June 18th, 2012
Selections from Richard Lehman’s Literature Review: June 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 June 2012 Vol 307
Imaging Risks (pg. 2400): We know surprisingly little about the long-term effects of low-dose ionizing radiation. This became a matter of intense debate during and after the era of above-ground nuclear weapons testing, and much of what we know about the subject is based on extrapolation from the effects of the weapons detonated over Hiroshima and Nagasaki. It is very hard to quantify the cumulative effects of exposure to diagnostic X-rays and to work out the benefit/harm ratio from this exposure: all that this study and others can tell us is that such exposure in advanced health systems is steadily increasing, mainly due to the use of CT scanning. In large integrated health systems in the USA, use of this modality more than doubled between 1996 and 2010.
NEJM 14 June 2012 Vol 366
Oral Contraception, MI, and Stroke (pg. 2257): Oral contraception began as a massive natural experiment in the 1960s, and it is one we are still learning from. Where better to go than Denmark, which has a superb National Registry of Patients and Register of Medicinal Products Statistics: combine the two and you can get data relating to 1,626,158 women, with 14,251,063 person-years of observation. Øjvind Lidegaard and a team of four crunched the numbers to give us the most detailed picture yet of the risk of myocardial infarction and thrombotic stroke attributable to each type of oral contraception. The type of progestin seems to make little difference, but the dose of oestrogen probably does. Pills with the standard dose of 30 mcg of ethinyl oestradiol may roughly double the risk of MI and thrombotic stroke in this population. This equates to about 1-2 extra events per 10,000 women annually. The title of the editorial sums it up: Hormonal Contraceptives and Arterial Thrombosis — Not Risk-free but Safe Enough.
Arch Intern Med 11 June 2012 Vol 172
Never Too Old to Quit (pg. 837): Richard Doll famously said that death in old age is inevitable, but death before old age is not inevitable. Amongst the avoidable factors he was referring to, smoking remains the most obvious, and after sixty years of preaching on the subject, he must be sighing in his grave to read yet another study proving that this is still so, regardless of where you set the threshold for “old age”. This systematic review shows that the mortality benefit of giving up can be seen even beyond the age of 80.
Wasteful Cardiovascular Tests (pg. 854): Less is More is the most essential series in any journal: not perhaps for its originality, not for its academic content, but simply because it carries the most important messages for all developed health systems. The drive to do useless things is nowhere near as strong in the NHS as in the pay-by-item American systems, but it happens all the time for all that. Exercise echocardiography in asymptomatic patients following coronary revascularization at any time following the procedure makes no difference to outcomes. It is a waste of resources and should not be done.
(pg. 837): The same can be said for a lot of stress testing following admission for chest pain in US hospitals. In one tertiary hospital, the authors found that “most patients who are admitted with low-risk chest pain undergo stress testing, regardless of pretest probability, but abnormal test results are uncommon and rarely acted on.” The need to factor in pre-test probability is a lesson that never seems to get learnt sufficiently.
June 14th, 2012
FDA Advisory Panel Recommends Expanded Indication for Sapien Transcatheter Heart Valve
Larry Husten, PHD
The FDA’s Circulatory System Devices Panel voted overwhelmingly on Wednesday to recommend an expanded indication for the Edwards Sapien Transcatheter Heart Valve in patients with symptomatic severe aortic stenosis who have high operative risk. The device is currently approved for use only in patients who are not surgical candidates.
The committee voted 10-2 that the Sapien device was safe, 12-0 that it was effective, and 11-0, with 1 abstention, that the benefits of the device outweighed the risks. Much of the day was spent by committee members wrestling with a number of difficult questions raised by FDA reviewers prior to the meeting, including the possible introduction of bias in the pivotal PARTNER A trial because some patients randomized to surgery did not undergo surgery, the difficulty of evaluating the transapical approach due to the small number of patients randomized in that stratum of PARTNER, and the higher incidence of stroke and aortic regurgitation in the Sapien group.
Ultimately, however, the committee was persuaded by the totality of the data from PARTNER and additional nonrandomized data from patients who received the device under a continued access protocol. An additional strong source of reassurance for the panel was the safeguard provided by the TVT registry, a joint initiative from the Society of Thoracic Surgeons and the American College of Cardiology that will closely monitor the use of TVR in clinical practice.
In sharp contrast to many recent advisory committee meetings, this panel was marked by the absence of drama and tension. A high point of the meeting for many observers was the public comment session. One speaker was a 92-year-old Sapien recipient who was a World War II veteran and prisoner of war who had survived the Bataan Death March. Another patient who spoke in favor of Sapien was the father of well-known Columbia University interventional cardiologist Jeffrey Moses, who helped develop the device. Moses said that he “wisely” chose to stay out of the case, though initially he did help persuade his father to accept the device after he refused to undergo surgery.
June 12th, 2012
ACC Releases Appropriate Use Criteria for Noninvasive Peripheral Vascular Tests
Larry Husten, PHD
The American College of Cardiology (ACC) has published appropriate use criteria (AUC) for peripheral vascular ultrasound and physiological testing. The criteria were developed in coordination with 10 other medical societies.
“This is the first systematic and comprehensive evaluation looking at appropriate indications for vascular testing, such as ultrasound or functional testing,” said Emile Mohler III, the chair of the writing committee, in an ACC press release. “We hope this document will help clinicians determine whether or not and when to refer individual patients for testing.”
The 19 members of the panel identified common clinical situations in which noninvasive vascular testing is often considered and then assessed the appropriateness of each indication. In half of the scenarios, testing was deemed to be appropriate. In general, tests were considered appropriate when they were prompted by clinical signs and symptoms.
About 20% of scenarios were judged inappropriate. Here are examples cited by the ACC in the press release:
- Ordering an ultrasound of the carotids or neck arteries in someone at low risk for heart attack or stroke.
- Screening for kidney artery disease in someone with peripheral artery disease with well-controlled high blood pressure (hypertension) on one medication
- Choosing to perform an abdominal ultrasound in a patient with nonspecific lower-extremity discomfort
- Ordering a mesenteric artery ultrasound as an initial test to evaluate the patient with chronic constipation or diarrhea
- Performing a follow-up study for a patient with a normal baseline study who has no new symptoms
June 11th, 2012
FDA Reviewers Raise Questions About Sapien Heart Valve System
Larry Husten, PHD
FDA reviewers have raised a number of questions about the safety and efficacy of the Sapien heart valve system. The review was published online ahead of Wednesday’s meeting of the Circulatory System Devices Panel meeting to evaluate the Sapien system for use in patients eligible but at high risk for aortic valve surgery. The Sapien system was previously approved (in November 2011) for patients not considered surgical candidates for aortic valve replacement.
The FDA briefing document cites numerous examples of possible bias in the pivotal PARTNER A trial. The most serious problem appears to be caused by the high number of patients randomized to surgery who did not undergo surgery, including 7.9% who refused treatment or withdrew from the study. By contrast, only 0.3% of transcatheter aortic valve replacement (TAVR) patients refused treatment or withdrew from the study. Surgical patients were also more likely to receive concomitant operations, another possible source of bias.
Another important topic of discussion will undoubtedly be the differences in outcome between patients receiving the transapical (TA) and transfemoral (TF) approaches. Unlike the TF stratum, where mortality was lower in the Sapien group, in the TA stratum mortality was higher in the Sapien group. Because there were only a relatively small number of patients in the TA group in the PARTNER trial, the panel will also consider TA patients treated outside the context of randomized trials.
The FDA reviewers were also concerned about stroke and aortic regurgitation. In the first 30 days, the stroke rate was doubled in the Sapien group, and there were more strokes overall in the Sapien group in the TA stratum. Concern was also raised about the 53% of Sapien-treated patients who had mild or greater aortic insufficiency.
One interesting point raised by the FDA is that TAVR is not nearly as noninvasive as many have been led to believe:
The results of this study show that the comparison was not between “open” AVR and percutaneous AVR. For patients having open AVR who had not had a previous operation, about one half of the patients had a minimally invasive approach. For TAVR patients, about three quarters required either an open surgical procedure for direct arterial access, or an open surgical procedure for vascular repair after a percutaneous approach. Therefore, this trial compared open AVR with transcatheter AVR that frequently required surgery for vascular access or repair.
The outcomes of FDA panels are notoriously difficult to predict. Wells Fargo analyst Larry Biegelsen wrote that he continued “to anticipate a challenging panel on Wednesday” but that ultimately he expected a positive vote, leading to FDA approval later this year.
June 11th, 2012
Basal Insulin and Omega-3 Fatty Acids Fail to Improve Outcomes in Diabetics and Prediabetics
Larry Husten, PHD
A large new study has found no evidence of cardiovascular (CV) benefits for either basal insulin or omega-3 fatty acids in a population of people with diabetes or at risk for diabetes. Results of the ORIGIN (Outcome Reduction with Initial Glargine Intervention) study were presented today at the annual meeting of the American Diabetes Association and published simultaneously in the New England Journal of Medicine.
In a 2 x 2 factorial design, more than 12,500 patients with impaired fasting glucose, impaired glucose tolerance, or diabetes were randomized to either insulin glargine or standard care and to either omega-3 fatty acids or placebo. After a median followup of 6.2 years, there were no significant differences in outcomes in either of the randomizations.
Insulin glargine versus standard care:
- Nonfatal MI, nonfatal stroke, or CV death: 16.6% versus 16.1% (hazard ratio, 1.02, CI 0.94 – 1.11, p = 0.63)
- Nonfatal MI, nonfatal stroke, CV death, revascularization or HF hospitalization: 28.6% versus 27.5%, HR 1.04, CI 0.97 – 1.11, p = 0.27)
People taking insulin glargine were more likely to gain weight and develop hypoglycemia, but had better glucose control than people receiving standard care. Patients without diabetes at baseline receiving insulin were less likely to progress to diabetes. There was no difference in cancer between the two groups.
The ORIGIN investigators noted that the glycemic benefit of insulin glargine might have an impact on microvascular or other outcomes but concluded that the trial does “not support changing standard therapies for early dysglycemia.”
Omega-3 fatty acids versus placebo:
- CV death (primary endpoint): 9.1% versus 9.3% (HR 0.98, CI 0.87 – 1.10, p = 0.72)
- Major vascular events: 16.5% versus 16.3% (HR 1.01,CI 0.93 – 1.10, p = 0.81)
- Death from any cause: 15.1% versus 15.4% (HR 0.98, CI 0.89 – 1.07, p = 0.63)
- Death from arrhythmia: 4.6% versus 4.1% (HR 1.10, CI 0.93 – 1.30, p = 0.26)
The authors cautioned that their results “may not be relevant to dietary recommendations to consume more fish, because dietary change not only increases the intake of foods containing n–3 fatty acids but is also associated with a reduction in the consumption of foods such as red meats, which may be harmful.”
June 11th, 2012
Selections from Richard Lehman’s Literature Review: June 11th
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 6 June 2012 Vol 307
Troponin and Mortality in Non-Cardiac Surgery (pg. 2295): If you want to get a paper in a major journal, go for something about prognosis. It couldn’t be easier. Take some bloods – or better still, use some that have already been taken and stored – and measure something that is bound to be associated with overall mortality: B-type natriuretic peptide, rise in creatinine, cystatin C, copeptin, or, as in this case, troponin T (TnT). Pick a clinical scenario: in this case non-cardiac surgery. Then shock horror: overall predictor of mortality predicts mortality in this population! A million people die every year within 30 days of surgery: measuring the peak fourth-generation troponin T (TnT) measurement in the first 3 days after noncardiac surgery will allow you to identify some of those at highest risk. Compared with what other clinical characteristics or biochemical markers? And what are you going to do with this information?
Ann Intern Med 5 June 2012 Vol 156
Predictors of HF Mortality (pg. 767): If in the year 2012 you sent a leading medical journal a case series describing the results of treatment for pneumonia using sulfanilamide, you might expect rejection – followed by an immediate visit from a disciplinary officer, perhaps accompanied by a psychiatrist. For therapy, we require that the most effective modern treatment be used, and that any new treatment should have a good chance of being shown to be more effective in a blinded randomized controlled trial. And taken alone, observational data are seldom enough. But as I’ve already hinted, it is so very different when the study is about prognosis. Here, it seems, the best is never the gold standard: any available combination of data will do. This Canadian study of mortality following acute heart failure crunches data relating to various emergency room measurements such as heart rate, creatinine, BP, oxygen saturation and troponin, and finds that you can derive a multivariate index which is somewhat predictive for mortality. Of course you can: but why ignore the best marker for mortality in heart failure, which is B-type natriuretic peptide? There are few clinical uses for BNP in real life, but the one that has been firmly established for 15 years is predicting death.
June 11th, 2012
The Changing Face of Mitral Valve Surgery
John A. Dodson, MD
It’s not easy to decide whether to refer an elderly patient with severe, symptomatic mitral regurgitation (MR) for surgery. Mitral valve repair and replacement remain the definitive treatments for symptomatic MR, but they come with particularly high risks in the elderly.
Given the lack of U.S. national surveillance data on this topic, my colleagues and I decided to study trends in the performance of mitral valve surgery, as well as postsurgery hospital readmission (30 days) and mortality (30 days and 1 year), for all Medicare fee-for-service beneficiaries from 1999 through 2008. Our results, published in May, included several key findings:
1. Mitral valve surgery patients are getting older: The overall rate of surgery remained relatively constant from 1999 through 2008, but the percentage of surgery patients who were age 85 or older increased from 8.8% to 12.7%.
2. Risk-adjusted mortality declined dramatically, both at 30 days (from 8.1% to 4.2%) and at 1 year (from 15.3% to 9.2%).
3. Risk-adjusted hospital readmission declined modestly (from 23.0% to 21.0%).
4. Improvements were generally seen across age, sex, and race subgroups, but mortality rates remained higher for women than for men − and for nonwhites than for whites − throughout the 10-year period.
Our study was not designed to explore the reasons for improvement. Possible contributors are the increasing rates of mitral valve repair, lower postoperative complications, and changes in referral patterns (e.g., being referred for surgery earlier).
Will these findings change your practice? What are your considerations as you decide whether to refer elderly patients for mitral valve surgery?
June 9th, 2012
Transient Glucose Regulation Helps Prevent Progression to Diabetes in Prediabetics
Larry Husten, PHD
Prediabetics — people with impaired fasting glucose or impaired glucose tolerance — can reduce their high risk for progressing to diabetes if they achieve even a transient return to normal glucose regulation, according to results of the Diabetes Prevention Program Outcomes Study (DPPOS), presented at the American Diabetes Association meeting and published simultaneously online in the Lancet.
Leigh Perreault and colleagues in the Diabetes Prevention Program Research Group analyzed data from 1,990 participants who had been randomized in the original DPP study to intensive lifestyle intervention, metformin, or placebo. The risk for developing diabetes was 56% lower in the participants who at some point during the DPP study had normal glucose regulation than in the participants who continued to have prediabetes (hazard ratio, 0.44; 95% CI, 0.37–0.55; P<0.0001). Diabetes prevention strongly correlated with the number of times that participants were found to have normal glucose regulation.
Attaining normal glucose regulation at any point during the study was the essential protective variable in preventing diabetes, regardless of the participants’ assigned treatment group. Among participants who remained consistently prediabetic, the risk for developing diabetes was significantly higher in the intensive lifestyle intervention group than in the placebo group.
The investigators wrote that the results of their study suggest “that the strategy is unimportant as long as the intervention is early (when someone has prediabetes) and can restore normal glucose regulation, even if transiently. Further, maintenance of prediabetes despite the potent glucose-lowering effects of intensive lifestyle modification represents a high-risk state and might warrant additional preventive strategies.”
In an accompanying comment, Natalia Yakubovich and Hertzel Gerstein write that “identification of regression to normoglycemia could be an important way to stratify people into those at higher and lower risk of progression to diabetes. Such stratification could therefore identify individuals for whom additional treatment might be needed to prevent diabetes or to slow down disease progression.”
June 7th, 2012
Growing Popularity of Dabigatran Leads to Increased Complications
Larry Husten, PHD
Since its approval in the United States in October 2010, dabigatran (Pradaxa) has been prescribed 3.2 million times to more than 600,000 patients with nonvalvular atrial fibrillation (AF), according to its manufacturer, Boehringer Ingelheim. The company also announced that, based on the pivotal RE-LY trial, the “Clinical Studies” section of the drug’s prescribing information now includes the statement that 150 mg twice daily of dabigatran “was superior in reducing ischemic and hemorrhagic strokes relative to warfarin.”
But the news about dabigatran is not entirely upbeat. According to new data compiled by QuarterWatch (PDF), in 2011 the FDA received more safety reports about dabigatran than any other drug. The data are not entirely unexpected, since the bleeding complications of dabigatran are well known and physicians are more likely to report adverse events associated with new drugs. The drug that dabigatran was designed to replace, warfarin (Coumadin), was the second most reported drug, and has been high on the FDA list for many years.
Dabigatran was the subject of 3781 serious adverse events reported to the FDA in 2011. This included 542 patient deaths and 2367 hemorrhages. Warfarin was the subject of 1106 serious adverse events, including 72 deaths.
QuarterWatch noted that the difference between the two anticoagulants “could be at least partly explained by differences in the reporting rate for an older generic drug with many manufacturers, and a newly launched brand name drug being promoted by a large sales force.” But, according to QuarterWatch:
What is clear, however, is that the FDA’s system is receiving a strong signal about this safety issue. A large share of dabigatran reports (79%) come from health professionals, suggesting that despite this well-known drug risk the bleeding was unexpected or unusually severe.
QuarterWatch notes that the rapid uptake of dabigatran is probably due to its ease of use — no frequent INR tests are required — and the lack of drug interactions. One likely source of complications is the use of the standard 150-mg dose in older patients or those with renal dysfunction. The label now recommends that physicians “assess renal function during therapy as clinically indicated” but QuarterWatch wonders “whether this modest language will lead to safer use.”
June 6th, 2012
Real-World Bleeding Risk with Aspirin in Primary Prevention Examined
Larry Husten, PHD
A new study published in JAMA provides substantial new evidence about the real-world effects of aspirin, including the risk for bleeding, in a broad population. The study also sheds important new light on the effects of aspirin in a diabetic population.
Giorgia De Berardis and colleagues analyzed data from more than 4 million people in Puglia, Italy and compared 186,425 people taking low-dose aspirin with the same number of matched controls not taking aspirin.
Major bleeding events requiring hospitalization:
- aspirin: 5.58 (5.39-5.77) per 1000 person-years
- controls: 3.60 (3.48-3.72) per 1000 person-years
- Incidence rate ratio (IRR) 1.55 (1.48-1.63)
Diabetics overall had an increased risk for major bleeding episodes, but this increased risk was not significantly associated with aspirin use:
- Hemorrhagic events in diabetics overall (compared with nondiabetics): IRR 1.36 (1.28-1.44)
- Hemorrhagic events in diabetics taking aspirin compared with diabetics not taking aspirin: IRR 1.09 (0.97-1.22)
The authors write that their findings demonstrate that bleeding events occur more frequently than had been observed in clinical trials. They calculate that for individuals with a 10-year risk for cardiovascular events between 10% and 20%, the risks and benefits of aspirin therapy are similar, causing two excess bleeds, and preventing two CV events, for every 1000 people treated each year.
In an accompanying editorial, Jolanta Siller-Matula writes that the benefits of aspirin in secondary prevention are “not disputed,” since aspirin can prevent six major vascular events at the expense of one major bleeding event. But there is no such consensus for primary prevention, and Siller-Matula writes that the findings of the Italian study reinforce current European guidelines, which do not recommend aspirin for primary prevention.
The JAMA study provides far more information about aspirin use in diabetics than had been previously available. Nevertheless, writes Siller-Matural, the decision whether to use aspirin for primary prevention in this population is still not clear, and will require additional data from ongoing studies.
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