November 22nd, 2010
SHARP: A Tale of Two Press Releases
Larry Husten, PHD
Two press releases were issued about the SHARP trial : one from Merck, the much-maligned and criticized manufacturer of Vytorin (the combination of ezetimibe and simvastatin), and one from the group running the trial, the highly-respected Clinical Trials Service Unit (CTSU) at Oxford. Here’s the surprise: compared to the Oxford press release, the Merck release is a paragon, fully disclosing important details about the trial. The Oxford release is also a paragon, but of a different type. It’s a model of a press release that tries to manipulate the reader to adopt its view of the trial and ruthlessly suppresses all information and perspective that doesn’t support its view.
Let’s review the deficiencies of the Oxford press release:
The press release headline touts the “big benefits” shown in the trial, and the first sentence begins: “Around a quarter of all heart attacks, strokes, and operations to open blocked arteries could be avoided in people with chronic kidney disease by using the combination of ezetimibe and simvastatin. . . .” The problem here is simple: the trial showed no such thing. The actual reduction in events was 16% and not 25%. The larger reduction in events comes from an extrapolation by the study investigators based on their estimates of the reduction that would have been achieved if every patient who was supposed to take Vytorin took the drug for the entire trial period. But, of course, that never happens, either in clinical trials or in real life, so the “big benefit” touted in the headline is pure fiction and manipulation. Such a calculation might be appropriate in the discussion section of a paper, or at the bottom of a press release or other communication if properly explained and qualified. But as the lead of a press release conveying the initial results of an important clinical trial, it is inexcusable.
The Oxford press release touts the benefits of adding ezetimibe to simvastatin, but in fact, SHARP is completely unable to make any assessment of the relative effects of ezetimibe and simvastatin versus simvastatin alone. With the exception of a small group of patients who were first randomized to simvastatin monotherapy during the first year of treatment and were then randomized to either placebo or Vytorin, all patients in the trial received either the Vytorin pill or placebo. It is therefore completely inappropriate for them to state:
“The SHARP results are also relevant to people who don’t have chronic kidney disease. The combination of ezetimibe and a statin produced similar benefits to those resulting from the same LDL cholesterol reduction achieved with a high dose of a statin. Since the lower the cholesterol the bigger the risk reduction, these results suggest that patients who remain at high risk of major atherosclerotic events despite maximal statin therapy may benefit further from adding ezetimibe to their current statin regimen.”
SHARP has no relevance to patients without chronic kidney disease, and it tells us almost nothing about the value of adding ezetimibe to simvastatin.
It is astonishing that the Oxford press release has so much to say about things that weren’t tested in the trial and has nothing to say about a number of major issues that were addressed in the trial. In particular, the press release doesn’t report the primary endpoint of the trial. As has been discussed on CardioBrief and elsewhere, earlier this year, near the completion of the trial, the SHARP investigators sought to change the primary endpoint (from first major vascular event to first major atherosclerotic event) and the planned statistical analysis of the trial to avoid producing a false-negative result. The trial sponsor, Merck, did not endorse their plan, and officially, the primary endpoint remains unchanged. The SHARP investigators, however, chose to ignore the actual primary endpoint, or any discussion about the change in the primary endpoint, in the press release.
The Oxford press release is severely deficient in another way: it presents no hard numbers for the results, including the actual number or percentage of events of either the primary or alternate endpoint or the individual components of the composite endpoints. The press release also includes no discussion about the statistical power of the trial or any of the findings. In essence, the investigators ask the readers of the press release to take their conclusions on faith.
By contrast, the Merck press release is both more detailed and more restrained. It explains (in a slightly confusing manner) the issue of the attempted change in endpoint and presents the actual percentages and P values for both the original primary endpoint and the alternate Oxford endpoint. The Merck press release also includes the information, completely absent in the Oxford press release, that in this study of patients with kidney disease, treatment with Vytorin had absolutely no effect on the progression of kidney disease.
In the past, I’ve been as critical as anyone of Merck’s handling of the Vytorin controversy. The interesting thing here is that Merck appears to have played it straight, while the Oxford CTSU doesn’t seem to have learned any of the lessons from earlier episodes of this long-running imbroglio.
November 22nd, 2010
Send Us Your Vexing Cases
Anju Nohria, MD
No matter how evidence-based we strive to be in our decision making, we all know that the patient in front of us is never exactly like those enrolled in large clinical trials. Thus at CardioExchange, we have highlighted cases where the application of evidence-based medicine and treatment guidelines is not straight-forward. And often, to our delight and to everyone’s benefit, you’ve responded with your views and your questions on how these patients should be treated.
Now, we want to build on that community by turning the tables: You show us the cases, ask the questions, and tell us what happened in the end. Submit a vexing case to us by e-mailing us here. If your case is selected to be presented and discussed, we’ll edit the content for clarity and HIPPA compliance, and you’ll get a great opportunity to interact with your colleagues.
We hope that these cases will engender exciting and even controversial conversations that will allow us all to learn from each other and ultimately improve the care of our patients.
November 22nd, 2010
A Clinical Conversation with Harlan Krumholz: CardioExchange and AHA
CardioExchange Editors, Staff
In a Journal Watch Clinical Conversations podcast, Editor Harlan Krumholz discusses CardioExchange and what he thinks of the top research presented at AHA 2010. Hear what Harlan has to say about anacetrapib, rivaroxaban, Tele-HF, and more.
Also, see Harlan’s posts at Forbes on remote patient monitoring (including his own Tele-HF study) and on the DEFINE study.
November 22nd, 2010
Treating Resistant Hypertension: Singe – Don’t Stent – The Renal Artery
Richard A. Lange, MD, MBA
For years, interventional cardiologists (and radiologists) have been stenting renal arterial stenoses in patients with resistant hypertension, despite evidence that doing so does not lower blood pressure. It appears we had the right organ (the kidney), but we’ve been doing the wrong procedure. We should have been delivering a singe, not a stent.
Advances in endovascular catheter technology now allow us to access the sympathetic nerves located in the renal arterial adventitia, making possible selective denervation of the human kidney with radiofrequency energy delivered in the renal arterial lumen. In the multicenter Symplicity HTN-2 trial, catheter-based renal denervation resulted in significant reductions in blood pressure in patients with treatment-resistant essential hypertension.
The investigators randomized 106 patients with treatment-resistant hypertension (i.e., systolic blood pressure ≥160 mm Hg [≥150 mm Hg for patients with diabetes] despite the use of ≥3 antihypertensive drugs) to renal sympathetic denervation or continued medical therapy.
Renal denervation resulted in impressive reductions in office-based measurements of blood pressure (average decline, 32/12 mm Hg at 6 months) as well as home-based (average decline, 20/12 mm Hg) and ambulatory (average decline, 11/7 mm Hg) measurements, whereas no reductions were observed in the control group. Importantly, no serious procedure-related complications occurred.
In short, renal denervation resulted in an impressive reduction in blood pressure in these patients with otherwise refractory hypertension.
Would you integrate percutaneous renal denervation into your practice now, or do you need validative findings from additional studies?
November 20th, 2010
SHARP Shows Benefit for Vytorin in Chronic Kidney Disease
Larry Husten, PHD
The long-awaited SHARP study has turned up positive results for Vytorin (ezetimibe and simvastatin) in a population of patients with chronic kidney disease. Results of SHARP (Study of Heart and Renal Protection) were presented on Saturday at the American Society of Nephrology meeting in Denver and were scheduled to be posted online on the trial’s website.
SHARP compared Vytorin to placebo in 9,438 patients with chronic kidney disease and found that Vytorin-treated patients had a significant (p=0.0010) 16.1% reduction in the incidence of first major vascular event (nonfatal MI or cardiac death, stroke, or revascularization). A first major vascular event occurred in 15.2% of patients in the Vytorin group compared to 17.9% of patients in the placebo group.
It should be noted that the SHARP steering committee sought to change the primary endpoint (from first major vascular event to first major atherosclerotic event) and the planned statistical analysis of the trial to avoid producing a false negative result. The trial sponsor, Merck, did not endorse their plan. However, the SHARP investigators reported a similar 16.5% reduction (p=0.0022) in the proposed new endpoint, which occurred in 13.4% of the placebo group compared to 11.3% in the Vytorin group.
It should also be noted that the primary analysis of major vascular events did not include approximately 1,000 patients who took simvastatin monotherapy for the first year of the trial before being re-randomized to either Vytorin or placebo. When this group is included in the analysis the results remain substantially the same, producing a 15.3% reduction (p=0.0012), with a major vascular event occurring in 17.6% of the placebo group versus in 15.1% of the Vytorin group.
During the first year, when compared to placebo, LDL dropped by 40% in the Vytorin group and 28% in the simvastatin group. At 2.5 years, LDL cholesterol was reduced by 30% in the Vytorin group.
About a third of patients in the trial were undergoing dialysis. Among patients not on dialysis at the start of the study, there was no difference in the progression to end-stage renal disease between Vytorin and placebo.
The investigators reported no unexpected safety issues. Cancer was reported in 9.4 % of patients in the Vytorin group versus 9.5% in the placebo group.
November 19th, 2010
Darvon and Darvocet Withdrawn from U.S. Market
Larry Husten, PHD
The FDA announced today that Xanodyne Pharmaceuticals had agreed to withdraw Darvon and Darvocet from the U.S. market. The drugs contain the opioid propoxyphene, which the FDA said “puts patients at risk of potentially serious or even fatal heart rhythm abnormalities.” The FDA said it had asked generic manufacturers of propoxyphene to withdraw their products also.
November 19th, 2010
Will This Be the HDL Decade? REVEAL Revealed, Mixed Results for Apo-A1
Larry Husten, PHD
For a long time, HDL has been called the “good cholesterol.” Are we now entering the HDL decade? Two HDL-related trials were presented Wednesday at the AHA, and an array of additional trials are planned or underway, prompting the lead investigator of one of those trials, Chris Cannon, to speculate that this decade may be the HDL decade.
Whether or not the 2010s turn out to be the HDL decade, there can be no question that the last day of AHA was HDL day. In addition to the excitement generated by Cannon’s trial, DEFINE, Merck, and Oxford announced a major mega-trial to test the drug used in that trial, anacetrapib, in 30,000 patients. Less easy to interpret were the results of a small study, ASSERT, looking at a novel compound and its ability to boost HDL.
REVEAL Revealed
At a news conference at the AHA, and in a press release, Oxford’s Rory Collins announced the REVEAL study, which will test anaceptrapib in 30,000 patients with heart disease on a background of statin therapy. Scheduled followup is 4 years, but if the clinical effect is as powerful as the effect on lipids, some experts believe the trial could be stopped earlier for efficacy.
DEFINE Defined
DEFINE was the hot topic of the day at the AHA. One program committee member told me that the trial was scheduled for Wednesday to keep people at the meeting. It also helps to have a charismatic investigator like Chris Cannon. There’s a reason some people in Boston call Chris Cannon TIMI TV. He gives great interviews and delivers perfect sound bites. The DEFINE press release quoted Cannon’s summation of the lipid effects of anaceptrapib in the trial: “Anacetrapib has a knock-your-socks-off effect on HDL and a jaw-dropping effect on LDL.”
At the press conference, Cannon preserved his quotability quotient. Asked about the difference in revascularizations in DEFINE (8 in the anaceptrapib group, 28 in the control group), Cannon told reporters: “When I saw those numbers, I actually sent a text message to Dr. Braunwald.” Cannon texted Braunwald (and that in itself is an interesting fact) that he (Cannon) thought this was the first real signal that CETP inhibition might actually have a clinical effect. Cannon told reporters that it was a “hint in reading the tea leaves.” (It should be noted that revascularization is a notoriously soft end point, and that although investigators were blinded to lipid levels during the study, patients and treating physicians may well have been influenced by their knowledge of lipid levels.)
Mixed Results for ASSERT
The ASSERT study tested the efficacy, safety, and tolerability at 12 weeks of RVX-208, an oral drug that stimulates apo A-1 synthesis. Theoretically, this should enhance HDL-mediated reverse cholesterol transport, which some believe is the body’s natural mechanism to reverse atherosclerosis. But, as many experts have pointed out, HDL is extremely complex and there remain large areas of uncertainty about the way it works.
ASSERT, which randomized 299 patients to placebo or one of 3 doses of RVX-208, missed its primary endpoint and raised a few safety concerns, but also exhibited some effects with fascinating potential. The primary endpoint — the median change in Apo A-1 from baseline — was not significantly higher in the combined RVX -208 groups than in the placebo group. In the high-dose RVX-208 group, total HDL increased only modestly, by 5%.
The other note of caution is that liver enzymes became elevated in 18 patients taking RVX-208. Study investigator SJ Nicholls reported that the elevations were reversed when the patients went off the drug, but obviously this area will be watched closely in future trials.
But here’s where the news gets better for RVX-208: In the high-dose group, large HDL increased by 21% and small HDL decreased by 4%. What this might mean is that the drug is in fact enhancing reverse cholesterol transport. In addition, at 12 weeks the investigators observed no plateau in the effect of RVX-208 in raising HDL components, suggesting that changes in these components might well grow larger over a longer period.
The discussant for the trial, Eliot Brinton, said that a drug like RVX-208 “that has a modest effect on HDL levels might have a large clinical effect.” Brinton talked about the difficulty of measuring the “‘goodness’ of good cholesterol” and pointed out that there is “no consensus in the field of what to measure or how to measure it.” HDL is complex in its composition, metabolism, and function, and “we are unable to accurately assess any HDL-related intervention in terms of its actual impact on atherosclerosis and cardiovascular risk.” he said. Apo A-1 “probably ‘knows’ how to prevent atherosclerosis,” he continued, and “it was reasonable to do a larger study.”
Steve Nissen, another highly visible cardiologist with a penchant for good quotes, told reporters that he would be leading the next trial of RVX-208, an IVUS study. Details are not yet decided, but Nissen mentioned a 26-week study as one possibility. Nissen said he was encouraged by both the DEFINE and ASSERT results and that HDL remains an exciting area of research.
November 18th, 2010
APPRAISE-2 Apixaban in ACS Study Discontinued Due to Increased Bleeding
Larry Husten, PHD
Bristol-Myers Squibb announced on Thursday evening the discontinuation of APPRAISE-2, the phase 3 trial comparing apixaban to placebo in patients with acute coronary syndrome. The decision was based on a recommendation from the data monitoring committee based on “a clinically important increase in bleeding among patients randomized to apixaban,” according to the company press release.
Robert Harrington, co-chair of the APPRAISE-2 steering committee, said the decision should not impact the “promising results” in phase 3 trials of apixaban in patients with venous thromboembolism and atrial fibrillation.
November 17th, 2010
Negative Trials, Positive Impact
John Ryan, MD
Several Cardiology Fellows who are attending this week’s AHA meeting are blogging together on CardioExchange. The Fellows include Susan Cheng, Madhavi Reddy, John Ryan, and Amit Shah. Check back often to learn about the biggest buzz in Chicago this week — whether it’s a poster, a presentation, or the word in the hallways. You can read the preceding post
After the sessions today, I grabbed a cup of coffee with a few friends before they flew out of town. After going through many of the results of the studies presented at the meeting, we recognized a common theme: there were a lot of negative studies. PFO closure is no different from medical therapy (CLOSURE 1), there is no benefit of clopidogrel dosing based on platelet function testing (GRAVITAS), Omega 3 is not effective for A Fib, and N-acetylcysteine NAC) makes “absolutely no difference” in contrast-induced nephropathy (ACT). However, in this setting, these negative (or, perhaps more appropriately, “neutral”) studies are likely to have a substantial effect on patient care. Or, at least one would expect that they should. Each of the studies was well designed and well executed. Will physicians now feel comfortable with not closing PFOs in patients with cryptogenic stroke? Defensive medicine has long generated concern among physicians and has been shown to significantly influence practice. So, over the next few months, it will be interesting to see whether these studies are sufficiently powerful to reassure physicians not to give NAC before coronary angiogram in patients with mild renal insufficiency. Because, after, all NAC does not have any adverse side effects. One of my colleagues commented that this is because “it also has no positive effects…you know what else has no side effects? Placebo.” What are people’s thoughts?
After the excitement surrounding my inaugural talk yesterday, today was more relaxing. The Chicago-land AHA had invited 187 high school students to the scientific sessions, and 11 fellows from the city volunteered to show them around the exhibition hall and talk to them about careers in science. I had a group of twelve students from north of the city. I did not know exactly how to tell them about the things we do. I was going to try and identify with them by talking about iCarly and Justin Bieber, but I suspected that it might not go over very well. So, instead I decided to give them an inspiring talk about all the great things that have been discovered and presented at AHA, such as Paul Dudley White, Goldstein and Brown, and Mason Sones. It was a lot of fun trying to engage these high school seniors in cardiology and telling them tales to inspire them. However, at the same time it was also a challenge to explain our everyday issues, such as MIs, arrhythmias, or heart failure, and break them down to a basic level. What do people normally do to try and inspire high schoolers to consider a career in medicine? Or would you even recommend a career in medicine, with the current changes that we are going through? I told them about the 8 years of training that follow medical school, and their eyes opened wide as they considered that it would take them almost twice as many years as the age they are right now to become cardiologists. I tried to put it in context by saying that master chef apprenticeships are just as long, hoping that they were Iron Chef fans. Needless to say, they were not. Nonetheless, I hope that I still made a positive impression on these students.
Thanks to all who have commented on our blogs over the last few days. This has been a fun venture, and I hope you have enjoyed it as much as we have.
November 17th, 2010
Early Career Day: Review from the Epi Breakout Session
Amit Shah, MD, MSCR
Several Cardiology Fellows who are attending this week’s AHA meeting are blogging together on CardioExchange. The Fellows include Susan Cheng, Madhavi Reddy, John Ryan, and Amit Shah. Check back often to learn about the biggest buzz in Chicago this week — whether it’s a poster, a presentation, or the word in the hallways. You can read the preceding post
At Early Career Day, I found a session on applying for training grants to be particularly interesting and useful. The presenters discussed not only that K Awards are quite competitive, but also that only about one third of those who win a K award go on to win an R01, and then obtaining a second R01 is still quite difficult. Given the pressures that academics face to obtain tenure and protected time, the whole process seems quite daunting, especially in light of possible future cuts in research funding.
On the flip side, I have often seen good work get rewarded, and many hard-working people become successful with perseverance. At the session, I learned some important keys to success:
1) Have innovative and clear specific aims that are related to, but do not depend on, each other.
2) Be concise and use diagrams that clearly state important concepts. Diagrams additionally break up the text and are a nice break on the eyes for the reviewers.
3) Discuss your grant proposal with the program officer, as she or he may give you helpful information.
The list goes on…for anyone applying for a training grant, I highly recommend watching the talks online if/when they become available. Look for the Epi breakout session for Early Career Day.
I think that applying for a training grant will be quite challenging, but it is my hope that in the end, if the science is excellent — and if the proposal is submitted to the right place — it will get funded. Perhaps this belief is too naive, but I find it more motivational than the other way around!
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