CardioExchange Archive

CardioExchange, an NEJM practice community for medical professionals dedicated to improving cardiac patient care, was active from 2009 to 2015. CardioExchange fostered discussion between clinicians from across the globe.

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June 3rd, 2013

How Do Patients with CAD Fare After TAVR?

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Sachin Goel discusses his research group’s literature review, published in JACC, focusing on patients with coronary artery disease (CAD) who are evaluated for — and those who undergo — transcatheter aortic valve replacement (TAVR). CardioExchange’s Erica Spatz conducted the interview.

THE STUDY

Goel and his research team report that 40% to 75% of patients who undergo TAVR have CAD. They note that the only randomized trial of TAVR (the PARTNER study) excluded patients with untreated, clinically significant CAD requiring revascularization, yet their literature review reveals that 11% to 23% of patients who undergo TAVR have previously undergone percutaneous coronary intervention (PCI). The article identifies patients for whom revascularization should be considered; summarizes the various management options for patients with severe CAD and severe aortic stenosis (AS) who are potential candidates for TAVR; and describes a multidisciplinary team approach to decision making about TAVR.

THE AUTHOR RESPONDS

Spatz: What did you learn in the process of doing this literature review? 

Goel: We learned that the effect of CAD on outcomes after TAVR is not well studied. Surgeons have traditionally bypassed all coronary lesions >50% at the time of valve replacement surgery. Among the 11% to 23% of patients who are revascularized percutaneously before undergoing TAVR, outcomes (procedural, short-term, and long-term) are generally good.

Spatz: Revascularization before surgery, including vascular surgery, has never been shown to improve outcomes, yet it seems to be an accepted practice before TAVR. What explains this?

Goel: One of the main concerns while performing TAVR in the presence of unrevascularized, severe proximal coronary stenosis subtending a large area of myocardium is the risk for ischemia and hemodynamic instability during rapid pacing and balloon inflation, both integral parts of the TAVR procedure. Patients with severe AS have reduced myocardial reserve, which is further reduced in the presence of severe CAD, particularly involving proximal epicardial coronary vessels subtending a large area of myocardium. Results from ongoing studies such as PARTNER II, SURTAVI and ACTIVATION will shed more light on which patients with severe CAD need to be revascularized before TAVR.

Spatz: At your institution, how is CAD evaluated in patients being considered for TAVR? How are decisions made regarding revascularization? 

Goel: While making decisions about PCI for patients with severe AS and severe CAD who are being evaluated for TAVR, we consider the clinical presentation to be the most important factor. When the clinical presentation is largely secondary to CAD (acute coronary syndrome), then PCI is performed. In terms of process, we use a “heart team” decision-making approach, whereby all patients referred for TAVR are evaluated in a weekly multidisciplinary meeting involving cardiac surgeons, interventional cardiologists, imaging cardiologists, clinical cardiologists, and nurse practitioners. The team reviews each patient’s clinical history, imaging studies such as coronary angiogram, and echocardiography to determine candidacy for surgical AVR versus TAVR. The team also decides whether — and when — to revascularize patients with severe CAD.

Spatz: Your review points to conflicting data about how best to manage CAD in patients undergoing TAVR. How do we make sense of current knowledge for patients who are considering different strategies? 

Goel: The conflicting data are partly due to lack of systematic evaluation of the risks and benefits of coronary revascularization in patients undergoing TAVR. The PARTNER trial excluded patients with unrevascularized severe CAD. Ongoing studies should help elucidate the role of revascularization in these patients. Notably, not all patients with severe CAD and AS need to be revascularized before TAVR. Again, the clinical presentation is critical: If a patient presents with symptoms that are largely secondary to CAD, then PCI should be undertaken before TAVR. Otherwise, in cases of stable CAD, we perform PCI only for the small subset of patients who have severe proximal stenoses subtending a large territory of myocardium. CAD that cannot be revascularized is rarely a contraindication for TAVR.

Spatz: What is the most important thing you want readers to take away from your study? 

Goel: The most important takeaway is that CAD often coexists with severe AS but that not all severe coronary stenoses need to be treated. The clinical presentation matters most in determining whether patients with severe AS and severe CAD should undergo TAVR. If the clinical presentation is largely related to CAD, revascularization should be considered. In other cases, PCI should be considered only on proximal coronary lesions subtending large areas of myocardium at risk prior to TAVR, pending results from ongoing studies. The multidisciplinary team approach is critical in decision making and achieving good outcomes.

How does your institution handle decision making about TAVR for patients with CAD? Will this new literature review affect how you approach this clinical issue? 

 

Categories: Vascular
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June 3rd, 2013

Waiting For ATP IV In Las Vegas

May 31– Today was the first full day of the National Lipid Association meeting in Las Vegas, Nevada. As a first time attendee, I notice many differences compared to the larger meetings. Firstly, there are ~ 700 people in attendance; this dwarfs in comparison to the AHA and ACC which count attendees in the thousands. As a fellow I appreciate the more intimate and collegial atmosphere; it allows for more opportunities to meet and connect with others who share similar interests and with leaders in the field. I also realized the true collaborative nature of the fields of lipidology and prevention, with its diverse roster of attendees from cardiology, internal medicine, endocrinology, pharmacy, and more.

The most crowded session of the day featured Neil Stone, from Northwestern University. As the chair of the ATP IV panel he gave a talk titled “Preparing for guidelines in 2013.” The room was packed full of people, likely looking for some small glimpse into the upcoming guidelines that have met with years of delay.

The main focus of the talk was on the importance of using strong evidence to make recommendations– mostly high-quality randomized clinical trials and meta-analyses of RCT’s, and why this is important. He briefly reviewed the evidence behind statins. He said that the guidelines will address statin side effects, but did not specify a position. Unfortunately, he was unable to provide a timeline for the release of these highly anticipated recommendations.

During the Q&A session, one attendee inquired about treating to LDL targets <70; interestingly, Dr. Stone responded that the data behind “lower is better” is actually debatable. Those who had lower LDL’s in the trials actually started at a lower LDL and may have had lower risk to begin with. Stone did not take a position either way on whether he supported “lower is better.”

So there were only a few slight hints of what to expect…unfortunately we will still have to wait (a little?) longer.

What are your thoughts on what to expect in ATP IV? Why do you think it is taking so long to be released?

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May 31st, 2013

Two FDA Officials Quarrel Over Safety of Angiotensin-Receptor Blockers

Two FDA officials are quarreling in public about their different views about the safety of angiotensin-receptor blockers (ARBs), according to a story by Thomas Burton in Friday’s Wall Street Journal.

One official, Thomas Marciniak, contends that ARBs may increase the risk for cancer. Marciniak has been a vocal critic of FDA’s efforts to assess drug  safety. In the past he has raised questions about other major drugs, including prasugrel, rosiglitazone, and rivaroxaban. But Marciniak’s boss, Ellis Unger, who is the acting director of the office of new drugs, told the WSJ  that Marciniak’s concerns are a “diversion.”

In 2010 the FDA announced it was reviewing the safety of ARBs following a study that raised the possibility that the popular drugs might cause a small but significant increase in the risk for cancer. One year later the FDA said that it had concluded its review and found no evidence of an increased risk for cancer. “We have no reason to tell the public anything new,” Unger told the WSJ.

Burton reports:

In a rare rebellion by an FDA reviewer, Dr. Marciniak has clashed with his bosses over his desire to spend time on ARB safety, instead of just on new-drug applications.

Marciniak claims that the FDA review was not sufficiently rigorous because it relied on summary data provided by drug companies. On his own initiative, Marciniak analyzed patient-level data and concluded that ARBs were associated with a 24% increase in the risk for lung cancer. Marciniak,  reports Burton, “sent a memo to senior FDA officials, saying: ‘The FDA needs to inform patients and physicians about the ARB lung-cancer risks. The FDA must act now.'”

But Unger disagreed with Marciniak’s analysis and told Burton that it was not reliable. Burton reports that Unger discouraged Marciniak from working on the topic, but Marciniak refused to discontinue his investigation.

 

 

Categories: General, Prevention
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May 30th, 2013

True or False: Fitness Program + Statin = No Fitness Program?

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Catherine Mikus and John Thyfault discuss their study group’s small randomized trial, published in JACC, suggesting that statin use may blunt the benefits of exercise. CardioExchange’s Payal Kohli conducted the interview.

THE STUDY

Thirty-seven previously sedentary, overweight, or obese adults with at least two other risk factors for metabolic syndrome were randomized to 12 weeks of aerobic exercising training plus 40 mg/day of simvastatin or to the exercise training alone (control). At the end of the study, cardiorespiratory fitness, as measured by maximal oxygen uptake, had increased by a significant 10% in the control group but by only 1.5% in the simvastatin group. The control group also showed a significant 13% increase in skeletal-muscle citrate synthase activity, a measure of mitochondrial activity in muscles, compared with a 4.5% decrease in the simvastatin group.

THE AUTHORS RESPOND

Kohli: What is the physiological mechanism for the observed results? May there be some heterogeneity between high- and low-potency statins?

Mikus and Thyfault: The precise mechanisms underlying our findings have yet to be elucidated. Some reports have shown that physiologic doses of simvastatin disrupt mitochondrial respiration, increase oxidative stress, and activate mitochondrial apoptotic pathways in skeletal muscle. Therefore, we suspect that statins may induce mitochondrial oxidative stress, thereby activating pathways of apoptosis or autophagy and mitigating increases in mitochondrial content and oxidative capacity in response to exercise training.

Although some statins (simvastatin, cerivastatin, fluvastatin, and atorvastatin) have been shown to induce cell death and impair mitochondrial respiration and beta-oxidation in rodent skeletal-muscle cell lines, others (such as pravastatin) do not exhibit those toxic effects, suggesting that individual statins may differentially affect skeletal-muscle mitochondrial content and function in the absence of exercise. Further studies must evaluate and compare how different classes of statins affect adaptations to exercise training.

Kohli: Statin users often report myalgias that may be exacerbated by aerobic exercise. Were there more patients in the statin group who reported myalgias than in the control group? And did the unblended design influence this issue?

Mikus and Thyfault: Initially, our primary aim was to study the effects of combining exercise and statin use on traditional cardiometabolic risk factors. It was not until the initial cohorts completed the trial that we noticed the conspicuous lack of improvement in cardiorespiratory fitness among participants in the statin-plus-exercise group. So the participants were not aware that we were studying the effects of statin use on changes in cardiorespiratory fitness or markers of skeletal-muscle mitochondrial content in response to exercise training. Thus, although we cannot exclude the possibility that the unblended design may have influenced our findings, it is unlikely that our results are attributable to a placebo effect, especially when the data are considered in light of accumulating evidence of the undesirable effects of statins on skeletal-muscle mitochondrial function.

Our data indicate that statins interfere with specific adaptations to exercise training in skeletal muscle, even among patients whose creatine kinase levels do not change with statin use, suggesting a physiological basis for complaints of muscle fatigue or discomfort that is not captured by current methods for screening and monitoring patients with sensitivities to statins. In our study, two participants in the statin group and none in the control group complained of muscle fatigue and mild myalgia. However, because the study was not designed a priori to evaluate the effects of statins on muscle or joint pain, we had no formal mechanism (e.g., a questionnaire) for systematically evaluating these endpoints; therefore, these data should be interpreted with caution.

Kohli: What are your study’s implications for clinical practice?

Mikus and Thyfault: We are excited that our study is stimulating discussions about pharmaco-lifestyle interactions. Unfortunately, we have much yet to learn. Although the data are not conclusive, some evidence suggests that coenzyme Q10 supplementation or initiating statin therapy and exercise training at different times may protect against some of the potentially unfavorable effects of statins. Alternatively, some statins (e.g., pravastatin) may be less likely to disturb skeletal-muscle mitochondrial content and function.

Our groups and others are working to identify therapeutic options that minimize the adverse effects of LDL-lowering therapies on adaptions to exercise training, but it may be years or even decades before we have sufficient evidence for consensus recommendations. If anything, our data highlight the need for further research into pharmaco-lifestyle interactions. For now, physicians and patients must bear the burden of carefully weighing the risks and benefits of statin use in the clinical setting.

How does this study’s findings affect your thinking about statin use in relation to exercise training?

Categories: Prevention
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May 30th, 2013

Large Meta-Analysis Quantifies Risks Posed by Coxibs and Traditional NSAIDs

Findings from a very large meta-analysis of clinical trials of NSAIDs may now allow physicians to quantify the cardiovascular and gastrointestinal risks associated with these drugs. The results of the Coxib and traditional NSAID Trialists’ (CNT) Collaboration, employing data from more than 350,000 randomized patients, have been published in the Lancet.

Here are some of the key findings:
  • The risk for major vascular events — mostly major coronary events– was increased by one third in people taking coxibs or high-dose diclofenac. Ibuprofen significantly increased the risk for major coronary events but not major vascular events.
  • Compared with other traditional NSAIDs (not coxibs), high-dose naproxen was not associated with an increased risk for major vascular or coronary events.
  • All NSAIDs were associated with an increase in the risk for heart failure hospitalization and GI complications. The increase in the rate of GI complications was lowest for the coxibs.

The investigators said that NSAIDs and coxibs caused a similar proportional increase in events across the spectrum of baseline risk. They reported:

Among those at low risk of vascular disease (the majority of participants in these trials), the predicted absolute risks of major vascular events were small irrespective of the particular regimen chosen. For high-risk individuals (about 40% of whom were taking aspirin), for every 1000 patients allocated to a year of treatment with a coxib regimen or high-dose diclofenac regimen, about seven or eight more would have a major vascular event, of which two would be fatal. High-dose ibuprofen may be associated with a similar risk, but is also likely to yield a higher risk of upper gastrointestinal complications than either a coxib or diclofenac.

“Whilst NSAIDs increase vascular and gastrointestinal risks to a varying extent, our analyses indicate that the effects of different regimens in particular patients can be predicted, which may help physicians choosing between alternative NSAID regimens to weigh up which type of NSAID is safest in different patients,” said lead author Professor Colin Baigent, in a Lancet press release.

In an accompanying comment, Marie Griffin suggests that “long-term use of high-dose NSAIDs should be reserved for those who receive considerable symptomatic benefit from the treatment and understand the risks.”

 

Categories: General, Prevention
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May 29th, 2013

Report on the RECORD Trial Released

An independent re-adjudication of the RECORD trial has confirmed the trial’s original finding that rosiglitazone does not increase cardiovascular risk. But critics of the trial and the drug are unlikely to be appeased by the new result.

The re-adjudication of RECORD will be the subject of an extraordinary 2-day FDA advisory committee meeting next week on June 5 and 6. GlaxoSmithKline posted a summary of the results on its website last October, but its presence was not generally known until the publication of an article in BioCentury on Tuesday.

The meeting next week may turn out to be the last major episode of the rosiglitazone controversy that began in 2007 when a New England Journal of Medicine meta-analysis raised concerns that people taking rosiglitazone might be at increased risk for myocardial infarction. The first author of that paper, Steve Nissen, has remained the most vocal critic of the drug and of the RECORD trial. RECORD was designed to demonstrate the safety of rosiglitazone, but critics of the trial — including Nissen and, ultimately, FDA reviewers — raised numerous questions about the conduct of the trial and the validity of the data. Following a 2-day FDA advisory panel in 2010, rosiglitazone was withdrawn from the market in Europe and its use was severely restricted in the U.S.

The FDA also required GSK to commission the independent re-adjudication of RECORD that now resides on the company’s website. The re-adjudication was performed by the Duke Clinical Research Institute (DCRI). According to BioCentury, “GSK said it does not typically publicize data put on its clinical trial registry and added that the Duke researchers are planning to submit the data for publication.”

Here is the conclusion of the DCRI re-adjudication:

As concluded by the independent DCRI RECORD CEC group, there was no evidence of treatment effect on all-cause mortality or cardiovascular plus unknown mortality. The results of the primary analyses and extensive sensitivity analyses using the re-adjudicated outcomes were consistent with the original RECORD results and did not show statistically significant differences between the RSG and the MET/SU groups for the primary composite of CV death (+unknown), MI or stroke and the individual components. Using both original definitions and new contemporary definitions for re-adjudication, RSG group had a numerically lower incidence of the composite MACE endpoint, higher incidence of MI events, and lower incidence of strokes compared with the MET/SU group.

As reported here last week, Nissen will not be participating in the panel and he is accusing the FDA of stacking the committee in favor of rosiglitazone. Nissen doesn’t believe the re-adjudication can truly confirm the safety of rosiglitazone. As he told me last week:

GSK supplied the files used by Duke to re-adjudicate the RECORD Trial. Given the unblinded nature of the study, how can this process be viewed as independent? Duke could only adjudicate what was provided to them by GSK. Given the pending court cases against GSK, the company was strongly incentivized to provide the information in a way designed to bias the outcome.

 

Partial Rosiglitazone/RECORD Chronology

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May 28th, 2013

Interpretations Differ Over Study of Coenzyme Q10 in Heart Failure

Coenzyme Q10 (CoQ10) may be beneficial in heart failure (HF), according to the results of the Q-SYMBIO study presented this past weekend at the Heart Failure 2013 meeting in Lisbon, Portugal. But the results should be viewed with a critical eye, say experts.

A possible role for CoQ10 in the treatment of HF has long been proposed. A recent meta-analysis found that CoQ10 may improve ejection fraction (EF) in HF patients, but the authors warned that “the results should be interpreted with caution” due to the small number of studies and patients included in the analysis.

Q-SYMBIO is now the largest trial to date of CoQ10 in HF in the modern era. SA Mortensen presented results from 420 patients with class III or IV HF who were randomized to CoQ10 three times daily or placebo. After two years there was a significant reduction in the incidence of major adverse cardiovascular events in the CoQ10 group: 14% (29 patients) in the CoQ10 group versus 25% (55 patients) in the placebo group (hazard ratio 2.0, CI 1.3-3.2, p=0.003). Mortensen also reported a significant reduction in overall mortality: 9% (18 patients) in the CoQ10 group versus 17% (36 patients) in the placebo group (HR 2.1, CI 1.2-3.8, p=0.01). There were also significant reductions in cardiovascular mortality (p=0.02) and HF hospitalizations (p=0.05).

In an ESC press release, Mortensen said: “CoQ10 is the first medication to improve survival in chronic heart failure since ACE inhibitors and beta blockers more than a decade ago and should be added to standard heart failure therapy.” CoQ10, he said, “is a natural and safe substance, corrects a deficiency in the body and blocks the vicious metabolic cycle in chronic heart failure called the energy starved heart.”

But the results of Q-SYMBIO are “not practice changing” Aldo Maggioni told MedPage Today. He pointed to the small number of patients and events in the trial. “You cannot change clinical practice all over Europe basing your conclusion on that.”

 

Categories: Heart Failure
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May 28th, 2013

Selections from Richard Lehman’s Literature Review: May 28th

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.

NEJM  23 May 2013  Vol 368

Mechanisms of Acute Coronary Syndromes and Their Implications for Therapy (pg. 2004): The “blocked pipes” metaphor for coronary heart disease is so embedded in our thinking that it’s quite a challenge to persuade people—even doctors—to realise that the most dangerous places in the coronary arteries are usually not the places which look narrowest on angiograms. On the contrary, the most likely places for acute ulceration and clot formation are the soft fatty uncalcified lesions that may not even cause much apparent stenosis. If only we had better methods for identifying them. You can read all about this—and much else—in a really helpful single-author update on mechanisms of acute coronary syndromes, which is well worth seeking out if you are not a subscriber.

BMJ  25 May 2013  Vol 346

The Gap in Life Expectancy from Preventable Physical Illness, Including CVD, in Psychiatric Patients: This is the most shocking and shaming medical paper I’ve read for a long time: a survey of the gap in life expectancy for preventable physical illness in psychiatric patients. It comes from Western Australia, which presumably enjoys the same standards of psychiatric care as the rest of the rich world. “When using active prevalence of disorder (contact with services in previous five years), the life expectancy gap increased from 13.5 to 15.9 years for males and from 10.4 to 12.0 years for females between 1985 and 2005. Additionally, 77.7% of excess deaths were attributed to physical health conditions, including cardiovascular disease (29.9%) and cancer (13.5%). Suicide was the cause of 13.9% of excess deaths.” This is a scandal which needs urgent further investigation: are we becoming indifferent to physical illness and early death in the mentally ill? And are the newer drugs like olanzapine and quetiapine that we hand out so liberally actually contributing to an epidemic of cardiovascular disease in these patients?

Ann Intern Med  21 May 2013  Vol 158

Comparative Effectiveness of Multivessel CABG and Multivessel PCI (pg. 727): If you have stable coronary artery disease, your choices lie between optimal medical therapy, percutaneous coronary intervention (which generally means drug-eluting stents these days) or coronary artery bypass surgery. As a certain number of cardiologists read these reviews, I will avoid entering this minefield and simply give you the conclusions of this study of 105 156 propensity score–matched Medicare patients aged 66 and over who were followed up between 1992 and 2008. “Patients with diabetes, heart failure, peripheral arterial disease, or tobacco use had the largest predicted differences in survival after CABG, whereas those with none of these factors had slightly better survival after PCI.”

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May 24th, 2013

Rivaroxaban Gains Approval in Europe for ACS Indication

Rivaroxaban (Xarelto, Bayer) has been approved in Europe for the prevention of atherothrombotic events (cardiovascular death, myocardial infarction, or stroke) following an acute coronary syndrome (ACS). The drug was approved at a dose of 2.5 mg twice-daily and should be used in combination with standard antiplatelet therapy. Rivaroxaban is now the only oral anticoagulant to receive an ACS indication.

The approval is based on data from the pivotal ATLAS ACS 2-TIMI 51 trial. In the United States, where Xarelto is marketed by Johnson & Johnson, the FDA has twice rejected an ACS indication for rivaroxaban.

The new indication joins the already-approved indications for higher doses of rivaroxaban for the prevention of venous thromboembolism in patients undergoing elective hip or knee replacement surgery, for the treatment of (and prevention of recurrent) deep vein thrombosis and pulmonary embolism, and for stroke prevention in patients with atrial fibrillation.

“We know that thrombin levels remain elevated long after an ACS event, leaving patients at risk. In the ATLAS ACS 2-TIMI 51 study, we’ve shown that treating these patients with a low dose of rivaroxaban in combination with standard antiplatelet therapy targets both pathways of clot formation providing more complete long-term protection, including significant reduction in mortality risk,” said C. Michael Gibson, the Principal Investigator of the ATLAS ACS2-TIMI 51 trial, in a Bayer press release. “This approval marks an important shift in the way we deliver protection to patients who are at risk of a secondary atherothrombotic event.”

 

Categories: Anticoagulation
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May 24th, 2013

Spinning RECORD: Battle Over Rosiglitazone Heats up Two Weeks Before Crucial FDA Meeting

Battle lines are being drawn two weeks before a highly unusual two-day FDA advisory committee meeting to discuss the contentious diabetes drug rosiglitazone (Avandia, GlaxoSmithKline [GSK]). This will be the second time an FDA panel has wrestled with the fate of the drug and expectations have been that the discussion will once again be heated.

But at least one source of fierce criticism won’t be participating in the panel. Steve Nissen, who originally raised concerns about the drug and who has remained the most consistent critic of the drug, will not participate in the deliberations or present to the committee. Early on Thursday, Nissen contributed a blog post on Forbes accusing the FDA of stacking the committee in favor of rosiglitazone. The FDA leadership, he says, is trying to use the meeting to “whitewash” its reputation:

The ostensible purpose of the June 5-6 Advisory Committee meeting is to consider the ‘re-adjudicated’ RECORD trial. However, this time the meeting seems systematically designed to absolve the drug of harm and the CDER leadership of any responsibility for ignoring the public health hazard of Avandia. The current effort is intended to ‘whitewash’ the Avandia scandal and re-write history. Certain respected and independent members of 2010 Advisory Committee have been recused from the 2013 meeting. I requested the opportunity to present an independent analysis to the Committee, but was denied and offered a 5-minute statement in the ‘open public hearing.’

Keen observers should compare the roster of this new committee to the 2010 hearings to determine which participants have been re-invited and which have not. Similarly, assess whether prominent drug safety experts within FDA, such as Dr. David Graham, are listed as speakers or excluded. Finally, will any GSK consultants address the panel?”

By the end of the day on Thursday both the FDA and GSK had published responses to Nissen. Here is the FDA’s explanation for why it did not invite Nissen to present at the meeting:

During the planning of the upcoming June 2013 AC meeting on rosiglitazone, Dr. Nissen contacted FDA staff and requested that he be invited as a guest speaker. To clarify the basis for his request, FDA staff asked Dr. Nissen to summarize what he proposed to present to the committees. Dr. Nissen indicated that he would summarize all of the available data on the CV safety of rosiglitazone; discuss the limitations of an attempt to readjudicate an old clinical trial; review any discrepancies between the adjudicated RECORD trial and the investigator-reported events; and discuss the public health implications of any decision to remove restrictions on the use of rosiglitazone.

FDA staff reviewed Dr. Nissen’s proposed topics and concluded they did not warrant a slot as an FDA guest speaker. The content of his proposed topics is expected to be covered by other speakers as agency staff plan to summarize the available data on the cardiovascular safety of rosiglitazone at the committee meeting, and multiple FDA speakers will address their review of the readjudication of RECORD trial based on the study reports submitted to the Agency.

FDA staff provided information to Dr. Nissen on how to request time to speak during the open public hearing portion of the meeting. Thus, Dr. Nissen was offered the same opportunity that is available to all members of the public interested in sharing their perspectives and opinions. It is our current understanding that Dr. Nissen has declined this opportunity.”

GSK said that “many inaccuracies exist in Dr. Nissen’s commentary and need to be addressed.” The company specifically denied the multitude of reports over the years that it had suppressed negative data about rosiglitazone. The GSK response offers one potentially very important piece of news. The main focus of the June 5-6 hearing will be the re-adjudication of the RECORD trial performed by the Duke Clinical Research Institute. No public disclosure of the results of the re-adjudication have been made, and in the normal course of events the details of the re-adjudication, along with the rest of the committee’s briefing documents, would appear two days before the start of the hearing on the FDA website. But FDA staff, advisory panel members, and the drug sponsor (GSK) have almost certainly already seen the re-adjudication. In its statement, GSK flatly states that the re-adjudication confirms the safety of rosiglitazone:

The RECORD study is the largest clinical trial designed to evaluate the cardiovascular safety of Avandia. The study conclusions have now been confirmed through a re-examination by one of the leading independent institutions in the country (Duke Clinical Research Institute). In the accepted hierarchy of evidence generation, the results of a randomized, controlled clinical trial usually take precedence over other forms of evidence such as meta-analysis and observational studies. Despite some limitations of trial design, including the open label nature of the study, RECORD remains the only randomized trial of cardiovascular outcomes for Avandia at this time. The confirmation of the RECORD results by the independent re-examination support a positive risk/benefit profile for Avandia for the treatment of type 2 diabetes in appropriate patients.”

It remains to be seen whether this is more RECORD spinning or an accurate summary of the Duke re-adjudication.

In sharp contrast to these posts, the American College of Cardiology sent a letter earlier in the week to the FDA that acknowledges the heated controversy without taking a controversial position or inflaming passions. The ACC acknowledges “that the events that triggered the FDA’s request for readjudication of the RECORD clinical trial data is atypical, but the College agrees that it exposed some concerns regarding the long-term safety of drugs and how it is studied and monitored, both before and after approval.” The ACC cites the rosiglitazone controversy as a perfect reason to utilize the ACC’s experience with registries to enhance safety monitoring.

Relevant Links:

Partial Rosiglitazone/RECORD Chronology

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