November 28th, 2012
Statins and Exercise: Independently Beneficial, Even Better in Combination
Larry Husten, PHD
It’s no secret that statins and exercise are good for people with dyslipidemia. Now a study published in the Lancet offers fresh evidence suggesting that the two may be independently beneficial, and that the two together may yield greater benefits than either alone.
U.S. researchers analyzed data from 10,043 people with dyslipidemia treated at either of two Veterans Affairs Medical Centers. Participants were followed for a median of 10 years, during which time nearly a quarter of them died. After adjustment for baseline characteristics and other risk factors, a mortality reduction was separately and independently associated with statin use and with greater fitness; the largest mortality reduction was found in the subgroup of patients who were taking statins and were highly fit (>9 metabolic equivalents).
The researchers further reported that only a moderate and achievable amount of exercise produced an effect similar to that of statins in people not taking statins. “Improved fitness,” they write, “is an attractive adjunct treatment to statins or an alternative when statins cannot be taken.”
“The fitness necessary to attain protection that is much the same or greater than that achieved by statin treatment in unfit individuals is moderate and feasible for many middle-aged and older adults through moderate intensity physical activity such as walking, gardening, and gym classes,” said lead researcher Peter Kokkinos, in a Lancet press release.
In an accompanying editorial, Pedro Hallal and I-Min Lee write that “the undervaluation of physical activity in clinical practice [is] unacceptable” and that “prescription of physical activity should be placed on a par with drug prescription.”
- Photo by T-Rex Runner (click on the the picture for background on the photo)
November 28th, 2012
The End of Fellowship: What Happens Next?
John Ryan, MD
Our training programs have a uniform deficiency — they do not prepare fellows on how to leave. I know this well, as I am currently transitioning from cardiology fellow to faculty member.
Fellows typically enter medical school in their twenties and over the next ten years become institutionalized into full-time understudies. Part of this is nice, because it helps fellows concentrate on developing the craft of medicine rather than being distracted by the perils of adult life (e.g., funding, RVUs). But perhaps a larger part makes them ill-prepared and naïve when it comes to the end of fellowship.
Increasingly, fellows are entering into 2+ years of subspecialty fellowships and advanced training. People argue that this is necessary because the individual fields within cardiology have become so complex that more time is needed to create better doctors. However, using expert consensus to justify this extension of training is contradictory to our field, where we rely so heavily on data and shun anecdotal medicine. Most leaders and master clinicians within cardiology did not do subspecialty fellowships but rather developed their skills as faculty members.
In addition, this situation involves a clear conflict of interest that would be unacceptable in any RCT: Faculty who want fellows to stay on benefit from having trainees under their purview. The counterargument of course is that the trainees also benefit from this apprenticeship — but how long can we justify that reasoning, while deferring major (both personal and professional) life decisions?
The phrase “boomerang generation” is applied to today’s young adults in U.S. and European society, because so many have chosen to cohabitate with their parents after a brief period of living on their own. I fear that we are creating our own boomerang generation of medical graduates who are underprepared for entering the workforce and who thereby extend the time they spend under the supervision of their mentors.
Like any species, we survive by sending our young into the world to make their own way. But, almost universally, formal training in how to search for a job is absent. Looking for a job itself is like the Wild West, with very few positions actually being advertised and no uniform time line for interviews and recruitment.
I know — this is real life. During my own job search, I did enjoy the anarchy, somewhat. But graduates are entering into a job market in complete disarray, having lived for the past decade in a protective bubble of matching systems and stability within training programs.
We need to train fellows how to graduate. We need to teach practical lessons — what is needed to get a job and how to enter into a job market. Fellows need some preparation, with objective guidance and mentorship. And I feel we currently are not doing that.
What changes would you make to help fellows make the jump into the job market? Or do you think that the system works well as is?
November 27th, 2012
Longer Warfarin Therapy After Bioprosthetic Aortic Valve Replacement May Be Beneficial
Larry Husten, PHD
Three months of warfarin is the usual standard of care following bioprosthetic aortic valve replacement (AVR), although the supporting evidence base for this practice is limited. A new, large registry study published in JAMA suggests that more-prolonged warfarin therapy may be beneficial.
Danish researchers identified 4075 patients who underwent bioprosthetic AVR. As expected, warfarin treatment between 30 and 90 days after AVR was associated with significant reductions in stroke, thromboembolic events, and cardiovascular deaths (compared with no warfarin treatment). The benefits continued between 3 and 6 months, though the reduction in stroke became statistically nonsignificant. The authors calculated that for every 23 patients not being treated with warfarin between 3 and 6 months, one additional cardiovascular death occurred, at a cost of 1 bleeding complication requiring hospitalization for every 74 patients.
“With no randomized trials to guide the length of warfarin treatment, our results call for a review of guidelines in the field to consider an extension of the treatment to 6 months after surgery, especially in patients with an increased risk of cardiovascular death,” the authors wrote.
In an accompanying editorial, Shamir Mehta and Jeffrey Weitz write that, despite the limitations of an observational study, the results support a change in clinical practice in favor of prolonged warfarin therapy for as long as 6 months. They observe that the trial does not provide information about the possible role for the newer oral anticoagulants or about the role of adjunctive aspirin.
November 26th, 2012
Model Finds High Cost for ECG Screening of Athletes
Larry Husten, PHD
A national program of ECG screening for U.S. athletes would save almost 5,000 lives over 20 years but would cost more than $50 billion dollars, according to a paper published in the Journal of the American College of Cardiology. The advisability of routine ECG screening for athletes has divided the experts: currently the ESC recommends ECG screening while the American Heart Association does not.
Israeli investigators developed a cost-projection model using data from a retrospective Italian study and based on population data derived from high school and college athletic associations and expense assumptions from Medicare. Currently there are more than 8.5 million student athletes. Over 20 years, the investigators predicted that a national screening program would result in 170 million ECG screenings and, based on an estimated 2% disqualification rate, 3.4 million disqualifications. This would cost between $51 and $69 billion dollars and save 4,813 lives, yielding a cost per life saved in the range of $10.6 to $14.4 million.
In an accompanying editorial comment, Antonio Pelliccia takes issue with the cost assumptions in the paper and maintains that pre-participation screening “should be priced as a package of preventive medicine program” rather than the more expensive individual diagnostic testing. He acknowledges that this “will require a change in the cultural attitude and current medical policy” in the U.S.
In a statement, the ACC said that automatic external defibrillators (AEDs) can be life saving “if used quickly on stricken athletes.” However, although AEDs are now commonly placed at sports venues and other public places, they “are only effective if actually used” and bystanders are often afraid to use them. “AEDs are life-saving,” said Joanne Foody, in the ACC statement. “While many fear they may cause more harm than good, it is not the case.”
November 26th, 2012
Selections from Richard Lehman’s Literature Review: November 26th
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 21 Nov 2012 Vol 308
Fish Oil and Postoperative AF: OPERA is the quintessential Italian art-form: devised as a return to the classical past, it is a brilliant transitory display of music, costume, and painted stage sets; an escape to a heightened form of existence and emotion. Palpitations are to be found everywhere: in fact the aria Di tanti palpiti from Rossini’s Tancredi was a great nineteenth century favourite. Oily fish, on the other hand, play but a small part in the operatic repertoire, to the best of my knowledge. Were I sufficiently versed in the full range of Italian musical drama, I might be able to cite the odd eel or mackerel. Perhaps there may be a herring in Lucia di Lammermoor. The climax of Maria Stuarda probably involves a salmon. Alas, I am an infrequent visitor of the opera house, and no sound guide on this important topic: all I am trying to do is to relieve the tedium of reporting on an Italian trial of fish oil in post-operative atrial fibrillation, called OPERA. “In this large multinational trial among patients undergoing cardiac surgery, perioperative supplementation with n-3-PUFAs, compared with placebo, did not reduce the risk of postoperative AF.”
NEJM 22 Nov 2012 Vol 367
Low-Dose Aspirin for Preventing Recurrent VTE (pg. 1979): When Felix Hoffmann, working for the Bayer company in 1897, acetylated salicylic acid and produced aspirin, he produced a drug that we are still learning new uses for. The ASPIRE trial looked at the effect of low dose aspirin (100mg) on events following the discontinuation of anticoagulation for a first episode of venous thromboembolism. The enteric-coated aspirin was provided free by Bayer (they still make plenty); the study was publicly funded in Australia and New Zealand. They had recruitment problems despite using 56 sites in 5 countries, but they did manage to conduct a double-blinded trial on 822 patients over 4 years. As far as thromboembolic event prevention went, the benefit did not reach significance—though taken with the results of the WARFASA trial, there is a definite signal for protection. But if you add in stroke, myocardial infarction and cardiovascular death, there was a significant reduction of 34%. It looks as if people who have had any episode of VTE might be well advised to take 100mg of Bayer enteric-coated aspirin daily: with this preparation, there was no increase in bleeding events.
Endovascular vs. Open Repair of Abdominal Aortic Aneurysm (pg. 1988): When you are trying to share decision making with patients, you need reliable data from a representative population, and you need it presented in a form that the patient can understand. Imagine that you are a man who has to decide on surgery for aortic abdominal aneurysm: you have a time-bomb ticking in your belly; it may never go off; if it does you may well die. Better have it repaired, then, but that too carries a small but significant risk of death, amounting to 3% if you have an open operation (in this study) or 0.5% if you have endovascular repair. In the long term, though, the mortality figures are equal, as this 881-strong trial shows. There is also a fine balance between major harms and complications. Here is a perfect example of a major preference-sensitive decision which requires an option grid. Don’t know what an option grid is? Look them up here.
BMJ 24 Nov 2012 Vol 345
Novel Oral Anticoagulants for Treatment of Acute VTE: Call me old-fashioned, but I think that if you want to compare two interventions, you have to do a randomized controlled trial of one versus the other. You can do indirect comparisons but only to generate hypotheses or give interim guidance to clinicians. It would be nice to believe this direct and indirect meta-analysis which claims that all novel oral anticoagulants are equivalent to warfarin in the management of venous thromboembolism, but I doubt whether it is as simple as that.
Resistant hypertension is the subject of this week’s BMJ Clinical Review, and the evenly high quality of the series continues. It really is worth taking some trouble over these patients. Poor compliance is often cited as a cause, but a person who is willing to keep coming back for BP checks is not likely to be non-compliant with therapy in my experience. There is more likely to be an underlying reason such as hyperaldosteronism. Forget QOF and look carefully at these high-risk people, and let this article be your guide.
November 24th, 2012
Author of Trial on Transcendental Meditation and Heart Disease Responds
Robert H. Schneider, MD, FACC
Dr. Robert H. Schneider, lead author of a recent study on cardiovascular benefits of Transcendental Meditation, responds to Larry Husten’s corrected critique of that study.
We appreciate the interest in our article published in the November 2012 issue of Circulation: Cardiovascular Quality and Outcomes. However, there are a number of critical inaccuracies in Mr. Husten’s blog about the study. Many of these points were addressed in our original article. Below are highlights.
1. This was a prospective, randomized, controlled, single-blinded clinical trial. This report is the first publication of data from the trial. It was revised in response to extensive peer review over the past months. Whatever unpublished version of the manuscript the bloggers had access to previously did not have the benefit of the most current peer review and revision.
2. A range of checks and balances were built into the study to ensure veracity. For example:
- Data were collected blindly at the clinical site in Milwaukee.
- The trial was monitored by an independent data safety and monitoring board.
- Endpoint events were adjudicated by an independent reviewer using standardized criteria.
- Survival results were confirmed by independent data analysis.
- Limitations are enumerated and discussed in the publication.
3. Regarding the hypothesis-testing capacity of the study, according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines, “Randomised clinical trials (RCTs) are generally considered to produce the most solid evidence for the effectiveness of medical interventions” (Keech et al., 2007). The CONSORT guidelines are recommended by the International Committee of Medical Journal Editors (ICMJE). The design, implementation, analysis, and reporting of this trial followed CONSORT guidelines. Thus, this clinical trial was an experimental study that tested a specific hypothesis. By contrast, an observational study, which this was not, generates hypotheses (http://en.wikipedia.org/wiki/Observational_study).
4. The total number of primary-endpoint events is within one of an earlier, unpublished version of the manuscript (noted in blog update November 18). In preparation for the revised manuscript, one additional event was identified. However, this had no meaningful effect on the results or statistical significance. That is, the main results are essentially unchanged from earlier, unpublished versions.
5. Regarding statistical adjustment, the discussion, page 7 explains: “The unadjusted results of the primary-endpoint analysis showed a nonsignificant statistical trend (p=.12). However, after adjustment for covariates of age, sex and antihypertensive medications was significant (p=.025).” According to CONSORT recommendations, “adjusted analyses frequently improve the precision of the estimate of the treatment effect” (Keech et al., 2007). Furthermore, because these factors were used in the stratified randomization procedure, it recommended to adjust for stratification factors to achieve the most efficient treatment comparison (Pocock et al., 2007; Committee for Proprietary Medicine Products, European Agency for the Evaluation of Medicinal Products, 2003). This is particularly relevant when the adjustment factors predict the outcome, as they did in this trial (Pocock, 2007). Thus, statistical adjustment is the recommended procedure for this type of data.
6. The number of patients assessed, excluded, randomized, followed, and analyzed are reported in the participant flow diagram, figure 1, page 3 (noted in blog update November 18). This is also in accordance with CONSORT guidelines (Keech et al., 2007). The results are analyzed by the intention-to-treat principle that includes all eligible subjects who were randomized to treatment groups, regardless of dropout or loss-to-follow-up status.
7. The Food and Drug Administration Amendments Act of 2007 that required registration of clinical trials was not enacted until Sept. 27, 2007 (PUBLIC LAW 110–85—SEPT. 27, 2007). It required trials that were ongoing in September 2007 or that began after 2007 to be registered. This trial began in 1998 and ended in June 2007. Thus, registration was not required by the NIH nor was it required by the International Committee of Medical Journal Editors at the time. As stated in their guidelines, ICMJE journals will accept ‘retrospective registration’ of trials that began before July 1, 2005…”. (http://www.icmje.org/faq_clinical.html).
8. Regarding the distribution of fatal and nonfatal events, the methods-outcomes section, page 2 describes that, “All clinical endpoints were adjudicated by a blinded, independent reviewer who applied standardized and validated criteria (ALLHAT, 2002).” As reported in the acknowledgments, the events adjudicator was at an outside university. It may be that when the sample size approaches the population size, the observed distribution of events in the sample approaches the population distribution. This general consideration is noted in the discussion-limitations section, page 7.
9. In the discussion section, page 6, it is proposed that the significant net differences in BP and anger expression may have plausibly contributed to lower event rates. However, it is also explained that this magnitude of BP change is associated with a 15% reduction in CVD clinical events. Therefore, we note that “it is possible that other mechanisms not evaluated in this study contributed to the reduced risk in the TM group.” Moreover, “previous studies have reported reductions in sympathetic nervous system tone, hypothalamic-pituitary-adrenal axis activation, insulin resistance, left ventricular mass, myocardial ischemia, carotid atherosclerosis and heart failure” (Barnes & Orme-Johnson, 2012). It is quite possible that an integrated set of changes in physiological mechanisms and intermediate outcomes synergistically contributed to the changes in event-free survival.
10. The description of the power analysis included sample size, event rates, and duration of follow-up and is provided in methods, page 3. “Power calculations were based on the approach of Proschan and Hunsberger for conditional power (1995 ).” “With the review and approval of the data and safety monitoring board, a single interim analysis determined that with 201 subjects….the trial had 80% power to detect a 50% risk reduction in the DSMB approved end point of all-cause mortality, nonfatal MI, and nonfatal stroke.”
11. There was only one primary analysis. Other analyses of survival were clearly labeled as secondary or sensitivity analyses. One does not adjust for multiple comparisons if there is only one prespecified analysis.
12. The significance for the primary outcome met prespecified criteria (p <.05). According to Drs. Sanjay Kaul and George Diamond (JACC 2010), “In clinical trials, investigators prespecify a significance level (most commonly 0.05)…”. Kaul et al. then refer to Panagiotakos (2008) when they write, “because p values are dependent on sample size, a p value of 0.001 should not be interpreted as providing more support for rejecting the null hypothesis than one of 0.05.” Further, in our trial, the single, primary analysis was confirmed by a series of secondary/sensitivity analysis that met the prespecified significance requirements (table 3).
13. Kaul and Diamond (2010) point out that clinical significance in a trial may be considered as important as statistical significance. The effect size on the primary outcome (48% risk reduction) in the current trial is similar to or greater than conventional drug therapies used in secondary prevention of cardiovascular disease (e.g., statins and antihypertensive medications; Smith 2011). Notwithstanding that the latter have been subjected to larger, phase III trials. Thus, the current findings indicate clinical as well as statistical significance. This is robust.
November 23rd, 2012
Undiagnosed Hypertension in Younger Adults
Heather M Johnson, MD, MS
Dr. Johnson answers CardioExchange editors’ questions about her research group’s retrospective study of undiagnosed hypertension in younger adults. It was presented at the American Heart Association conference earlier this month.
THE STUDY
The cohort comprised 30,000 adults who met guideline criteria for hypertension and regularly received primary care. Patients were excluded if they had a previous diagnosis of hypertension or had been prescribed antihypertensive medication. Emergency room blood pressure readings were not counted.
After at least 2 years of follow-up, patients age 18 to 39 were less likely to receive a diagnosis for their hypertension than were patients age 60 or older. After adjustment for patient demographics, comorbidities, and provider factors, hazard ratios for a hypertension diagnosis were as follows:
18- to 24-year-olds: HR, 0.35; 95% CI, 0.29-0.42
25- to 31-year-olds: HR, 0.39; 95% 0.35-0.43
32- to 39-year-olds: HR 0.51; 95% CI, 0.47-0.55
The likelihood of receiving a hypertension diagnosis was especially low among young adults whose primary spoken language was not English, but also (surprisingly) among young adults of white race. Female providers were more likely than male providers to diagnose hypertension in young adults.
THE AUTHOR RESPONDS
How do you know that these diagnoses of hypertension were truly “missed” versus ignored? That distinction would change how clinicians address the problem.
I agree – that distinction does change how the problem is addressed. Our research does not answer the question of “missed” versus ignored elevated blood pressure. Additional research that includes qualitative methodology is needed to determine whether elevated blood pressures were missed or ignored.
Why do you suspect that having a male healthcare provider was associated with a missed diagnosis?
One possible reason that having a male healthcare provider was associated with a missed hypertension diagnosis among young adults comes from previously published studies showing that male and female providers differ in patient-provider communication. Further research is needed to understand how this difference may affect young adults’ awareness, understanding, and diagnosis of hypertension.
Were providers just as likely to miss all grades of hypertension severity?
Providers were less likely to diagnose milder levels of hypertension.
How do you suggest that we decrease these rates of missed diagnoses? Would you tackle it on a patient/public level or on a physician/provider level?
The primary implication of our study is that it emphasizes the need for interventions to be tailored to young adults with elevated blood pressure, in order to improve hypertension diagnosis rates. In addition, our research demonstrates that multiple factors contribute to low hypertension diagnosis rates in this age group. The most effective interventions are likely to be system-level interventions that address multiple components and not just focus on providers.
Offer your thoughts about this study by Dr. Johnson and her colleagues.
November 21st, 2012
HeartWare LVAD Approved By FDA For Transplant Patients
Larry Husten, PHD
The FDA said today that it had granted approval to the HeartWare Ventricular Assist System for use in heart failure patients waiting for a transplant. Approval of the device had been expected after the FDA’s Circulatory System Devices panel recommended approval of the device earlier this year.
HeartWare was approved based on data from the pivotal ADVANCE trial, in which 140 patients received the Heartware device and were compared to historical controls who had received Thoratec’s HeartMate II device. The FDA said this was the first time it had approved an LVAD using registry data as a control. Unlike Thoratec’s HeartMate II VAS, which is surgically implanted in an abdominal pouch, the HeartWare VAS is implanted next to the heart.
The FDA said that surgical outcomes were comparable in the two groups. Because of the risk of stroke associated with the device, the FDA said patients and clinicians should “discuss all treatment options before deciding to use the device.”
HeartWare said that the FDA was requiring the company to perform a post-approval study in the form of a registry consisting of 600 HeartWare patients and an additional 600 control patients. The FDA will also require sites that implant the device to undergo training with an approved program.
November 21st, 2012
What’s The Best Treatment For Abdominal Aortic Aneurysm?
Larry Husten, PHD
Endovascular repair of AAA (abdominal aortic aneurysm) gained enthusiastic acceptance after initial results from three trials (EVAR 1, DREAM, and OVER) found an early survival advantage for endovascular repair compared to open repair. Some of the enthusiasm waned, however, after long-term results from the first two trials found no difference in survival between the groups after the first two years. Now the results of the third trial, the Open versus Endovascular Repair (OVER) Veterans Affairs Cooperative Study Group, have been published in the New England Journal of Medicine. and these confirm the pattern found in the other trials.
The trial randomized 881 patients with asymptomatic AAA who were eligible for either approach. Although in the early years of the trial endovascular repair was superior to open repair, after a mean followup of 5.2 years there were no significant differences in mortality between the two groups, with the same number of deaths (146) deaths occurring in each. Here are the hazard ratios for endovascular repair:
- at 5.2 years: 0.97, 95% CI 0.77 – 1.22; P=0.81
- at 3 years: 0.72, 95% CI, 0.51 – 1.00; P=0.05
- at 2 years: 0.63, CI 0.40-0.98; P=0.04
Summarizing their findings, the OVER investigators wrote that the two procedures “resulted in similar long-term survival. The perioperative survival advantage with endovascular repair was sustained for several years, but rupture after repair remained a concern. Endovascular repair led to increased long-term survival among younger patients but not among older patients, for whom a greater benefit from the endovascular approach had been expected.”
In an accompanying editorial, Joshua Beckman places OVER within the context of EVAR 1 and DREAM, and points out that “the results of these three clinical trials” have been “incredibly consistent.” All three trials found “an upfront reduction in mortality with catch-up later.” With no significant differences in mortality between the procedures, “patients can weigh the value of open repair, a major operation with greater upfront morbidity and mortality, against that of endovascular repair, with its lower early-event rate but the need for indefinite radiologic surveillance.”
November 20th, 2012
PFO Occluder Devices Don’t Get No RESPECT
L. David Hillis, MD
In the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial, 980 patients were randomly assigned to (1) PFO closure with the AMPLATZER PFO occluder device (St. Jude Medical, which sponsored the trial) or (2) medical therapy. The trial’s primary endpoint was a composite of recurrence of nonfatal stroke, fatal ischemic stroke, or early (within 45 days after randomization) all-cause mortality.
Patients assigned to received the AMPLATZER device had a 46.6% relative reduction in event risk compared with those assigned to medical management (9 vs. 16 events). However, in the intent-to-treat (ITT) analysis, this difference did not reach statistical significance (p = 0.157).
Does what followed call to mind a straight man, a song and dance, or a comedy routine?
The statistician noted a differential length of follow-up in the two arms, which was attributed to “late trial fatigue”: More of the patients in the medical group than in the device group left the study early (90 vs. 48) — some because they wanted to get an off-label device outside the study — resulting in more years of observation in the device group for events to occur (1,375 vs. 1,184 patient-years; P=0.009). As a result, the ITT raw-count analysis was deemed invalid and a prespecified Kaplan Meier (i.e., time to event) analysis was performed, which showed a strong trend toward benefit (P value, 0.08–0.09). Not statistically significant. . .but close.
The investigators next performed an analysis that excluded events that occurred in the device arm before a closure procedure was attempted. The resulting per protocol analysis (which eliminated 3 of the 9 strokes in the device arm) showed a 63% reduction in the primary endpoint with the device as compared with medical therapy (P=0.032).
The punch line: The RESPECT investigators concluded that their study” provides evidence of benefit in stroke risk reduction from closure with the AMPLATZER PFO Occluder over medical management alone.”
Rodney Dangerfield was famous for claiming, “I don’t get no respect.” After all the slicing and dicing of these data, should the PFO Occluder device get any respect?
