SHARP Results Published in Lancet 4

The main results of SHARP (Study of Heart and Renal Protection) have now been published in the Lancet, following their preliminary presentation last November at the American Society of Nephrology meeting. The results are also posted online on the trial’s website.

In brief, SHARP randomized 9270 patients with chronic kidney disease (one-third of whom were on dialysis) to either placebo or the combination of simvastatin and ezetimibe. After a median followup of 4.9 years the rate of major atherosclerotic events (defined as nonfatal MI or coronary death, non-hemorrhagic stroke, or arterial revascularization excluding dialysis access procedures) was significantly reduced from 13.4% in the placebo group to 11.3% in the combination therapy group (RR 0.83, CI 0.74-0.94, p=0.0021).

For the individual components of the endpoint, there were nonsignificant differences in nonfatal MI  (3.4% for placebo versus 2.9% for combination therapy, p=0.12)  and CHD death (1.9% versus 2%, p=0.95). Non-hemorrhagic stroke was significantly reduced from 3.8% in the placebo group versus 4.6% in the combination group (p=0.01) and revascularizations were reduced from 7.6% in the placebo group to 6.1% in the combination group (p=0.0036).

In their discussion the SHARP investigators said that the SHARP results are “relevant… to most patients with chronic kidney disease” because “the proportional reduction in major atherosclerotic events produced by a given absolute reduction in LDL cholesterol is broadly similar irrespective of age, sex, diabetes, history of vascular disease, and presenting lipid profile.”

The authors further wrote that because previous trials with statins have found that the reduction in risk “is chiefly determined by the absolute reductions in LDL cholesterol,” and because ezetimibe “reduces LDL cholesterol by the equivalent of around three doublings of the statin dose,” ezetimibe “therefore offers a potentially useful method of increasing benefits in high-risk populations.”

In an accompanying comment, Kathryn Stevens and Alan Jardine offer a “pragmatic interpretation” of SHARP and recommend the use of lipid lowering therapy in CKD patients, including those who will progress to end-stage disease.” They note, however, that coronary disease plays only a relatively small role in the deaths of patients with advanced CKD, thereby limiting the ultimate effect of lipid lowering therapy in this group of patients.

James Stein sent the following comment to CardioBrief:

Simvastatin is a good drug, atorvastatin showed the same thing in 4D, it tells us nothing about ezetimibe.This study does not answer the question of whether or not they would have gotten the same result if they used simvastatin alone (ie, if ezetimibe had anything to do with the observed results) or if ezetimibe is safe.  But, it is notch on the belt in favor of the drug, because it is a RCT that used ezetimibe and reduced events.
The German Diabetes and Dialysis Study (4D) showed significant reductions in stroke and “all cardiac events” with atorva 20 mg daily – so it is an overstatement to say that they are “first and only prospective clinical study in patients with chronic kidney disease” to reduce atherosclerosis-related cardiac events as they did in their press release. The paper refined that to say “two trials of statin therapy “had not detected significant benefits in their primary outcomes.”  True enough, but not very compelling since the SHARP investigators changed their primary endpoint to essentially the secondary endpoint in 4D.    Indeed, the secondary endpoint in 4D (“all cardiac events”) was essentially the primary endpoint in SHARP.  Atorva had a similar relative benefit (18%) but a greater absolute difference (6% vs 2%).  The p value was higher because study was a lot smaller)  Rosuva 20 mg in AURORA did not show a benefit, but AURORA and 4D subjects were very different than those in SHARP.  All were on dialysis.  Only 1/3 of SHARP were, so they had less advanced kidney disease and less likely to die of dialysis-related problems (including cardiac) and more likely to die of atherosclerosis complications.  The differences lie in the study populations, causes of death, degree of kidney disease. Also, we already knew that those with GFR from 30-60 had CVD reductions from the pravastatin meta-analysis, so this result is completely expected.   I think patients with advanced kidney disease will benefit from statin therapy, if their life expectancy is long enough to see benefits.  The magnitude of the benefit probably is lower once they are on dialysis, but it is important when people have advanced by not dialysis dependent CKD.

A Merck representative sent the following comment to CardioBrief about SHARP:

The SHARP study involved more than 9,000 patients who, on average, had advanced or end stage CKD, and was the first prospective clinical study to demonstrate that intensive LDL-C lowering with VYTORIN (ZETIA 10 mg/simvastatin 20 mg) significantly decreased major vascular events in patients with CKD.

Neither VYTORIN, nor ZETIA with simvastatin, is indicated to reduce major vascular events or atherosclerotic events in patients with chronic kidney disease. Merck is pursuing plans to seek regulatory approval for the use of VYTORIN and for the use of ZETIA with simvastatin in patients with CKD based on the results from the SHARP study.  In the U.S., VYTORIN is currently indicated as adjunctive therapy to diet to reduce elevated total cholesterol, LDL cholesterol, Apo B, and trigylcerides and to increase HDL cholesterol in patients with primary hypercholesterolemia or mixed hyperlipidemia.  ZETIA in combination with a statin is currently indicated as adjunctive therapy to diet to reduce total cholesterol, LDL cholesterol and Apo B in patients with primary hyperlipidemia.

Lingering Concerns

For the record, a number of issues that were raised last fall by CardioBrief and others are still unresolved. As we noted in November, 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 point is somewhat moot now as the two analyses yielded very similar results.

Furthermore, last November I expressed concern about 2 press releases that 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. Surprisingly, compared to the Oxford press reelease, the Merck release was a paragon, fully disclosing important details about the trial. The Oxford release was 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. (Click here to read my article about the 2 press releases.)

Sadly, it appears that the CTSU authors have continued to embrace their position, once again hyping the trial results. Here’s the comment released to the press along with the Lancet paper:

Embargoed 00.01, 9th June 2011

The Lancet – SHARP: Study of Heart and Renal Protection

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

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.

Comment and further background to this paper published in The Lancet 9th June 2001.

 

Professor Colin Baigent, Clinical Trial Service Unit (CTSU), University of Oxford, who led the study, said:

 

“Reducing cholesterol 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.

“This is good news for kidney patients. People with this disease are in desperate need of new treatments not only to combat the disease itself, but also to reduce pain and suffering, such as heart attacks and strokes, due to side effects of the illness.

“Over half of people with kidney disease will eventually be killed, not by their kidney disease, but by cardiovascular diseases. We now know there is something we can do about this – and I believe this study will have a positive impact on the lives of many millions of people currently being treated for chronic kidney disease in the UK and around the world.”

Professor Baigent has a personal interest because he developed kidney disease 30 years ago and needed dialysis before receiving a kidney transplant. “Many of the young people who were receiving dialysis at the same time as me are now dead from cardiovascular disease,” he said.

“Progress in the prevention of cardiovascular disease with drug treatments in kidney patients has lagged behind other patient groups. The research community has tended to neglect testing promising treatments in kidney patients, partly because of fears that some drugs may turn out to be dangerous in people with damaged kidneys.

“The SHARP study now shows clearly, however, that it is possible to find safe and effective drugs for the prevention of cardiovascular disease in kidney patients.”

With over 3% of the NHS budget currently devoted to treating kidney patients, and that figure likely to rise, there is a need for better care of such patients, and the prevention of cardiovascular diseases should be a high priority, said Professor Baigent.

  • Kidney disease is common, particularly in people with diabetes and high blood pressure, and the numbers with disease will increase rapidly over the next few decades;
  • The kidneys regulate body water content, excrete harmful substances, and produce vital hormones, so their failure produces a range of health problems;
  • These problems are potent causes of cardiovascular disease such as heart disease and stroke. There is an increased risk even among people with only mild loss of kidney function, which some estimates suggest might be as much as 10% of the population;
  • Over half of people with kidney disease will eventually be killed, not by their kidney disease, but by cardiovascular diseases;
  • Some cardiovascular diseases are preventable, but doctors have not been certain whether the types resulting from kidney disease can be prevented by commonly used drugs, such as statins.

SHARP was a global study involving 9,500 people with chronic kidney disease at 380 hospitals in 18 countries. It cost £40 million over 7 years.

The UK Renal Association and British Renal Society are holding a joint 4-day conference 6-9th June, Birmingham. The country’s top kidney specialists will be there. Professor Baigent presents his findings at the conference on the morning of the 9th June.

The story is embargoed by The Lancet until 0001 UK time Thursday 9th June (also the publication date).

Notes:

1.     Link: British Renal Society meeting:

http://www.britishrenal.org/Conferences/Conferences-Home/BRS-RA-Conference-2011/Monday.aspx

2.     Kidney Research UK is also celebrates 50 years of funding kidney research this year.

3.     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.

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4 comments

  1. James Stein’s information about the 4D trial of atorvastatin in dialysis patients is incorrect. The 2005 NEJM publication showed “Atorvastatin had no statistically significant effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke in patients with diabetes receiving hemodialysis.” Additionally, there was absolutely no reduction in strokes with atorvastatin, and fatal strokes in the atorvastatin arm were significantly higher than the placebo arm.
    Here is the brief summary of the results: “Atorvastatin had no significant effect on the individual components of the primary end point, except that the relative risk of fatal stroke among those receiving the drug was 2.03 (95 percent confidence interval, 1.05 to 3.93; P=0.04). Atorvastatin reduced the rate of all cardiac events combined (relative risk, 0.82; 95 percent confidence interval, 0.68 to 0.99; P=0.03, nominally significant) but not all cerebrovascular events combined (relative risk, 1.12; 95 percent confidence interval, 0.81 to 1.55; P=0.49) or total mortality (relative risk, 0.93; 95 percent confidence interval, 0.79 to 1.08; P=0.33).

  2. Hi DCoyne –

    Thanks for commenting.

    To clarify, in 4D, the atorvastatin arm showed a significant reduction in “all cardiac events” (RRR 18%, ARR 6%, p=0.03). My point was that this secondary endpoint (cardiac death, non-fatal MI, PCI, CABG,) was similar to the “new” atherosclerosis-related primary endpoint in SHARP. Including “stroke” was a typographical error on my part and you correctly pointed out that there were more strokes in the atorvastatin arm of 4D than the placebo arm. Sometimes I type too quickly. But to be precise, the parallel between the studies is “ischemic stroke” which occurred in 5% of placebo and 8% of atoravastatin (no p value reported). – not the “fatal” strokes statistic you reported. Regardless, I still think the claims of the SHARP authors over-reach since the 4D team saw the same results in regard to CHD events.

    Jim Stein

  3. Thanks for clarifying Dr. Stein. 4d was a negative trial because the excess strokes pushed atovastatin into the neutral column. I agree with your statements regarding the interpretation of SHARP. It shows statin therapy can be effective in CKD and dialysis pts which was unproven beforehand. It should not mean all pts need a statin or Vytorin as the authors promote. Many Sharp pts were high risk – such as PVD and should be treated. Low risk pts should not be treated until higher risk factors or events indicate a need for statins. That is how I interpret the results.

    • Hi DCoyne –
      I agree completely with your interpretation. I think we are on the same page. Thanks for the civil discourse.
      Jim Stein

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