SHARP: A Tale of Two Press Releases 2

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 reelease, 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 at the top of the press release 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 restrained. It explains (in a slightly confusing manner) the issue about 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.

Here’s the Oxford press release:

Good news for kidney patients

World’s largest kidney disease trial shows big benefits from reducing cholesterol

Denver: 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 to lower blood cholesterol levels. That’s the conclusion from the world’s largest ever randomized trial in kidney disease.

Unveiling the key findings today (Saturday 20 November) at the American Society of Nephrology, the trial’s principal investigator Professor Colin Baigent said: “This is excellent news for patients who have kidney disease. It was already known that cholesterol-lowering could reduce the risk of heart attacks, strokes and the need for surgery to unblock arteries in people with normal kidney function. But, this trial now shows that cholesterol-lowering has similar effects in people with chronic kidney disease, irrespective of the severity of their illness. Taking ezetimibe plus simvastatin long-term would avoid around one quarter of heart attacks, strokes and operations to unblock arteries, leading to their prevention in at least 250,000 people with kidney disease worldwide each year.”

The Study of Heart and Renal Protection (SHARP) involved almost 9,500 volunteers aged 40 or over with chronic kidney disease recruited from 380 hospitals in 18 countries. Patients included in the trial had lost at least 50% of their normal kidney function, with a third of them requiring dialysis treatment. None had had a previous heart attack or needed bypass surgery or “stents” to unblock their heart arteries. Volunteers in this double-blind placebo-controlled trial were randomly allocated to take either cholesterol-lowering therapy with a tablet containing ezetimibe 10mg daily and simvastatin 20mg daily, or matching dummy “placebo” tablets. Study treatment and follow-up continued for an average of 5 years.

SHARP was designed, conducted and analysed independently of all funding sources by the Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU) of Oxford University, with guidance by an independent Steering Committee that included many of the world’s leading kidney specialists. The study was supported by Merck (known as MSD outside of the US and Canada), who also supplied the study treatments, with additional support from the Australian National Health and Medical Research Council (NHMRC), the British Heart Foundation (BHF) and the UK Medical Research Council (MRC). Planning began in the mid-1990s, with two pilot studies followed by a main study that started in 2003 and ended in September of this year.

Summary of major findings:

  • The patients allocated to take ezetimibe plus simvastatin had one-sixth fewer heart attacks, strokes or operations to unblock arteries (“major atherosclerotic events”), with similar reductions observed in all types of patient studied.
  • During this long trial, the proportion of patients who stopped taking their allocated treatment was about one third, but this was not generally due to side-effects and was the same for both real and dummy treatments. If taken without interruption, however, ezetimibe plus simvastatin could have even larger effects than were seen in SHARP, potentially reducing risk by about one quarter.
  • Adding 10mg daily of ezetimibe to 20mg daily of simvastatin produced a large reduction in LDL (“bad”) cholesterol safely. This combination treatment may be particularly good for kidney patients, as it avoids the possibility of side-effects with high statin doses.
  • There was no support for previous concerns with ezetimibe about possible adverse effects on cancer, and no evidence of an increased risk of muscle or liver problems.

Professor Baigent said: “We knew from previous trials that statins reduce the risk of heart attacks and strokes in people with normal kidney function. But it had been widely believed that raised cholesterol was not an important cause of heart disease or stroke in people with chronic kidney disease, so that lowering cholesterol might not be beneficial for them. SHARP now provides the first direct evidence that cholesterol-lowering is indeed effective in kidney patients, and that the benefits are substantial.”

SHARP co-principal investigator, Dr Martin Landray said that SHARP provides reassuring evidence about the safety of the ezetimibe and simvastatin combination: “There was no evidence of any serious adverse effects and, in particular, no support for earlier concerns that ezetimibe might cause cancer. SHARP shows clearly that the large cholesterol reduction produced with this treatment is safe, and provides similar benefits to those seen in people with normal kidney function.”

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.

Chronic kidney disease affects about one in 10 people worldwide. People with chronic kidney disease tend to have a very high risk of developing heart disease or experiencing a stroke. Until now, it has not been known how to prevent these conditions in such patients. Consequently, it is likely that the SHARP results will result in cholesterol-lowering treatment being used widely in this large group of high-risk people who were previously not being given such treatment.
Weblink: www.sharpinfo.org

ENDS

Here’s the Merck press release:

YTORIN® (ezetimibe/simvastatin) Significantly Reduced Major Vascular Events in Patients With Chronic Kidney Disease in a New 9,000-Patient Investigational Study

SHARP is the First and Only Prospective Clinical Study in Patients With Chronic Kidney Disease to Show That an LDL Cholesterol-Lowering Medicine Reduced Major Vascular and Atherosclerotic Events
DENVER, CO, Nov. 20, 2010 – In a new investigational study of VYTORIN®(ezetimibe/simvastatin), the cholesterol-lowering medicine from Merck (known as MSD outside the US and Canada), VYTORIN 10/20 mg reduced the incidence of first major vascular events — defined as non-fatal heart attacks or cardiac death, stroke or any revascularization procedure — by a highly statistically significant 16.1 percent compared to placebo (p=0.0010). This was the pre-specified primary endpoint of the study. The SHARP (Study of Heart and Renal Protection) study involved more than 9,000 patients who, on average, had advanced or end-stage chronic kidney disease (CKD), and is the first prospective clinical study in patients with CKD to demonstrate the benefit of lowering LDL (bad) cholesterol on major vascular events. The results were presented today during Renal Week, the American Society of Nephrology’s annual meeting, by Professor Colin Baigent, F.F.P.H., F.R.C.P., and Dr. Martin Landray, Ph.D., F.R.C.P., the principal investigators of SHARP, from the Oxford University Clinical Trial Service Unit (CTSU), Oxford, England.

“This is an important study,” said Dr. Peter S. Kim, Ph.D., president, Merck Research Laboratories. “Patients with CKD have a high risk of ischemic vascular disease and increased rates of heart attack, stroke, other cardiovascular events and revascularization procedures. In SHARP, the investigational use of VYTORIN significantly reduced the risk of these events in a spectrum of patients with chronic kidney disease — and this was the first demonstration that an LDL-cholesterol lowering medicine could do so.”

Merck plans to seek regulatory approvals for the use of VYTORIN in patients with CKD based on the results from the SHARP study. VYTORIN is currently indicated as adjunctive therapy to diet for the reduction of LDL cholesterol in patients with primary hypercholesterolemia or mixed hyperlipidemia.

VYTORIN is a prescription medicine and should not be taken by people who are hypersensitive to any of its components. VYTORIN should not be taken by anyone with active liver disease or unexplained persistent elevations of serum transaminases. Women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant should not take VYTORIN.

SHARP is the largest prospective study of LDL-lowering in patients with CKD
SHARP is the largest clinical trial of VYTORIN conducted to date, and enrolled a total of 9,438 patients under the care of a nephrologist for chronic kidney disease. One-third of patients were undergoing dialysis therapy for end-stage kidney disease at the time of entry, and the remaining patients were pre-dialysis patients with advanced CKD with an average estimated glomerular filtration rate (a measure of kidney function) of 26.5 ml/min/1.73m2. Patients with a prior history of myocardial infarction or a revascularization procedure were excluded from the study. At randomization, the average LDL cholesterol of all patients enrolled in SHARP was 108 mg/dL.

Patients were initially randomized in a ratio of 4:4:1 to receive VYTORIN 10/20 mg daily versus placebo versus simvastatin 20 mg alone (for purposes of assessing drug safety). After one year, patients initially allocated to simvastatin alone were re-randomized to either VYTORIN 10/20 mg daily or placebo for the remainder of the study period. Patients were followed for a median of 4.9 years.

The protocol-specified primary endpoint for the study was the incidence of first major vascular events, defined as the composite of non-fatal heart attack or cardiac death, stroke or revascularization procedure in the two groups randomized to VYTORIN or placebo at study initiation. (This analysis did not include patients initially randomized to simvastatin alone for the first year.) In the intention-to-treat analysis, VYTORIN reduced first major vascular events by 16.1 percent compared to placebo (p=0.0010). In the group that received VYTORIN (n=4,193) 15.2 percent of patients had a major vascular event, compared to 17.9 percent of patients taking placebo (n=4,191).

In addition, in the full study population of patients, including patients who took simvastatin alone for the first year and were then re-randomized to either VYTORIN or placebo, VYTORIN reduced first major vascular events by 15.3 percent compared to placebo (p=0.0012). The rate of major vascular events in patients taking VYTORIN (n=4,650) was 15.1 percent, compared to 17.6 percent of patients taking placebo (n=4,620).

Results on Major Atherosclerotic Events Also Presented
Based on information from clinical studies of other LDL-lowering medicines that became available after the original SHARP study protocol was implemented in 2003 and before the study ended, the independent SHARP Steering Committee determined that the most relevant “key outcome” for the study should be the incidence of first “major atherosclerotic events.” Major atherosclerotic events were defined as the combination of non-fatal heart attack, coronary death, ischemic stroke or any revascularization procedure; this analysis excluded non-coronary cardiac death and hemorrhagic stroke from the protocol-specified primary endpoint of major vascular events. (The Steering Committee’s rationale and statistical analysis plan are discussed in a paper published on-line in the American Heart Journal). In the intention-to-treat analysis, VYTORIN also reduced first major atherosclerotic events by 16.5 percent compared to placebo (p=0.0022). The rate of first major atherosclerotic events in patients taking VYTORIN (n=4,65) was 11.3 percent, compared to 13.4 percent in patients taking placebo (n=4,620).

In the first year of the trial, VYTORIN 10/20 mg lowered LDL cholesterol by 40 percent compared to placebo, while simvastatin 20 mg lowered LDL cholesterol by 28 percent versus placebo; the reduction achieved by VYTORIN was 30 percent greater than that achieved by simvastatin alone. After two and half years of treatment, which was approximately mid-way through the study, VYTORIN lowered LDL cholesterol by 32 mg/dL, or 30 percent from baseline, compared to placebo.

The researchers noted that the reduction in major vascular events and major atherosclerotic events based on the LDL-cholesterol reduction achieved with VYTORIN in SHARP was consistent with reduction of outcomes that would be predicted based on the recently published Cholesterol Treatment Trialists’ (CTT) meta-analysis of large-scale statin trials. The CTT analysis, published online in The Lancet, examined the relationship between LDL-cholesterol lowering and reduced rates of cardiovascular events.

One of the secondary endpoints for SHARP was the progression to end-stage renal disease (ESRD) among patients who were not yet on dialysis at the start of the study. A patient was considered to have progressed to ESRD if they started long-term dialysis or proceeded to kidney transplantation following randomization. On this endpoint, there was no difference between VYTORIN and placebo; 33.9 percent of patients receiving VYTORIN (n=3,117) proceeded to ESRD, compared to 34.6 percent of patients on placebo (n=3,130).

VYTORIN 10/20 mg Safety Profile Over the Nearly Five Years of Follow-up
In terms of assessing safety in SHARP, the researchers assessed reports of serious adverse events as well as adverse events that were pre-specified: cancer, myopathy with levels of creatine phosphokinase (CK) >10 x but ≤40 x upper limit of normal (ULN), and reports of myopathy with CK >40 x ULN, hepatitis, persistently elevated liver enzymes (ALT/AST >3 x ULN), complications of gallstones, other hospitalizations for gallstones, and pancreatitis without gallstones.

Overall, the safety profile of VYTORIN 10/20 mg in this study was consistent with the profile described in the current approved label.

VYTORIN (n=4,650) was comparable to placebo (n=4,620) in the incidence of cancer and cancer-related deaths: cancer was reported in 9.4 percent of patients taking VYTORIN versus 9.5 percent of patients taking placebo (p=0.89); mortality due to cancer was reported in 3.2 percent of patients taking VYTORIN versus 2.8 percent of patients taking placebo (p=0.20).

For other safety analyses that were pre-specified, VYTORIN was also comparable to placebo in the incidence of CK > 10 x but ≤ 40 x ULN (0.4 percent for VYTORIN versus 0.3 percent for placebo), CK >40 x ULN (0.1 percent in each group), hepatitis (0.5 percent for VYTORIN versus 0.4 percent for placebo), persistently elevated ALT/AST>3 x ULN (0.6 percent in each group), complications of gallstones (1.8 percent for VYTORIN versus 1.6 percent for placebo), other hospitalizations for gallstones (0.5 percent for VYTORIN versus 0.6 percent for placebo) and pancreatitis without gallstones (0.3 percent for VYTORIN versus 0.4 percent for placebo).

“Merck is proud to support clinical trials such as SHARP and we thank the Oxford University and the thousands of patients and health care professionals who participated in SHARP for their contributions to this study to address this important medical question for patients with CKD,” Kim said.

Important Information about VYTORIN
VYTORIN contains simvastatin and ezetimibe. VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo B, triglycerides and non-HDL cholesterol and to increase HDL cholesterol in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.

VYTORIN is not indicated to reduce major vascular events or atherosclerotic events in patients with chronic kidney disease. The prescribing information for VYTORIN states that it has not been shown to reduce heart attacks or strokes more than simvastatin alone.

No dosage adjustment is necessary in patients with mild or moderate renal impairment. Caution should be exercised when VYTORIN is administered to patients with severe renal insufficiency. VYTORIN should not be initiated in such patients unless the patient has already tolerated treatment with simvastatin.

VYTORIN is a prescription medicine and should not be taken by people who are hypersensitive to any of its components. VYTORIN should not be taken by anyone with active liver disease or unexplained persistent elevations of serum transaminases. Women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant should not take VYTORIN.

Muscle pain, tenderness or weakness in people taking VYTORIN should be reported to a doctor promptly because these could be signs of a serious side effect. VYTORIN should be discontinued if myopathy is diagnosed or suspected. To help avoid serious side effects, patients should talk to their doctor about medicine or food they should avoid while taking VYTORIN.

In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases were 1.7 percent overall for patients treated with VYTORIN and 2.6 percent for patients treated with VYTORIN 10/80 mg. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.8 percent overall and 3.6 percent for patients treated with VYTORIN 10/80 mg. These elevations in transaminases were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. Doctors should perform blood tests before, and periodically during treatment with VYTORIN when clinically indicated to check for liver problems. People taking VYTORIN 10/80 mg should receive an additional liver function test prior to and three months after titration and periodically during the first year.

Due to the unknown effects of increased exposure to ezetimibe (an ingredient in VYTORIN) in patients with moderate or severe hepatic insufficiency, VYTORIN is not recommended in these patients. The safety and effectiveness of VYTORIN with fibrates have not been established; therefore, co-administration with fibrates is not recommended. Caution should be exercised when initiating VYTORIN in patients treated with cyclosporine and in patients with severe renal insufficiency.

VYTORIN has been evaluated for safety in more than 10,100 patients in clinical trials. In clinical trials, the most commonly reported side effects, regardless of cause, included headache (5.8 percent), increased ALT (3.7 percent), myalgia (3.6 percent), upper respiratory tract infection (3.6 percent), and diarrhea (2.8 percent).

VYTORIN is available as tablets containing 10 mg of ezetimibe combined with 10, 20, 40 or 80 mg of simvastatin (VYTORIN 10/10, 10/20, 10/40 or 10/80 mg, respectively).

About Merck
Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.

Forward-Looking Statement
This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2009 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

VYTORIN® is a registered trademark of MSP Singapore Company, LLC.

Prescribing Information and Patient Product Information for VYTORIN® is available athttp://www.msppharma.com/msppharma/documents/vytorin_pi.pdf andhttp://www.msppharma.com/msppharma/documents/vytorin_ppi.pdf.

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2 comments

  1. I was a SHARP site investigator, and attended the oral presentation by the Oxford leaders of SHARP results at the ASN on Saturday. I thought the presentation was more like a sales pitch than a scientific academic discussion. I was stunned to see there was absolutely no reduction in total mortality (24.6 vs 24.1%), and the CV-related mortality was very tiny and also not significant (7.8 vs 8.4%). The rate of total deaths was higher in the vytorin arm. The Oxford leaders inappropriately presented Oxford’s imagined number to needed to treat (based on a 25% reduction in CV related events) without actually giving the real number to needed to treat. When called on the fact that there was no reduction in total deaths with treatment in >4500 patients for 5 years, one of the Oxford leaders blew it off, and said we weren’t powered to detect a reduction in total deaths! They were in fact powered (at 80%) to detect a 15% reduction in CV deaths from vytorin. The actual results were a reduction in deaths less than 1/2 of that, and they were more than balanced by more “other” deaths in the vytorin arm. By my calculation, one would need to treat 48 patients for 5 years at a cost of $288,000 to prevent one event, which is most likely to be a revascularization procedure – and you will not reduce the person’s likelihood of dying over those 5 years.
    Three hours after the program, I saw on-line where Merck had given Oxford another $150 million to do another lipid lowering trial.

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