AHA 2008: SEARCH Me: Null Trial "Morphed" Into Positive Meta-Analysis

November 09, 2008

November 9, 2008 (New Orleans, Louisiana) — Attempting to lower homocysteine using folic acid and vitamin B12 did not have any effect on vascular events compared with placebo in a new trial in more than 12 000 heart-attack survivors. The SEARCH study also looked at more vs less LDL lowering, comparing 80-mg and 20-mg doses of simvastatin. Although the 80-mg dose failed to reduce vascular events significantly, there was a reduction in LDL with this higher dose, and the results are consistent with previous trials of more vs less statin, said the investigators.

Dr Rory Collins

Dr Rory Collins (Clinical Trial Services Unit, Oxford, UK) presented the findings of the SEARCH study during a late-breaking clinical trial session here at the American Heart Association 2008 Scientific Sessions, and his colleague Dr Jane Armitage (Clinical Trial Services Unit) discussed the results at a press conference. She said those who received the 80-mg dose of simvastatin had 0.35-mmol/L (14-mg/dL) lower LDL than those who got the 20-mg dose, which translated into a 6% further reduction in vascular events, "which on its own was not significant but is in line with all the other combined more-vs-less data. When we look at the combined data, we see a very clear picture emerging."

But discussant of the SEARCH study, Dr Peter Wilson (Emory University, Atlanta, GA), said: "This was a null trial that was morphed into a positive meta-analysis. I don't want to be unfair, but I think that's what we just saw."

Also, there were significantly more cases of myopathy with the 80-mg dose of simvastatin than with the 20-mg dose (53 vs 3), Armitage noted, adding that "quite clearly the myopathy risk is higher with 80 mg and safety is an issue with simvastatin." Other doctors questioned by heartwire said they would likely chose a more potent statin than simvastatin if they needed to intensively lower LDL.

More vs Less Statin Comparison

This was a null trial that was morphed into a positive meta-analysis.

In SEARCH, 12 064 MI survivors were randomized to either 20 mg or 80 mg of simvastatin daily for the more vs less LDL-lowering comparison and to folic acid 2 mg plus vitamin B12 1 mg daily or placebo for the homocysteine-lowering comparison for a total of seven years.

The primary end point was major vascular events, consisting of major coronary events, stroke, and revascularization. For the more-vs-less-statin comparison, there was a further reduction of 0.35 mmol/L (14mg/dL) in LDL in the intensive arm compared with the 20-mg arm, equating to around a 14% further reduction in LDL, Collins noted.

But there was no difference in the primary end point between the groups: 1477 events (24.5%) in the 80-mg simvastatin group vs 1553 events (25.7%) in the lower-dose group (p=0.10).

Reassuringly, however, there was no evidence that further reducing LDL increased the risk of cancer, which has previously been a concern, Collins noted.

Although not significant, these findings are consistent with other trials in the field, including TNT, PROVE-IT, IDEAL, and A to Z, said Armitage, and show that larger reductions in LDL with intensive statin therapy produce further reductions in each of the components of major vascular events, including revascularization and nonfatal MI/coronary death.

The combined evidence illustrates that further reducing LDL by 0.5 mmol/L provides an additional 16% relative reduction in vascular events, a 1.5-mmol/L decline provides a 33% relative risk reduction, and a 2-mmol/L drop gives a further 40% relative reduction in events, she concluded.

Does lower LDL lead to lower cardiovascular risk post-MI? The SEARCH trial didn't answer that question.

Discussant Wilson said the difference seen between the two statin groups in the SEARCH trial "was not enough to show that lower is better, and the LDL was only modestly lower in the 80-mg simvastatin group," although he commented that a difference may have emerged had the trial lasted longer. "Does lower LDL lead to lower cardiovascular risk post-MI? The SEARCH trial didn't answer that question," he said.

"The LDL story from 80 to 100 is getting very solid," he added, "but the challenge is what happens below 80. We don't have the answer that many of us would like to know for the next round, below 70mg/dL."

Dr Gordon Tomaselli (Johns Hopkins University, Baltimore, MD) commented to heartwire that the SEARCH trial "reinforces the notion that statins are potent drugs that have an effect on lowering events, particularly in secondary prevention, although it does raise the question as to how low do you have to go--maybe there is a 'floor' below which you get no added benefit?" he noted, although he added that the JUPITER results, also reported today, give a hint of what to expect in this regard.

Also, more attention must be paid to absolute rather than relative risk reduction, Wilson stressed. "We're growing more and more interested in absolute risk, which is 1% per year after a MI with a low-dose statin, and it's not that much different with a high-dose statin. We now need to consider absolute risk and residual risk, which is a newer term referring to absolute risk for those getting the most benefit."

Myopathy an Issue With 80 mg of Simvastatin

Both Collins and Armitage flagged the fact that, in SEARCH, there was more myopathy in the 80-mg group, which Collins noted "was reported to regulators a few years ago and added to the data sheet."

It's always good to start a statin at a dose that is well tolerated and gets people to target quickly. For me, that would be rosuvastatin or atorvastatin.

Armitage noted that the "vast majority of the patients taking 80 mg of simvastatin tolerated it well," but for those who do develop myopathy there are a couple of options, she noted: the dose of statin can be reduced--"40 mg [of simvastatin] rarely causes myopathy"--or there is the option of trying to identify, via genetic means, those who are at increased risk of myopathy. (The Oxford team has identified a genetic marker for myopathy that accounts for 60% of myopathies, Collins said.)

Collins commented: "There are other drugs that can produce this effect more safely--for example, ezetimibe." Other doctors interviewed by heartwire , however, said that given the poor results with 80 mg of simvastatin and the myopathy problem, they would simply use a more potent statin, such as atorvastatin or rosuvastatin.

Tomaselli said that faced with a patient who required intensive lipid lowering, he would opt for one of the more potent statins over 80 mg of simvastatin.

Dr Andrew M Tonkin (Monash University, Melbourne, Australia) agreed. "SEARCH is really consistent with other trials that lower is better, and it extends the evidence base." He, too, said he would opt for a more potent statin: "It's always good to start a statin at a dose that is well tolerated and gets people to target quickly," he said. "For me, that would be rosuvastatin or atorvastatin."

Null Effect of Homocysteine-Lowering Arm

In the homocysteine-lowering arm of SEARCH, there were 1537 major vascular events in the folic acid/vitamin B12 arm vs 1493 in the placebo arm, to give a risk ratio of 1.04.

Armitage said there is "clear evidence from SEARCH that homocysteine lowering does not affect the risk of vascular events--it's really a very robustly negative result, and there were no subgroups in whom there was any benefit." Collins concurred: "We can now rule out unequivocally any effects of homocysteine lowering on vascular events," he noted.

Crucially, Armitage noted, they found no safety issue with folic acid and vitamin B12--specifically, no increase in the risk of cancer--something that is of "particular importance" because of the fortification of food with folic acid in many countries.

Armitage said the SEARCH findings are consistent with previous trials in this field, including CHAOS-2, WENBIT, VISP, NORVIT, WAFACS, and HOPE-2, and she reported on a meta-analysis of all these trials, including SEARCH.

Discussant Wilson said: "We just saw four different presentations: one on statins in SEARCH, one on homocysteine in SEARCH, and two meta-analyses."

The door is slowly closing on the homocysteine lowering for cardiovascular disease prevention.

Wilson said the homocysteine side of the trial "is discouraging. The numbers from SEARCH fit right into the portfolio. We would like to think that taking B vitamins would improve things, but these vitamins are not preventing recurrent events in this trial." However, "B vitamins are safe; we've known that for a while," he added.

"The door is slowly closing on the homocysteine lowering for cardiovascular disease prevention," he concluded.

But Tomaselli said he does not believe that SEARCH sounds a death note for the homocysteine hypothesis; however, it does "strike a note of caution. There are plenty of biological plausibility studies and reasons to believe that lowering homocysteine will lower risk, but the methods currently used to lower it are not effective. "We need to better understand how to lower homocysteine to lower risk," he commented.

Merck funded the SEARCH trial.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.



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