy over the value, or lack of value, of this procedure; but, as an accompanying editorial states, both advocates and critics of PFO closure will find source material for their arguments in these papers.
The PC Trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism) randomized 414 patients with PFO who had had an ischemic stroke, a TIA, or a peripheral thromboembolic event to either medical therapy or PFO closure with the Amplatzer PFO Occluder.
After 4.1 years of follow-up in the closure group and 4.0 years in the medical-therapy group, there were no significant differences in the primary endpoint (the composite of death, nonfatal stroke, TIA, or peripheral embolism) or the individual components of the endpoint:
- Primary endpoint: 3.4% in the closure group versus 5.2% in the medical-therapy group (HR 0.63, CI 0.24 – 1.62, p=0.34)
- Nonfatal stroke: 0.5% versus 2.4% (HR 0.20, CI 0.02 – 1.72, p=0.14)
- TIA: 2.5% versus 3.3% (HR 0.71, CI 0.23 – 2.24, p=0.56)
The RESPECT trial similarly randomized 980 patients to medical therapy or PFO closure. More patients in the medical-therapy group dropped out during the course of the trial. There was no significant difference in the main, intention-to-treat analysis, which was performed after 25 primary endpoint events occurred (a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization), but prespecified per-protocol and as-treated analyses turned up significant benefits for PFO closure:
- Primary endpoint (intention-to-treat): 9 events in the closure group versus 16 in the medical-therapy group (HR 0.49, CI 0.22 – 1.11, p=0.08).
- Recurrent stroke (per-protocol): 6 versus 14 events (HR 0.37, CI 0.14 to 0.96, p=0.03)
- Recurrent stroke (as-treated): 5 versus 16 events (HR 0.27, CI 0.10 – 0.75, p=0.007)
In the accompanying editorial, Steven Messé and David Kent write that both trials suffered from slow enrollment, “which was probably due to widespread off-label use of atrial septal closure devices.” They note that RESPECT and PC, like the only other randomized trial in the field, CLOSURE 1, did not show significant benefits in the main intention-to-treat analysis, but did present some evidence of possible benefit.
They conclude:
…we are left for the moment to make decisions under conditions of uncertainty. In such circumstances, evidentiary standards vary among decision makers — patients, clinicians, authors of practice guidelines, and regulatory authorities — depending not only on the interpretation of the results, but also on the potential consequences of their decisions. Some of them may interpret the data as supporting closure of a patent foramen ovale as a viable therapeutic option, even while conceding the failure of trials to show the superiority of closure over medical therapy. Yet given the prevalence of patent foramen ovale in the general population, the enormous potential for overuse of percutaneous closure of a patent foramen ovale, and the relatively low risk of stroke in patients who are treated medically, the routine use of this therapy seems unwise without a clearer view of who, if anyone, is likely to benefit…. Randomized studies of closure may come to an end, however, if the Amplatzer device is approved. Thus, all eyes will be on the regulatory agencies to see how they will interpret these results in light of their own evidentiary standards.
March 20th, 2013
Chlorthalidone Associated with More Electrolyte Problems Than Hydrochlorothiazide
The diuretics chlorthalidone and hydrochlorothiazide are similarly effective at preventing cardiovascular events among older adults with hypertension, but electrolyte abnormalities are more common with chlorthalidone, according to a study in the Annals of Internal Medicine.
Canadian researchers used healthcare databases to identify nearly 30,000 adults over age 65 recently prescribed varying doses of chlorthalidone or hydrochlorothiazide. During follow-up, the rate of the primary outcome — a composite of death or hospitalization for MI, stroke, or heart failure — did not differ significantly between the chlorthalidone and hydrochlorothiazide groups (3.2 and 3.4 events per 100 person-years).
Hospitalization for hypokalemia was more likely among chlorthalidone recipients (0.69 vs. 0.27 events per 100 person-years), as was hospitalization for hyponatremia.
The authors conclude that in the absence of a large, randomized trial comparing the two treatments, “it may be reasonable to conclude that hydrochlorothiazide is safer than chlorthalidone in elderly patients at typically prescribed doses.”
Reprinted with permission from Physician’s First Watch
March 20th, 2013
High Potency Statins Linked to Increased Risk for Acute Kidney Injury
Larry Husten, PHD
Although the beneficial effects of high-potency statins have been well-characterized in clinical trials, these same trials have lacked the power to illuminate rare but potentially important adverse events. A suggestion of one such area of concern, acute kidney injury, was first raised in the SATURN trial. Now, a new study published in BMJ provides further information about this area.
Researchers in the Canadian Network for Observational Drug Effect Studies (CNODES) performed a retrospective observational analysis of administrative databases in Canada, the U.K., and the U.S. containing more than 2 million patients newly treated with statins. Of these, 59,636 of the subjects already had chronic kidney disease. One-third of the subjects received high potency statins, defined as ≥10 mg rosuvastatin, ≥20 mg atorvastatin, and ≥40 mg simvastatin.
Within 120 days of starting treatment there were 4691 hospitalizations for acute kidney injury in patients without pre-existing kidney disease and 1896 hospitalizations in patients with pre-existing disease. Patients without pre-existing disease on high potency statins were 34% more likely to be hospitalized with acute kidney injury than patients on other statin regimens. Patients with pre-existing disease did not have a significant increase in risk if they were taking high potency statins.
The authors estimated that 1,700 patients without pre-existing kidney disease would need to be treated with a high potency statin instead of a low potency statin to cause one additional acute kidney injury requiring hospitalization. The findings, according to the authors, are broadly consistent with the JUPITER trial. They write:
Given what is likely to be a small magnitude of incremental cardiovascular benefit of high potency statins over low potency statins in reality, a pressing question is how to identify patients for whom the risk-benefit balance for high potency statin treatment is unfavourable.
In an accompanying editorial, Robert Fassett and Jeff Coombes write that “clinicians should use low potency statins whenever possible to provide cardiovascular benefits without the increased risk of acute kidney injury.” Further, they note, “despite extensive experience with the use of statins over many years, optimization of doses to derive benefit but minimize risk is still evolving.”
March 18th, 2013
Vena Cava Filters: Little Evidence and Wide Variation in Use
Larry Husten, PHD
- Despite the absence of any evidence demonstrating benefit or showing how best to use them, vena cava filters (VCF) are used in most hospitals. Now a new study published in JAMA Internal Medicine suggests that this same lack of evidence results in an extremely broad rate of use in different hospitals. An accompanying viewpoint raises the question: “How could a medical device be so well accepted without any evidence of efficacy?”
Researchers conducted a retrospective observational study that compared the frequency of VCF use in 236 California hospitals by analyzing data from 130,643 acute VTE hospitalizations over four years. Overall, the rate of VCF placement was 14.95%, but there was a very broad variation in the percentage of acute VTE cases in which a VCF was placed, from 0% to 38.96%. The authors said that this finding places VCF “among surgical procedures with the greatest variation in geographic studies in the United States.” Even after adjusting for differences in patient populations between hospitals, the variation between hospitals remained significant.
Overall, VCF was more likely to be used in people who had acute bleeding at admission, who required a major operation after admission for VTE, who had metastatic cancer, and who had extreme severity of illness. Smaller hospitals, rural hospitals, and private hospitals not in the Kaiser system were more likely to use VCFs.
There was no significant difference in VCF use between for-profit and not-for-profit hospitals, “suggesting that the wide variation in VCF use is not likely explained by exploitation of the fiscal benefits of VCF placement by for-profit private hospitals.” Further, both socioeconomic factors and geographic location did not appear to influence the likelihood that a hospital would use VCFs. The authors wrote that “these findings suggest that an important factor affecting the use of VCFs is the local culture and practice pattern within each hospital. Although we could not gather reliable data regarding the number of interventional radiologists or vascular surgeons who work at each hospital, one possible explanation for the higher frequency of VCF use in larger private hospitals is the availability of specialists who are skilled in inserting these devices.”
In a second study, Shayna Sarosiek and colleagues performed a retrospective review of 952 patients who received a retrievable VCF at Boston Medical Center. Despite VCF placement, 7.8% of the patients had a venous thrombotic event. Although many of the devices were placed “because of a perceived contraindication to anticoagulants,” fully a quarter of the patients were receiving anticoagulant therapy at the time of discharge. Only a small percentage (8.5%) with retrievable VCFs had their filter removed successfully.
In their editorial, Vinay Prasad, Jason Rho, and Adam Cifu observe that despite their “poor evidence base” VCF filters have never been rigorously reviewed by the FDA, because the first devices were developed prior to the premarket approval process and all subsequent devices have gained approval based on the far less burdensome 510(k) process. Despite the need for randomized controlled trials of VCFs, “there is little incentive for manufacturers of filters to embark on trials that can only eliminate their products’ market share. Therefore, we need either the FDA to require current filter manufacturers to perform efficacy studies of their devices as a condition for remaining on the market or a large federally funded study to determine if this expensive device leads to greater benefit than harm. Until then, clinicians and patients face difficult choices. Follow current standard of care and place filters where guidelines advise, or do not place filters, after informed consent informs patients that there is evidence of harm without evidence of benefit.”
March 18th, 2013
Selections from Richard Lehman’s Literature Review: March 18th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections 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.
JAMA 13 Mar 2013 Vol 309
Association of Smoking Cessation and Weight Change With CV Disease Among Adults With and Without Diabetes (pg. 1014): It’s a troublesome fact that most people who give up smoking (and come off nicotine replacement) gain weight. Together with the desperately addictive qualities of nicotine, this is a major cause for people to continue smoking. I am sure that you already tell them that the health benefits of giving up far outweigh the health hazards of a few extra pounds in weight; and the Framingham Offspring Study proves you right, with 6 years of follow-up showing a halving of cardiovascular events in the quitters, irrespective of weight gain.
NEJM 14 Mar 2013 Vol 368
Risk of Ischemic Heart Disease in Women after Radiotherapy for Breast Cancer (pg. 987): Last week, I lambasted the NEJM for publishing a truly terrible pharma-funded trial, but this week there are none of these, presumably because the feeding needs of the publishers have been satisfied for the time being. I await next week’s issue with interest. Meanwhile, enjoy this excellent study based on long-term data from all women in Stockholm and Denmark who underwent radiotherapy for breast cancer under the age of 70 between 1958 and 2001 in the case of the Swedes, and under the age of 75 between 1977 and 2000 in the case of the Danes. Their radiation doses were calculated using original records where possible, and they were compared with carefully matched controls for the occurrence of cardiac events. These themselves were carefully validated from hospital records and autopsies. “Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women.” Observational science at its best.
Long-Term Outcomes in Elderly Survivors of In-Hospital Cardiac Arrest (pg. 1019): If you’re looking for great outcomes research in cardiology, you could find most of it by going to PubMed and searching under the names of Harlan Krumholz, John Spertus, and increasingly Brahmajee Nallamothu. Not too surprising, then, that all three of these names appear on this paper about long-term outcomes in elderly survivors of in-hospital cardiac arrest. The figures are much better than you might surmise: “Among elderly survivors of in-hospital cardiac arrest, nearly 60% were alive at 1 year, and the rate of 3-year survival was similar to that among patients with heart failure. Survival and readmission rates differed according to the demographic characteristics of the patients and neurologic status at discharge.”
March 15th, 2013
Azithro a No Go?
Richard Joseph Kovacs, MD
Earlier this week, the FDA issued a warning regarding the risk of QT interval prolongation and torsades de pointes associated with the use of the antibiotic azithromycin. Last year, in response to reports about these problems published in the New England Journal of Medicine, we invited a panel to weigh in on the use of this drug. To put the latest warning into perspective, we invited drug safety expert Richard Joseph Kovacs, MD, to offer his analysis.
First, some context:
1. The new FDA warning on azithromycin is a reaction to data accumulated over several years. Practicing doctors should be aware that many non-cardiac drugs have significant risks of cardiac toxicities. Azithromycin is just one of many noncardiac drugs with QT risk – the best source of up-to-date information is
2. There are common factors that increase the cardiac risk of these drugs that practitioners should be aware of: female sex, heart failure, and electrolyte abnormalities – especially low magnesium or low potassium.
3. The QT change produced by these drugs is quite small in any individual. The drug /disease interactions are too complex for a practitioner to be able to accurately predict an untoward event in an individual. We should develop smart tools that can integrate patient characteristics, lab and EKG data, and drug information into a risk profile available to the prescriber at the point of care – to identify patients at high risk and suggest alternative drugs before the prescription is written.
4. Practitioners may not be aware, but for the past decade, every new drug presented to the FDA (as well as other drug regulatory agencies around the world) is thoroughly evaluated for the risk of QT prolongation in humans according to a harmonized process – to read more go to http://www.ich.org/ and look up the document E14.
Now for my clinical bottom line: When I am faced with a patient who needs an antibiotic, and there is an alternative antibiotic with similar efficacy and lower QT risk, I will choose the antibiotic with lower QT risk. I will be even more cautious if the patient is on a QT prolonging drug (such as an anti-arrhythmia drug), has heart failure, is a woman, or has the potential for electrolyte abnormalities (chronic diuretic use) – those patients have higher risk for drug-induced torsade de pointes. Of course, it’s worth noting that I don’t prescribe a lot of antibiotics in a consultative cardiology practice, but when I do prescribe them I tend to avoid azithromycin and I’m much more likely to use amoxicillin in my patients.
March 15th, 2013
FDA Studying Whether Certain Diabetes Drugs Pose Pre-Cancer Risk
The FDA is investigating whether diabetes drugs in the class known as incretin mimetics pose an increased risk for pancreatic duct metaplasia.
The agency is looking at unpublished data on pancreatic toxicity in a small number of tissue samples taken from patients with diabetes who died. It will examine the researchers’ methodology and the samples firsthand before concluding whether there is a risk to patients.
Incretin mimetics include exenatide (Byetta, Bydureon), liraglutide (Victoza), sitagliptin (Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (Onglyza, Kombiglyze XR), alogliptin (Nesina, Kazano, Oseni), and linagliptin (Tradjenta, Jentadueto). The drugs’ labels already carry warnings about the risk for pancreatitis.
Healthcare providers may continue prescribing the drugs according to the labels and should report adverse events to the FDA.
NEJM Journal Watch — Recent Cardiology Articles- Diagnosing and Managing Kawasaki Disease
- Does TAVR Benefit Patients with Moderate Aortic Stenosis and Systolic Heart Failure?
- Reevaluating Genetic Associations in Hypertrophic Cardiomyopathy
- Does Use of Drug-Coated Devices Improve Outcomes in Chronic Limb-Threatening Ischemia?
- New Recommendations for Lipid Management in Patients with Acute Coronary Syndromes