August 12th, 2011
The Third Year
John Ryan, MD, James De Lemos, MD and Andrew M. Kates, MD
For most cardiology fellowships, the bulk of the clinical training is in the first two years. The third year is rather variable, with some fellows taking the time to get to level two certification in several of the subspecialties. Fellows going into interventional fellowships typically spend time in the catheterization lab to increase their skills. We ask John Ryan, co-moderator of the Fellowship Training discussions on CardioExchange, about his third year.
How is the third year structured in your fellowship?
During third year, we have a couple of weeks of clinical responsibilities, such as perform cardiology consults, act as senior imaging fellow, and work in the CCU. However, the third year of our program is designed to give us the opportunity to do research, be it clinical or basic science. The expectation is to produce some published manuscripts; also we present at cardiology Grand Rounds at some point during the year. We also need to apply for subspecialty fellowships such as heart failure or interventional – these applications can take up a lot of time as well. It seems to be a busy year, but it’s a lot more autonomous than the preceding years of our training.
How did you decide what to do for your third year?
The reason I came to the U.S. originally was to get trained in basic science. However, between doing Chief residency and fellowship, it has taken a while to start doing legitimate research. So for my third year, I wanted to go into the research lab. University of Chicago has a large pulmonary hypertension program; so it made sense to take advantage of the mentorship and bench research that are available here. Right now, I am working on models of Group 2 pulmonary hypertension (PH secondary to heart failure)
How is your research going?
So far it is okay. The hardest thing is that by the end of second clinical year, I could do almost everything that was asked of me, whereas now I am essentially getting retrained. With no formal training in basic science or statistics, I am starting from scratch. I face a few other struggles as well, one in particular being that data do not lie. Sometimes when taking care of patients, doctors can discover no exact right answer. However, experiments are different. They are either done right or done wrong. If you get an unexpected answer, provided you did the experiment the right way, you have to find a way to explain it.
How is the third year structured in your fellowship? How would you change it?
How do you decide what you are going to do for your third year? Would you combine it with a fourth year — for example, two years of EP?
What type of research opportunities are available in your third year?
August 11th, 2011
Danger of Cigarettes Greater in Women Than in Men
Larry Husten, PHD
Compared with men, women have a significant 25% increase in risk for coronary heart disease caused by cigarettes, according to a large meta-analysis published in the Lancet.
Rachel Huxley and Mark Woodward analyzed data from 2.4 million participants in studies that adjusted for cardiovascular risk factors and found that the female-to-male relative risk ratio (RRR) of smoking compared with not smoking was 1.25 (95% CI, 1.12-1.39; P<0.0001). For every additional year of follow-up the researchers found an additional 2% increase in the RRR for women (P=0.03).
The authors speculate that their analysis might have underestimated the true difference in relative risk between the sexes, given that in many regions women have started to smoke in large numbers only in recent years. “It will be some years before the full effect of smoking on coronary heart disease risk is known in women,” they write. In addition, women smokers tend to consume fewer cigarettes than men and may be more likely to underreport their smoking habits.
In an accompanying comment, Matthew Steliga and Carolyn Dresler observe that although in most places more men than women are smokers, more men than women quit smoking and “in some societies the number of female smokers is rising.” Further, they note, “the tobacco industry views women as its growth market.” They conclude that “targeting of both sexes is imperative for smoking prevention and cessation on a global, national, and individual basis.”
August 10th, 2011
Rethinking Trilipix — And the Process for Approving Lipid-Modifying Drugs
Sanjay Kaul, MD
Editor’s Note: In an article published in the New England Journal of Medicine, three members of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (Allison Goldfine, Sanjay Kaul, and William Hiatt) offer their perspective on the May 19 committee meeting to review the controversial ACCORD-Lipid Study. Here, one of those authors, Sanjay Kaul, provides his own account of the session for CardioExchange members.
After reviewing data from the ACCORD Lipid Study, the 13-person Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) of the FDA has voted unanimously to request that Abbott conduct a new trial of its lipid-modifying drug Trilipix (fenofibric acid). Specifically, EMDAC advises that the trial identify whether men and women who are at high risk for coronary heart disease (CHD) and who have already reached their LDL-cholesterol goals on a statin — but who have persistently high triglycerides and low HDL levels — benefit from Trilipix as add-on therapy.
The original, NHLBI-sponsored ACCORD Lipid Study involved 5518 high-risk patients with type 2 diabetes and LDL levels of 60 to 180 mg/dL (mean, 101 mg/dL). Combination therapy with daily Trilipix (160 mg) plus simvastatin showed no advantage over placebo plus simvastatin in preventing adverse cardiovascular events during a mean follow-up of 4.7 years (annual rate, 2.2% vs. 2.4%). Among women treated with Trilipix, there was a suggestion of harm from the drug; among the subgroup of patients with baseline triglyceride levels ≥204 mg/dL plus HDL levels ≤34 mg/dL (the so-called “dyslipidemic profile”), there was a suggestion of benefit.
Penetrating the nuances of the new EMDAC recommendation requires some background beyond these facts.
A Brief History of Fibrates
After statins, fibrates are the most widely used lipid-modifying agents. Annual sales in the U.S. for the three fibrates currently approved by the FDA to treat hyperlipidemia — gemfibrozil, fenofibrate, and fenofibric acid (Trilipix) — are in the billions of dollars. Trilipix is the only fibrate approved as combination therapy with a statin to reduce triglycerides and increase HDL levels in patients who have mixed dyslipidemia and CHD or a CHD risk equivalent (and who are on optimal statin therapy to achieve LDL goals). The Trilipix/statin combination-therapy approval was based on three 12-week studies of the drug’s impact on lipid biomarkers. No clinical-outcome data currently support this indication.
Indeed, unlike statins, fibrates have had mixed results in placebo-controlled trials when it comes to reducing CHD risk and actually saving lives. Studies of gemfibrozil (conducted before the statin era) have shown primary- and secondary-prevention benefits, whereas trials of fenofibrates have not (see this recap of major fibrate trials). And as summarized above, the recent ACCORD Lipid Study did not show a benefit of fenofibric acid as an add-on to simvastatin in high-risk patients with type 2 diabetes and mixed dyslipidemia.
Nevertheless, fibrate use in the U.S. doubled from 2002 to 2009. Furthermore, the two agents with no clear demonstrated benefit — fenofibrate and fenofibric acid — are gradually displacing gemfibrozil in terms of market share: Fenofibrates and fenofibric acid now command about three-quarters of the fibrate market, compared with about one-quarter for gemfibrozil. Fenofibric acid specifically is used (as add-on to a statin) primarily in dyslipidemic patients, in line with the indication on the prescribing label.
The FDA Committee’s Discussion and Vote
From its review of the ACCORD Lipid Study, EMDAC determined that the trial was not specifically designed to assess the clinical benefit of treating patients with residual low HDL and high triglyceride levels who were on a full-dose statin. Thus, the trial could not adequately evaluate the benefits of Trilipix as add-on therapy.
With regard to the two prespecified subgroup analyses (gender and “dyslipidemic profile”), the committee expressed general caution against acting on the basis of these data. They cited, among other concerns, that the trial as a whole was negative, that the analyses were limited by relatively small numbers of patients and events, and that other relevant adjustments were not performed.
The unanimous vote to call for a new trial came despite the fact that the trial’s aim would be to prove whether the indications already listed on the current medication label are supported by evidence of clinical benefit. With regard to how to handle that conundrum, the committee’s vote was split: 3 in favor of maintaining the current label, 6 in favor of revising the label, and 4 in favor of withdrawing the approved indication.
The committee also discussed the regulatory standard for approving lipid-modifying agents (currently based on proof of improvements in surrogate lipid biomarkers). Some members said that the FDA should instead consider requiring a preapproval cardiovascular-outcomes trial. Others felt that the current surrogate-biomarker–based approval process allows potentially beneficial therapeutic options to become available before results from a definitive outcome study can be obtained.
The Regulatory Fallout
In my opinion, the EMDAC decision has major regulatory implications. Taken together, the data from the ACCORD Lipid Study, ILLUMINATE, and AIM-HIGH strengthen the argument for changing the standard for approving lipid-modifying therapies: from an emphasis on surrogate lipid biomarkers to one on clinical benefits and cardiovascular outcomes. Although such outcome trials are likely to be time- and resource-intensive, if the duration of drug patents were extended, financial risk to the manufacturers would be mitigated. Pharmaceutical companies could fulfill the preapproval outcome-trial requirement yet still have sufficient time to market the drug and earn a return on their investments.
Specifically with regard to Trilipix, if the FDA were to ask the sponsor to conduct the clinical trial recommended by EMDAC, the following conditions would need to be considered:
- Start the trial ASAP, preferably within 6 to 9 months of the FDA’s decision.
- Enroll high-risk cohorts of interest (at least 30% to 40% women and minority groups; at least 50% patients with a “dyslipidemic profile” of elevated triglycerides plus low HDL).
- Ensure proper trial design and conduct, and minimize rates of crossover and dropout.
- Enroll subjects quickly and complete the study within 3 to 5 years.
- Allow the FDA to withdraw the indication if the sponsor does not complete the trial in a timely and efficient manner. Only then would the FDA be able to discourage the sponsor from taking an approach like Merck’s with ezetimibe or GlaxoSmithKline’s in RECORD.
What are your thoughts on the EMDAC recommendations with respect to Trilipix? Does this development affect how you view the general process for approving lipid-modifying drugs?
August 10th, 2011
Rivaroxaban Compared with Warfarin in 14,000 AF Patients
Larry Husten, PHD
In ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), researchers tested rivaroxaban (20 mg/day) against warfarin in 14,264 patients with nonvalvular atrial fibrillation (AF). The results of the trial, which were first presented last November at the American Heart Association meeting, have now been published in the New England Journal of Medicine.
The primary per-protocol analysis demonstrated that rivaroxaban was noninferior to warfarin: the rate of stroke or systemic embolism was 1.7% per year in the rivaroxaban group compared with 2.2% per year in the warfarin group (HR for rivaroxaban: 0.79, CI 0.66-0.96, p<0.001 for noninferiority).
The intention-to-treat analysis also demonstrated noninferiority but did not demonstrate superiority: the event rate was 2.1% per year with rivaroxaban compared with 2.4% per year with warfarin (HR 0.88, CI 0.74-1.03, p<0.001 for noninferiority, p=0.12 for superiority).
The ROCKET AF investigators write that the difference between the two analyses “reflects the fact that among patients who discontinued therapy before the conclusion of the trial, no significant difference in outcomes would have been anticipated, and none was seen.”
The rate of major and nonmajor clinically relevant bleeding did not differ significantly between the two groups, but rivaroxaban was associated with significant reductions in intracranial hemorrhage and fatal bleeds:
- Major and nonmajor clinically relevant bleeding: 14.9% per year with rivaroxaban and 14.5% per year with warfarin, HR 1.03, CI 0.96-1.11, p=0.44)
- Intracranial hemorrhage: 0.5% versus 0.7%, p=0.02
- Fatal bleeding: 0.2% versus 0.5%, p=0.003
In an accompanying editorial, Gregory del Zoppo and Misha Eliasziw note that treatment with both rivaroxaban in ROCKET AF and dabigatran in RE-LY resulted in a lower rate of intracranial hemorrhage compared with warfarin, although no difference in overall major bleeding events was observed in either trial. They speculate that cerebral vascular beds may “have protective features that are more apparent at the doses of either of the new agents tested.”
The editorialists conclude that “oral alternatives to warfarin have arrived,” but hedge their enthusiasm by noting that “comparisons seem to depend on how easily the patient can be treated with warfarin.”
August 9th, 2011
New Study Finds Wide Variation Among Hospitals in Diagnostic Yield for Angiography
Larry Husten, PHD
Last year a report in the New England Journal of Medicine from the National Cardiovascular Data Registry (NCDR) raised concerns about the low diagnostic yield for diagnostic coronary angiography. Now a new analysis of the NCDR registry appearing in the Journal of the American College of Cardiology finds a great deal of variability among hospitals in the diagnostic yield.
Pamela Douglas and colleagues analyzed data on 565,504 patients without known coronary disease who underwent elective angiography at 691 hospitals in the U.S. from 2005 to 2008. The rate of obstructive disease identified upon angiography ranged across hospitals from 23% to 100% (median 45%; interquartile range: 39% to 52%). Hospitals with a low diagnostic yield performed angiography on patients who were younger, had lower risk, had no or atypical symptoms, or did not have a noninvasive assessment of ischemia. Hospitals with a better diagnostic yield were more likely to prescribe optimal medical therapy, including aspirin, beta-blockers, antiplatelets, and statins. Hospitals that performed fewer procedures had a lower diagnostic yield.
The authors note that the rate of catheterization in western countries ranges from 12 per 10,000 in the Netherlands to 83 per 10,000 in the U.S. In the U.K., with a rate of 26 catheterizations per 10,000, the diagnostic yield is 62%.
The authors acknowledge that their “data cannot indicate what the ideal or ‘optimal’ CAD rate is for elective coronary angiography” but write that their findings “suggest that improved patient selection could increase the rate of finding CAD” in some hospitals. They conclude that “local clinical practice patterns may be the most influential factor in guiding use of diagnostic coronary angiography and could be a target for quality-improvement efforts, including appropriate use criteria development. “
August 9th, 2011
Will ISCHEMIA Tell Us More than COURAGE? PART II: Banking on Eight Years of Equipoise
Judith Hochman, L. David Hillis, MD and Richard A. Lange, MD, MBA
(Continued from Part I: Aiming to Beat Bias with Blinding)
On August 1, 2011, the Langone Medical Center at New York University announced that the National Heart, Lung, and Blood Institute has provided a grant to fund the ISCHEMIA study of an invasive strategy versus optimal medical management in patients with stable coronary artery disease and moderate-to-severe ischemia. We welcome the members of the study Executive Committee, chaired by Dr. Judith Hochman, to answer questions posed by L. David Hillis and Richard Lange, the co-moderators of the Interventional Cardiology blog on CardioExchange. The other members of the committee are William Boden, Gregg Stone, Bob Harrington, Bruce Ferguson, David Williams, and David Maron.
Hillis and Lange: How will you assess the accuracy of the noninvasive studies (nuclear imaging, stress echo, cardiac MR perfusion) for determining the presence and extent of ischemia?
ISCHEMIA Executive Committee: It is critical to the success of this trial that patients who are enrolled have a sufficient degree of ischemia to test the study hypothesis. Therefore, all stress imaging studies will be initially reviewed by a core laboratory prior to confirmation that the patient is eligible to participate in the trial. Once a site has demonstrated its concordance with core lab interpretations, it will be able to enroll patients before core lab confirmation, although we will continue to monitor the accuracy of site interpretations during enrollment.
Hillis and Lange: “Optimal” medical therapy is often in the eye of the beholder. Will it be prescribed for all patients? What will it be?
ISCHEMIA Executive Committee: We use the term optimal medical therapy (OMT) to indicate lifestyle and pharmacologic interventions that are intensive and evidence-based. OMT in ISCHEMIA will be very similar to what was delivered in COURAGE. It will be applied in both the invasive and conservative treatment strategies. Bill Boden and David Maron co-chair the optimal medical therapy committee. Behavioral interventions will focus on smoking cessation, nutrition, physical activity, weight control, and medication adherence. Pharmacologic interventions will be anti-atherosclerotic and anti-ischemic, in keeping with ACC/AHA/ESC guidelines.
Hillis and Lange: What are the participation criteria for the 150 medical centers in the U.S. and hundreds of sites in 33 countries worldwide that will be enrolling patients? Are there criteria regarding revascularization outcomes?
ISCHEMIA Executive Committee: The most important criterion is that cardiologists at a participating site have clinical equipoise and are therefore able to enroll adequate numbers of patients with at least moderate ischemia. The other important considerations are volume and mortality statistics for PCI (≥400/year per site; in-hospital mortality <1.5%) and CABG (≥125/year per site; non–risk‐adjusted in‐hospital mortality <3.0%), access to a coronary CT angiography facility, and the ability to transmit images electronically. We invite primary care and cardiology practices to contact us if they want to participate as enrolling sites.
Hillis and Lange: What is a realistic time for enrollment, and when should we expect to see results?
ISCHEMIA Executive Committee: We anticipate that enrollment will begin in 1 year and will continue for approximately 4 years. The average duration of follow-up will be 4 years. Results will be available in 8 years.
August 8th, 2011
Will ISCHEMIA Tell Us More Than COURAGE? Part I: Aiming to Beat Bias with Blinding
Judith Hochman, L. David Hillis, MD and Richard A. Lange, MD, MBA
On August 1, 2011, New York University announced that the National Heart, Lung, and Blood Institute would fund the ISCHEMIA study of an invasive strategy versus optimal medical management in patients with stable coronary artery disease and moderate-to-severe ischemia. We welcome the members of the study Executive Committee, chaired by Dr. Judith Hochman, to answer questions posed by L. David Hillis and Richard Lange, the co-moderators of the Interventional Cardiology blog on CardioExchange. The other members of the committee are William Boden, Gregg Stone, Bob Harrington, Bruce Ferguson, David Williams, and David Maron.
Hillis and Lange: What information will the ISCHEMIA study provide above and beyond what we learned from COURAGE?
ISCHEMIA Executive Committee: COURAGE taught us that as an initial management strategy for patients with stable ischemic heart disease (SIHD) and known coronary anatomy, adding PCI to optimal medical therapy did not reduce clinical events. ISCHEMIA builds upon that information and addresses gaps left by both COURAGE and BARI 2D. If PCI (or CABG in BARI 2D) isn’t necessary as an initial strategy, is it necessary to catheterize patients in the first place? Did the use of cardiac catheterization before randomization result in selection bias such that many patients, including those at the highest risk and those most anatomically suitable for revascularization, did not participate in these clinical strategy trials? In COURAGE, ischemia of any severity — even mild — was an entry requirement. ISCHEMIA is restricting entry to patients with at least moderate ischemia, a more homogeneous, higher-risk SIHD population, who may be more likely to derive benefit from revascularization. In the COURAGE nuclear substudy, there was a trend toward an independent association of less residual ischemia at 6–18 months and lower death/MI rates during follow-up. However, additional data demonstrate that there was no reduction in events with PCI for those with moderate-to-severe ischemia at baseline, without regard to ascertainment of a follow-up stress nuclear scan — hence the need for the ISCHEMIA trial.
ISCHEMIA will include a much higher proportion of DES recipients and provide the opportunity to see if the early greater improvement in angina and need for fewer antianginal medications associated with improved quality of life in the COURAGE PCI recipients, especially in those with greater degrees of angina at baseline, is durable. We will also examine the effect of CABG. Based on lessons from COURAGE, we are prespecifying angina-related quality of life as the major secondary endpoint.
Hillis and Lange: Are you concerned that cardiologists will find it difficult not to recommend revascularization to their patients with ischemia? Will they be blinded to the extent of ischemia?
ISCHEMIA Executive Committee: Yes, we are concerned that some will be biased toward revascularization. We believe that cardiologists will enroll patients for the following reasons: 1) A survey that we conducted of 500 cardiologists from around the world found that the vast majority would be willing to participate, provided that patients at very high risk for death — e.g., significant left main stenosis — would be excluded. 2) Prior to randomization, patients will undergo blinded coronary CT angiography to exclude patients with significant left main disease. 3) Results from COURAGE and BARI 2D demonstrate that it is safe to treat initially with optimal medical therapy alone and to defer revascularization. 4) It may be easier for cardiologists to enroll patients if they — and the patients — don’t see the anatomy. It is possible that this will prevent the well-described “oculostenotic reflex.”
Cardiologists will not be blinded to the extent of ischemia because the test will be ordered for clinical indications, and eligible patients will only be identified after the test results are known.
Hillis and Lange: Who decides the best method of revascularization? Are you encouraging (or mandating) a “Heart Team” approach?
ISCHEMIA Executive Committee: In ISCHEMIA, we are testing the concept of optimal revascularization as well as that of optimal medical therapy. Gregg Stone chairs the optimal revascularization committee, David Williams chairs its PCI subcommittee, and Bruce Ferguson and Philippe Menasche chair the CABG subcommittee. These expert committees of interventionalists and surgeons have developed trial guidelines for site investigators regarding the optimal method of revascularization. We will require that each site establish a Heart Team composed of an interventional cardiologist and cardiac surgeon. In most cases, it is desirable for the local Heart Team to discuss each case after diagnostic angiography and subsequent discussion with the patient to reach a consensus about the best revascularization modality. We recognize, however, that this is not always practical, and in some cases of non-complex coronary artery disease, the performance of ad hoc PCI immediately after diagnostic angiography may be preferred. As a general guideline, PCI is recommended for SYNTAX scores of 0–22, CABG for SYNTAX scores ≥33, and PCI or CABG for SYNTAX scores of 23–32 (if in doubt, CABG is recommended). Heart Team review will be expected for all patients with a SYNTAX score of 23–32.
Find more questions and answers from the ISCHEMIA Executive Committee in Part II: Banking on Eight Years of Equipoise.
August 8th, 2011
Bernadine Healy, First Woman to Head the NIH, Dead of Brain Tumor
Larry Husten, PHD
Bernadine Healy, a cardiologist who was the first woman to head the NIH, died on Saturday from complications of a brain tumor. She was married to cardiac surgeon Floyd Loop, a former CEO of the Cleveland Clinic. She had two daughters, one from a previous marriage.
Healy was born in 1944 and grew up in New York City. She went to Hunter College High School, Vassar College, and Harvard Medical School. She completed her training in internal medicine and cardiology at Johns Hopkins, where she eventually joined the faculty after a stint at the NHLBI. She was chosen by President Reagan in 1984 to be the deputy director of the White House Office of Science and Policy.
In 1991 President Bush chose her as the first woman director of the NIH, where she served until 1993. One major accomplishment during her tenure at the NIH was the establishment of the Women’s Health Initiative, which continues to have a broad impact on public health to this day. She was the Dean of the College of Medicine at Ohio State University from 1995 to 1999 and the president of the American Red Cross from 1999 through 2001.
A funeral for Healy will take place in Ohio on Wednesday. A memorial service in Washington, DC will be scheduled at a later date.
Resources:
- Bernadine Healy (third row, third from left) with her Harvard Medical School class, ca. 1970 (image courtesy of the NIH)
August 7th, 2011
Help Cover ESC for CardioExchange
Harlan M. Krumholz, MD, SM
Will you be traveling to Paris for the European Society of Cardiology meeting? Interested in offering your observations and analysis in very succinct notes on CardioExchange? Our community would love to hear from you. Just email Larry Husten for details.
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