May 1st, 2015
Dear CardioExchange Members:
In 2009, NEJM Group launched CardioExchange as an experiment in creating an online community and fostering professional, clinical dialogue. The experiment was a valuable one, and for the past six years, CardioExchange has offered a unique perspective on developments in cardiology — shaped, in large part, by contributing members’ perspectives. Under the leadership of Dr. Harlan Krumholz, CardioExchange has been a forum for lively and articulate conversation about matters of importance to practicing clinicians and their patients.
Six years in, it’s time to look for ways to apply some of our community’s lessons elsewhere within NEJM Group. We will start this transition on May 15, when we will no longer post new material at blogs.jwatch.org/cardioexchange. As of May 29, the site will no longer be available. However, the CardioExchange archive will be posted on the NEJM Journal Watch site.
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Jonathan Adler, MD
Clinical Strategy Editor, NEJM Group
May 1st, 2015
In a 1966 interview for CBS News, Martin Luther King, Jr., described a riot as “the language of the unheard.” King believed that nonviolence was the path to change, but he also knew that unrest in America’s urban communities is a symptom of economic inequality and of the unequal treatment that too many black men, women, and children in our country face.
This week’s events in Baltimore (and in other cities this past year) have given me greater insight into the constant state of vulnerability that many of our black brothers and sisters feel every day. The anger and frustration expressed in both nonviolent and violent protests in Baltimore reveal a hard truth: A growing number of our fellow citizens, especially if they are black, feel unheard, unseen, unrecognized — invisible.
What happened in Baltimore goes beyond policing. It has more to do with growing, systematic inequalities that disempower large swaths of our population. Young black men, especially, face a toxic combination of racism, poverty, economic inequality, and injustice — in an environment where many leaders cannot even agree that a minimum wage of $7.25 an hour is unlivable and that healthcare should be a universal right.
As members of a community of physicians and researchers, we would be foolish to treat patients in a vacuum, without awareness of the social, economic, and political determinants of health. Poor patients with chronic conditions of heart failure, end-stage renal disease, or COPD are hard-pressed to be “compliant” with their treatment regimens, given their many competing priorities.
Last year, after attending the American Heart Association’s Quality and Cardiovascular Outcomes (QCOR) conference in Baltimore, a dozen of us stayed on to volunteer at the Bea Gaddy Family Center, a multiservice center for homeless families and other people in need of food. The director, Cynthia Brooks, eloquently explained that health is often the fourth or fifth priority for many of the center’s clients, who contend each day with finding food, shelter, safety from drug violence, and jobs.
I called Cynthia the day after the Baltimore riots, which occurred within one block of her center. She was saddened by the damage and the loss, noting that most Baltimore residents were horrified at the violence in their beloved city. Anger at the death of Freddie Gray was warranted, no doubt, but looting and arsons only worsened the social and economic climate in blighted areas of Baltimore. The torched CVS stores were used by many poor residents to shop for food and needed medications, especially in sections that are “food deserts.” Other CVS stores in the area were temporarily closed, further depriving poor residents of this central source of food and medicine. The implications of the riots are clear — fewer jobs as shops are closed, longer distances to walk or take a bus to get basic necessities, and the likelihood of even less future economic development in the poorest parts of Baltimore.
When I asked Cynthia what the local community needs most, she did not discuss the issue of policing. Her response was quick and clear — the critical need for mentors for Baltimore’s youth. She explained that many young people in the area have no relationships with anyone outside the blighted sections of their city — so, for them, hope is an illusory concept, and many have simply stopped pursuing their dreams.
If every child had a big brother or sister, if every teen had a mentor who was employed in a stable job, Cynthia explained, it would transform Baltimore by breaking down walls of division between rich and poor, black and white. It would allow residents who live outside the inner city to move from viewing residents in poor parts of East and West Baltimore as “the other” to seeing them as civic partners. Bonds would be forged, friendships built, and relationships sustained so that each would understand the other better. Cynthia acknowledged that mentors are only a first step, but nonetheless a vital one in giving employers and businesses the courage to double-down on bringing economic development to blighted parts of Baltimore, thereby benefiting the entire city.
The socioeconomic and political determinants of health have been well studied by physician researchers, social scientists, public health experts, and policymakers. As a physician, I believe that we are in a unique position to be mentors for disadvantaged youth in our cities. Many of us also have important civic and business connections, and we should work hard to engage business leaders in thinking creatively and courageously beyond the usual profit motive.
If we can build relationships as big brothers and big sisters, if we start conversations on both sides of the economic divide, if we encourage businesses to see investments in poor communities as an opportunity to make a fair profit while paying fair wages, we will give our poorest patients a better chance to remain healthy and lead a full life. In doing so, we can move from decrying the riots as destructive to promoting constructive peace for people who feel unheard and powerless.
JOIN THE DISCUSSION
What role do you think physicians should play in areas with great economic challenges?
May 1st, 2015
CardioExchange welcomes this guest post from clinical cardiologist Anthony Pearson. This piece originally appeared on his blog, The Skeptical Cardiologist.
Over the years I’ve had a number of patients tell me that they prefer to take over-the-counter (OTC) dietary supplements containing “natural” cholesterol lowering ingredients rather than the statin drug I have prescribed.
Red yeast rice (RYR) is a common ingredient in these supplements and is promoted widely and enthusiastically across the internet and in supplement or natural-food stores for the purpose of lowering cholesterol and heart disease risk.
RYR has been used for centuries in China for coloring, food, and medicine. It is made by fermenting red rice with a specific type of yeast (Monascus purpureus) and contains chemicals that are similar to prescription statin medications. One of these, called monacolin K, is chemically identical to the statin drug lovastatin (brand name Mevacor).
The History of Statin Drug Development
The history of the discovery and isolation of lovastatin, the first FDA-approved statin, is worthy of a digression here as I think it illustrates the process of discovery, isolation, and characterization of a chemical that becomes a safe and effective treatment.
Akira Endo, whose research over decades was crucial to discovering statins, writes that he was inspired by Alexander Fleming, who discovered penicillin in the blue-green mold belonging to the genus Penicillium in 1928. He writes: “Although no metabolites that inhibited any enzymes involved in cholesterol synthesis had been isolated previously, I speculated that fungi like molds and mushrooms would produce antibiotics that inhibited HMG-CoA reductase. Inhibition of HMG-CoA reductase would thus be lethal to these microbes.”
Endo began analyzing thousands of molds and fungi for biologically active chemicals that would inhibit HMG-CoA reductase. In 1971, after studying 3800 different strains of fungi, he found a promising candidate: citrinin. Unfortunately, “Citrinin strongly inhibited HMGCoA reductase and, furthermore, lowered serum cholesterol levels in rats. However, the research was suspended because of its toxicity to the kidneys.”
Endo spent 10 more years isolating another promising HMG-CoA reductase inhibitor — compactin — from mold and studying it in rats and other animals. Compactin demonstrated marked cholesterol-lowering properties in dogs and monkeys and in the few humans who received it, but the pharmaceutical company he worked for shut down the project after it appeared that, in doses 200 times what were considered appropriate, it increased lymphoma risk in dogs.
The large pharmaceutical company Merck got wind of Endo’s studies with compactin, studied his data, and realized the potential of similar but safer HMG-CoA reductase inhibitors. Drugs that inhibited HMG-coA reductase were now being termed statins. Merck set out to find its own statins and in February 1979 isolated a statin very similar to compactin in chemical structure, called mevinolin, from the fungus Aspergillus terreus.
Working seperately, Endo also isolated another statin in February 1979 — monacolin K — from cultures of Monascus ruber (RYR). In the fall of the same year, it was confirmed that monacolin K and mevinolin were the same compound (later both changed to lovastatin).
The drug showed dramatic activity in lowering LDL cholesterol, with very few side effects. This led Merck to begin large-scale clinical trials of lovastatin in patients at high risk and long-term toxicity studies in dogs in 1984. The drug dramatically reduced cholesterol levels and was well tolerated. No tumors were detected. In 1987, Merck gained FDA approval and lovastatin became the first commercial statin.
Since then, six other statin drugs, some of which are synthesized in the laboratory rather than isolated from mold, have been approved for human therapy. These drugs have prevented thousands of heart attacks and contributed to the dramatic drop in cardiovascular deaths seen in developed countries over the last 30 years.
RYR and Cholesterol Lowering
This brings us back to RYR and its ability to lower cholesterol. Small studies using a version of RYR that contained lovastatin have demonstrated a reduction in cholesterol compared to placebo. However, because many RYR supplements contained lovastatin (also called monacolin), in May 1998 the FDA ruled that Cholestin (the RYR product used in the studies showing cholesterol-lowering benefit) was not a dietary supplement but an unapproved drug.
As a result, Pharmanex removed RYR from Cholestin. Since that ruling, the FDA has written warning letters to several other dietary supplement manufacturers to remove drug claims or eliminate RYR with high lovastatin levels from their products, including Heart and Cholesterol (Mason Vitamins, Miami Lakes, Florida), Cholestrix (Sunburst Biorganics, Baldwin, New York), Red Yeast Rice and Red Yeast Rice/Policosanol Complex, and Red Yeast Rice (Nature’s Way Products, Inc.)
A study in 2010 found levels of monacolins varying one-hundred fold in 12 RYR preparations available commercially (total monacolins (0.31-11.15 mg/capsule), monacolin K (lovastatin) (0.10-10.09 mg/capsule), and monacolin KA (0.00-2.30 mg/capsule).
Even more worrisome was that four products had elevated levels of citrinin. You remember citrinin, don’t you? That is the chemical that Endo initially identified as a candidate for a cholesterol-lowering drug but rejected because it was causing kidney failure in his rats.
Because of limited government oversight and variable manufacturing processes, one can also expect that the same manufacturer will have marked variation of monacolin content and citrinin from batch to batch or bottle to bottle.
Problems With Alternative Medicine In General
These problems with RYR supplements are typical of all supplements. As the the authors wrote: “Our results highlight an important issue with red yeast rice and many other alternative medicines: the lack of standardization of active constituents. Standardization of ingredients is difficult for several reasons: (1) There are variable growth and/or culture conditions and differences in harvesting and processing among manufacturers; (2) medicinal agents from natural sources are complex substances with many chemical constituents, many of which have unclear roles in their pharmacologic activity; and (3) different manufacturers may standardize products to amounts of 1 or 2 chemicals thought to be active ingredients, while other constituents are not standardized and may also have biologic and pharmacologic activity.”
One has to ask, given this background: Why would a patient choose to take a “natural” OTC supplement containing an unknown amount of both a) effective cholesterol-lowering chemicals and b) potentially toxic extraneous chemicals over the precisely formulated, carefully regulated, fully studied, pure statin drug available by prescription? It’s especially baffling to me when one considers that lovastatin comes from RYR. Thus it would have to be considered “natural.”
Akira Endo spent decades carefully identifying the effective and safe chemical portion of RYR. It is now available as a generic costing pennies per pill. We know exactly how many milligrams you are consuming. We know what benefits to expect and what side effects can occur based on studies in hundreds of thousands of patients who have taken a similar dosage.
You are much better off taking the prescribed statin drug than RYR.
April 30th, 2015
A new study uncovers some potentially important new details about the association between sugared drinks and diabetes.
In a paper published in Diabetologia, researchers in the U.K. report on more than 10 years of followup of more than 25,000 adults. During the course of the study 847 participants went on to develop diabetes. Instead of relying on a food-frequency questionnaire, as in most earlier studies, the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study used dietary information obtained from seven-day food diaries filled out by the study participants. According to the authors, diaries are more reliable and allow for a more detailed analysis of different dietary components.
Overall, each 5% increase in the amount of calories coming from sugar-sweetened beverages (SSB) was associated with an 18% increase in diabetes. Soft drinks, sweetened milk beverages, and artificially sweetened beverages (ASB) were all associated with a greater than 20% increase in diabetes. However, the association with artificially sweetened beverages lost statistical significance when the researchers took into account people’s weight, suggesting that the association was likely “an artifact of reverse causality where those who are overweight or obese and at higher risk of chronic disease consume a higher amount of ASB than those at lower risk.” Replacing soft drinks and sweetened-milk drinks with water or unsweetened tea or coffee would significantly cut the rate of diabetes, the authors calculated.
The association of tea and coffee has not been well studied in the past. The new study found that sweetened tea or coffee had no association with diabetes while unsweetened tea or coffee had an inverse association. The study is also the first to link sweetened-milk beverages to diabetes, but the authors write that the association is “unsurprising” since added sugar contributes more than half the sugar contained in milkshakes and flavored milks.
The authors conclude that “it is now timely and appropriate to consider population-based interventions to reduce SSB consumption and increase the consumption of suitable alternative beverages.”
In a press release, the senior author of the paper, Nita Forouhi, said, “The good news is that our study provides evidence that replacing a daily serving of a sugary soft drink or sugary milk drink with water or unsweetened tea or coffee can help to cut the risk of diabetes, offering practical suggestions for healthy alternative drinks for the prevention of diabetes.”
April 29th, 2015
Each year, approximately 400 cardiovascular outcomes researchers gather at the American Heart Association’s Quality of Care and Outcomes Research (QCOR) meeting to discuss and debate some of the most pressing concerns in American medicine today, including healthcare disparities. This remarkable venue showcases outstanding science and affords the entire research community an opportunity to connect again with old friends and new colleagues.
This year promised to be no different. With a slate of amazing abstracts and presentations scheduled for this Wednesday afternoon, the stage was set for an outstanding program that reflected the hard work of devoted individuals. Many of us were particularly excited to return to Baltimore, one of America’s truly great cities, where the QCOR meeting has been held several times.
Two days prior to the beginning of the conference, however, circumstances changed. Protests and riots erupted after the funeral of Freddie Gray, a 25-year-old black man who lost his life last week while in the custody of the Baltimore police. After thoughtful deliberation by AHA staff on the ground in Baltimore, the meeting was canceled.
This was an unfortunate but appropriate decision. And in all honesty, it wasn’t very tough. By Monday evening, downtown hotels were in lockdown, Maryland’s governor had declared a state of emergency, and the National Guard had been called. With the prospect of more protests and ongoing concerns about escalation of the riots, the safety of our attendees played a paramount role in this decision — as it should.
That said, so much hard work goes into each of these meetings by its planners, participants, and attendees. Naturally, I am saddened that this year’s event could not proceed. QCOR’s cancelation is a comparatively small setback within a larger tragedy, but in the wake of the decision, I do want to reflect on a few issues and recognize some important contributors.
For many young researchers, QCOR is a first chance to present their work nationally. I feel saddest about being unable to witness these presenters engage us. The slate of abstracts we were set to review for the Young Investigator Award and Travel Award competitions represented a strong group.
We also had planned to publish two outstanding papers in Circulation: Cardiovascular Quality and Outcomes, simultaneously with their oral presentations: Tim Fendler’s “Incidence and Predictors of Cognitive Decline in Patients with Left Ventricular Assist Devices” and Masahiko Hara’s “Different Impacts of Time From Collapse to First Cardiopulmonary Resuscitation on Outcomes After Witnessed Out-of-Hospital Cardiac Arrest in Adults.”
We will miss a number of outstanding plenary and concurrent sessions, including a stroke session that actually has further brought patients into the QCOR’s planning and implementation process.
I am also very disappointed that we will not have the chance to reflect on and celebrate the career of John Spertus, a colleague and friend who is receiving the QCOR Lifetime Achievement Award this year. He has dedicated his life to outstanding scholarship and mentorship. He is simply the best.
For those of you who had planned to attend, I’d ask a favor. As you get back a bit of your calendar during the next couple of days, please try to take an afternoon to review some of the wonderful abstracts that were set to be showcased at QCOR — and to recognize that work. We will work hard during the next day or so to try to provide you with a single web link connecting you to all of this wonderful science. We are also working with the AHA and its staff, who have been extraordinarily helpful, to salvage as much of the programming as we can for the fall’s larger Scientific Sessions, including the possibility of celebrating John’s wonderful career in the way he deserves.
Please remember that QCOR will return in 2016, in Phoenix, coupled with the EPI/Lifestyle meeting for the first time. We are excited to have this opportunity to share our event with them, given the many natural synergies between our communities in the area of population health. We hope to exploit these connections to help both research communities grow even stronger.
Lastly, take some time to keep the city of Baltimore in your prayers. Many of us have taken the time to get to know and explore Baltimore during previous years. Last year, Paul Chan wrote a thought-provoking piece in Circulation: Cardiovascular Quality and Outcomes about the experiences of a few members of our research community who visited the Bea Gaddy Family Center and the Viva House — two local, private organizations that provide food, shelter, and social and economic support to some of Baltimore’s poorest residents. Since the latest wave of unrest started, I have thought a lot about the issues raised in that piece, including the need for us to refocus our goals and priorities in healthcare disparities research.
Baltimore is a beautiful place that, like all great cities, has its flaws. The recent events are a setback for Baltimore, but even in this dark hour there are amazing stories of leaders calming the unrest. The Charm City will bounce back, and so will we.
Brahmajee Nallamothu, a cardiologist at the University of Michigan and the Ann Arbor VA Medical Center, is the chair of this year’s AHA QCOR meeting.
JOIN THE DISCUSSION
Share your reflections on the recent events in Baltimore and on QCOR’s cancelation.
April 28th, 2015
Late Monday afternoon, Merck released the top line results of TECOS, the cardiovascular outcomes trial with its diabetes drug sitagliptin (Januvia). The company said that the trial “achieved its primary endpoint of non-inferiority for the composite cardiovascular (CV) endpoint.” Merck announced only one additional detail: “Among secondary endpoints,” they reported, “there was no increase in hospitalization for heart failure in the sitagliptin group versus placebo.”
The FDA has been wrestling for a number of years now with the problem of the cardiovascular effects– whether positive or negative– of diabetes drugs. The first large outcomes trials with two other DPP-4 inhibitors, saxagliptin (Onglyza, AstraZeneca) and alogliptin (Nesina, Takeda Pharmaceuticals), were reported in 2013 and found no impact of the drugs on cardiovascular outcomes.
However, a troubling signal emerged suggesting a possible raised risk for heart failure, though the endpoint was not rigorously studied in the trials. Two weeks ago the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee reviewed the trials and rejected recommendations from critics for new restrictions on their use, but they did say that information from the two clinical trials should be added to the drugs’ labels.
Sanjay Kaul, a frequent FDA adviser, pointed out the paradox of the large commercial success of sitagliptin despite the absence of any proven clinical benefit:
“So, we have a drug that yields modest glycemic efficacy, is neutral with respect to cardiometabolic factors (lipids, weight, blood pressure), does not kill you or land you in a hospital, and yet is a blockbuster drug nearly 5 times over! What is the big news here? That it does not kill you or land you in a hospital? Or that it is a blockbuster drug nearly 5 times over without evidence of microvascular or macrovascular outcome benefit? Miracle of medicine or miracle of marketing?”
April 28th, 2015
Despite a lack of supporting evidence many patients with acute venous thromboembolism (VTE) receive inferior vena cava filters to prevent pulmonary embolism (PE). Now a new study published in JAMA offers no evidence of benefit for the use of these devices in a high-risk population already receiving anticoagulant drugs.
A group of French physicians randomized nearly 400 hospitalized patients with acute, symptomatic PE to receive a retrievable inferior vena cava filter in addition to anticoagulation or anticoagulation alone. At 3 months, recurrent PE had occurred in 6 patients (3%) in the filter group compared with 3 patients (1.5%) in the control group. The two-fold increase in risk with the filter was not statistically significant. All 6 cases in the filter group and 2 of the 3 cases in the control group were fatal. Between three and six months there was one additional case of recurrent PE in each group.
The authors note that the increased use of filters has likely been fueled by the availability of retrievable inferior vena cava filters. Their results show that these devices confer “no benefit in terms of pulmonary embolism recurrence or mortality” in these patients.
Based on previous studies the authors say they had anticipated a much higher rate of recurrent PE, about 8%, in the control group. “We believe that the low rate of events observed in the control group of our study is consistent with contemporary care, indicating that modern management with full-dose anticoagulation therapy is likely very effective even in patients usually considered to be at high risk for recurrence, rendering unnecessary additional therapy such as inferior vena cava filters,” they write. In addition, “we believe that our negative findings likely reflect the low event rate with effective anticoagulation alone rather than lack of filter efficacy.” They note, however, that they excluded patients who were unable to take an anticoagulant or who had a recurrence despite adequate anticoagulation.
April 27th, 2015
A new analysis of available data from early trials with PCSK9 inhibitors adds to the growing evidence showing that this much-anticipated new class of drugs dramatically lowers LDL cholesterol and offers additional preliminary evidence showing that they are safe and may confer a mortality benefit. But, the authors and other outside experts warn, the outcome findings should be interpreted with caution until long-term, dedicated outcome studies are completed.
In a paper published in Annals of Internal Medicine, a group of researchers combined data from 24 phase 2 and 3 trials that included more than 10,000 patients randomized to treatment with or without a PCSK9 inhibitor. The headline for the study will undoubtedly be the statistically significant 55% reduction in mortality. But it is less clear if the same reports will focus on the fact that there were only 40 deaths in all the trials and the absolute rate of death was extremely low: the death rate was 0.31% (19 of 6187 patients) in the PCSK9 inhibitor group and 0.53% (21 of 3971 patients) in the control group (OR, 0.45; CI 0.23 – 0.86, p= 0.015). There was a similar, but not statistically significant, reduction in cardiovascular mortality and a statistically significant reduction in myocardial infarction.
To no one’s surprise, people treated with PCSK9 inhibitors had a large 47% reduction in LDL cholesterol. In the trials in which PCSK9 inhibitors were tested as an addition to ezetimibe, the PCKSK9 inhibitors resulted in an average 36% reduction in LDL.
In an accompanying editorial, Miguel Cainzos-Achirica and colleagues at Johns Hopkins note that the findings are consistent with previous efforts to assess outcomes with the PCSK9 inhibitors. But they warned that the “included trials were of small or moderate size and mostly had short follow-up periods.” They also pointed out that “little is known about the long-term adverse effects of sustained PCSK9 inhibition, including neurocognitive outcomes and diabetes.”
The cost of PCSK9 inhibitors will also be an important factor in their clinical role, say the editorialists. Although the future cost of PCSK9 inhibitors when they become available is unknown, statins are now mostly available in inexpensive generic formulations and ezetimibe will become generic in the near future.
“Ultimately,” the editorialists conclude, “trials with long follow-up periods together with real-world experience will be necessary to better characterize the safety profile of PCSK9 inhibition, as well as the patient’s tolerance of chronic subcutaneous injections.”
Asked to comment on the study, Sanjay Kaul said that the “bottom line” is that “without data derived from dedicated, long-term outcome studies with prespecified hypotheses, the results of such analyses should be interpreted with a grain of salt!”
April 27th, 2015
CardioExchange is pleased to reprint this selection 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 Intern Med Apr 2015
A Contemporary Appraisal of the Heart Failure Epidemic in Olmsted County, Minnesota, 2000 to 2010 (OL): In a couple of week’s time I’m due to give a talk entitled “Heart Failure and Other Misnomers.” The epidemiology of heart failure is a mass of perplexity. Rule number one is to forget the systolic ejection fraction and go by clinical criteria like those from Framingham. The EF may help align your management strategy with the clinical trials (usually very inaccurately), but you will then ignore at least half of the patients who have the clinical syndrome. Let me shut up now and commend the Olmsted County cohort to your attention. Between 1 January 2000, and 31 December 2010, the age—and sex—adjusted incidence of HF declined by 37.5%. Do you hear this shouted with joy by every cardiologist in the land? No, because they are all Jeremiahs, or rather Jonahs, like the Old Testament prophet who went into a sulk when his preaching succeeded so well that God didn’t have to smite the people of Nineveh. But the people who got heart failure in Olmstead continued to die at the same rate. Why? Because heart failure is a signal for the gradual approach of death, and our treatments for it, though numerous, are largely futile in the elderly. We fail to switch our humanity on and address it as a form of dying. We are incentivized to pile on drugs and monitor everything by the day. Personally I would prefer to die with less molestation and more kindness, accepting mortality as inevitable and wishing for an honourable truce rather than a pointless battle. And in fact most of these patients, though they died as surely as in the past, ended up with something other than “heart failure” as their primary cause of death.
Lancet Apr 14 2015
Ex-Vivo Perfusion of Donor Hearts for Human Heart Transplantation (OL): I prefer the title of another editorial on the website: “Donor heart preservation: straight up, or on the rocks?” As you might have guessed, it’s about a study of donor hearts flown in on ice versus fresh local hearts. The chilled ones can work very nicely if carefully prepared. Oh, and could I have a twist of lemon with mine, please.
April 27th, 2015
The original version of this post appears on Rory J. Spiegel’s blog EM Nerd.
Reading the literature on endovascular therapy for acute ischemic stroke is like being on a small seafaring vessel trying to map the shoreline through dense fog. The fog occasionally lifts, and you glimpse the shore, only for obscurity to return. Recent publications on endovascular therapy for acute ischemic stroke have shown a definitive benefit of mechanical reperfusion therapy, but each study is so incomplete that it’s hard to see anything more than a general appearance of benefit. The premature truncation of trials, too early to definitively characterize the benefits and risks, obscures the finer details.
The MR CLEAN trial, published earlier this year in the NEJM and discussed ad nauseam in previous posts, marked the first of what is now a litany of trials demonstrating a benefit of endovascular therapy in acute ischemic stroke (1). MR CLEAN’s release resulted in the subsequent premature cessation of a number of key trials examining endovascular therapy. Although all of those trials boast impressive results, each stopped enrollment prematurely, not due to a preplanned interim analysis but rather because of MR CLEAN’s positive results. ESCAPE and EXTEND-IA were the first to halt enrollment and hastily publish their results (2,3).
More recently, the NEJM has reported findings from the next two trials that were prematurely stopped after MR CLEAN’s success. The first is the SWIFT-PRIME trial, by Saver et al (4). This trial’s initial results were presented at the 2015 International Stroke Conference, alongside those from EXTEND-IA and ESCAPE. Like its counterparts, SWIFT-PRIME enrolled patients who presented with large ischemic infarcts and radiographically identified occlusions in the terminal internal carotid artery (ICA) or the first branch (M1) of the middle cerebral artery (MCA). In addition, patients had to have a favorable core-to-ischemic penumbra ratio on perfusion imaging. Patients were enrolled if they were able to undergo endovascular interventions within 6 hours after symptom onset.
Like ESCAPE and EXTEND-IA, SWIFT-PRIME had impressive results. The authors boast a 25% absolute difference in the number of patients with a modified Rankin Scale (mRS) score of 0–2 at 90 days. Though notable, the definitive magnitude of effect is hardly concrete. The authors cite a number needed to treat (NNT) of 4 to have one more patient alive and independent at 90 days, and an NNT of 2.6 to have one patient less disabled. These calculations derive from the dichotomous and ordinal analyses, respectively. Although the authors cite impressive P values (<0.001), the confidence interval surrounding this 25% point estimate is far broader (11%–38%). Therefore, the NNT is somewhere between 2.6 and 9 patients.
EXTEND-IA and ESCAPE have similarly wide confidence intervals surrounding their point estimates (4). EXTEND-IA’s confidence interval is 8% to 50% surrounding a point estimate of 31% (2); ESCAPE has a confidence interval of 13% to 34% surrounding its 23.7% point estimate (3). All three of these trials were stopped early secondary to MR CLEAN’s results. And though both EXTEND-IA and ESCAPE came close to reaching their predefined sample sizes, SWIFT-PRIME was stopped before its first interim analysis (with fewer than 200 patients enrolled) (4).
Like EXTEND-IA, ESCAPE, and SWIFT-PRIME, the second of the relevant trials just published in NEJM — the REVASCAT trial, by Jovin et al., was also stopped prematurely secondary to the publication of MR CLEAN. In fact, even though REVASCAT failed to reach the prospectively determined efficacy threshold for stopping the trial, at the first interim analysis, the data and safety monitoring board felt that, given the MR CLEAN data, there was a loss of equipoise and that further randomization would be unethical (5).
Despite its apparent success, REVACAT has results that are far less impressive than those from EXTEND-IA, ESCAPE, or SWIFT-PRIME. The REVASCAT trial planned to enroll 690 patients presenting to the emergency department (at 4 centers across Catalonia) with symptoms consistent with a large-vessel stroke that could be treated with endovascular therapy within 8 hours after symptom onset. Unlike EXTEND-IA, ESCAPE, or SWIFT-PRIME, the REVASCAT trial did not use perfusion imaging to select patients with favorable areas of salvageable tissue. Rather, it employed CT angiography to identify occlusion in the ICA or the M1 branch of the MCA — and it utilized the less accurate ASPECT score, derived from the initial noncontrast CT, to assess potential for viable ischemic tissue (5).
REVASCAT enrolled 206 patients before its premature termination. And like the three trials before it, it showed a statistically significant improvement in mRS at 90 days in the patients who underwent endovascular therapy. The REVASCAT trial cites an absolute increase in the number of patients with an mRS of 0–2 by 15.5%. This is surrounded by a confidence interval of 2.4% to 28.5%. Furthermore, unlike the previous three trials, which either boast an outright survival benefit or demonstrate trends in favor of endovascular therapy, REVASCAT showed an impressive 4.8% absolute increase in the rate of death within 7 days after randomization (5).
The results of REVASCAT are far from positive. If it were not part of the optimistic fervor that currently surrounds endovascular therapy, REVASCAT might even be considered a negative trial. Why were the results of REVASCAT far less impressive than those of EXTEND-IA, ESCAPE, and SWIFT-PRIME? Was it just random chance, the true effect size of endovascular therapy falling somewhere between the two extremes of the 13.5% difference observed in MR CLEAN and the 31% in EXTEND-IA? Or, rather, was it that the patient populations selected in EXTEND-IA, ESCAPE, and SWIFT-PRIME led to trials’ success? EXTEND-IA, ESCAPE, and SWIFT-PRIME all used some form of advanced imaging to determine the size of viable ischemic tissue (2,3,4). MR CLEAN and REVASCAT used only the CTA to identify a reachable lesion, and the noncontrast CT to determine tissue viability (1,5). If any one of those trials were followed to completion, the results would be likely to yield a better understanding of which patients will benefit from endovascular therapy and the exact magnitude of this benefit.
This is a problem of certainty. Our faith in endovascular interventions was so unyielding that at the first sign of success we claimed victory and discontinued any further scientific inquiries. The bloated results from EXTEND-IA, ESCAPE, and SWIFT-PRIME are the consequences of this premature resolution. We know that trials stopped early for benefit are likely to overestimate the effect size of the treatment in question. In fact, the smaller the sample size is at the time of closure, the greater the amplification will be (6). In 1989, Pocock et al. showed this to be a mathematical inevitability (7), later validated by Bassler et al. in a meta-analysis of 91 trials stopped prematurely for benefit (8). Bassler et al. revealed that the degree of embellishment was directly related to the size of the sample population at trial cessation and independent of the quality of the trial or the presence of a predetermined methodology for early stoppage.
Although the exact patient population that stands to benefit from endovascular therapy is unclear, it is certainly a small fraction of the overall patients who present to the ED with acute ischemic stroke. All patients enrolled in the REVASCAT trial were also included in a national registry known as SONIA. SONIA catalogued 2576 patients (only 15.6% of all stroke patients seen) with some form of reperfusion therapy during the period when REVASCAT enrolled patients (5). The vast majority of those patients (2036; 79%) received only t-PA; Of the 540 patients (21%) who underwent endovascular therapy, only 111 (24%) were eligible for enrollment in the REVASCAT trial. Only 4.3% of the patients in the SONIA registry, and only 0.3% of all stroke patients during the 2-year period, were eligible for inclusion in REVASCAT (5). This accounts for a small minority of the stroke patients presenting to the ED with symptoms consistent with acute ischemic stroke. Notably, the REVASCAT trial’s eligibility criteria are more inclusive than those used in EXTEND-IA, ESCAPE, and PRIME-SWIFT, which if you believe were successful because of their inclusion criteria, would account for an even smaller portion of stroke patients presenting to the ED. In the SWIFT-PRIME trial, it took 2 years and 39 centers to recruit 196 patients (4). That comes out to 0.2 patients per center per month. EXTEND-IA and ESCAPE recruited only 0.3 and 1.44 patients per center per month, respectively (2,3).
Even the greatest skeptics will find it difficult to deny the definite treatment effect observed in the recent trials of endovascular therapy in acute ischemic stroke. The magnitude of this effect has yet to be defined. Its borders are obscured by the murkiness of small sample sizes, extreme selection bias, and prematurely stopped trials. This invasive procedure also has clear harms. Both the REVASCAT trial and the earlier trials of endovascular therapy (IMS-III, SYNTHESIS, and MR RESCUE) demonstrated that when performed on the wrong patient population, endovascular therapy will not only fail to provide benefit, but it may also be harmful (5,9,10,11).
In short, this is simply not a yes or no question. The resources required to build an infrastructure capable of supporting endovascular therapy on a national level are daunting. Although we have reached a certain degree of clarity that endovascular therapy for acute ischemic stroke provides benefit, how well and in whom remains murky. The overeager truncation of important trials has left us adrift in a sea of fog, unsure whether the shoreline is a warm, welcoming beachfront or a rocky coast set to demolish our vessel upon arrival.
- Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372(1):11-20.
- Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372 (11): 1009-18
- Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372(11): 1019-30
- Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015; Apr 17: epub ahead of print
- Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 Hours after symptom onset in ischemic stroke. N Engl J Med 2015; Apr 17: epub ahead of print
- Guyatt GH, Briel M, Glasziou P, Bassler D, Montori VM. Problems of stopping trials early. BMJ 2012; 344:e3.
- Pocock SJ, Hughes MD. Practical problems in interim analyses, with particular regard to estimation. Control Clin Trials 1989; 10(suppl 4):209-21S.
- Bassler D, Briel M, Montori VM, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA 2010; 303(12):1180-7.
- Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013; 368(10):893-903.
- Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013; 368(10):904-13.
- Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013; 368(10):914-23.
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