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High-Dose Statins in Acute Coronary Syndromes

http://www.npr.org/rundowns/rundown...ug-2004&prgId=3
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Not Just Lipid Levels

Steven E. Nissen, MD

JAMA. 2004;292DOI 10.1001/jama.292.11.1365).

For more than a decade, statin drugs have accumulated a remarkable record of successful clinical trials, demonstrating robust evidence for reduction in clinical events, including myocardial infarction, stroke, and cardiovascular death in primary and secondary prevention populations.1-4 Recent trials have shown that intensive statin therapy is superior to moderate therapy for reducing morbidity following an acute coronary syndrome (ACS) event5-6 and for slowing the progression of coronary atherosclerosis.7 Statin trials have also demonstrated a favorable safety profile with only rare and isolated cases of serious toxicity.8 Given the spectacular success of this class of drugs, the failure of a statin clinical trial to meet its prespecified objective and evidence of an adverse safety profile are unusual and mandate careful analysis of potential responsible factors.

Phase Z of the A to Z trial,9 published in this issue of JAMA, is to date the largest trial testing the effects of aggressive statin therapy in ACS. The investigators randomized approximately 4500 patients following an ACS event to receive either high-dose simvastatin (40 mg/d for 1 month and then 80 mg/d thereafter) or to a regimen of placebo for 4 months and then a 20-mg/d dose of simvastatin thereafter. The high-dose regimen failed to show a statistically significant benefit for reducing the primary composite end point of cardiovascular death, myocardial infarction, readmission for ACS, or stroke (absolute risk reduction, 2.3%; hazard ratio, 0.89 [95% confidence interval, 0.76-1.04] P = .14). In addition, the high-dose simvastatin regimen was associated with an unusually high rate of myopathy. Ten patients (9 in the high-dose treatment group) experienced elevated creatine kinase levels greater than 10 times the upper limit of normal with accompanying muscle symptoms and 3 patients developed frank rhabdomyolysis (creatine kinase levels >10 000 units/L). Because 32 clinical events were avoided, approximately 1 adverse myopathic event occurred for every 3 patients protected.

Both the lack of efficacy and the unfavorable adverse event profile would seem improbable to those familiar with the statin clinical trial literature. Two other trials in ACS patients showed safety and efficacy (Table 1). The Myocardial Ischemia Reduction with Aggessive Cholesterol Lowering (MIRACL) trial compared 80 mg/d of atorvastatin with placebo for 4 months in 3086 patients and showed a 16% reduction in events.6 The Pravastatin or Atorvastatin Evaluation and Infection Therapy trial (PROVE IT) compared outcomes of 4162 patients receiving 80 mg/d of atorvastatin or 40 mg/d of pravastatin and also showed a significant 16% event reduction.5 Both studies demonstrated a rapid onset of clinical benefit. In MIRACL, the study duration was only 4 months, whereas in PROVE IT the event curves separated within the first 30 days, reaching statistical significance by 6 months. In contrast, post hoc analysis of the A to Z trial showed no effect during the first 4 months (hazard ratio, 1.01), but there did appear to be some later benefit from aggressive treatment.


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Table. Intensive Statin Therapy in Acute Coronary Syndromes


Explaining the lack of efficacy for high-dose simvastatin in the A to Z trial is difficult. The authors emphasize that fewer events occurred than anticipated by power calculations. While correct, this observation only partially explains the lack of statistical efficacy. Consider the following comparison between the A to Z trial and the MIRACL trial. Both studies showed large low-density lipoprotein (LDL) cholesterol differences between the group receiving active treatment and the group receiving placebo during the first 4 months (62 mg/dL [1.61 mmol/L] in the A to Z trial and 63 mg/dL [1.63 mmol/L] in the MIRACL trial). Despite nearly identical lipid level effects, the A to Z trial showed no risk reduction during the first 4 months, whereas MIRACL showed a 16% reduction in similar end points (Table 1).

How can identical lipid level lowering with 2 drugs yield such different outcomes? The authors propose that improved concomitant therapies "competed" for risk reduction in the A to Z trial, thereby reducing drug efficacy. However, PROVE IT used similar contemporary therapies and showed a 16% reduction in events, which was evident by 30 days and was virtually constant for the trial duration. Even more surprisingly, PROVE IT achieved statistical significance while comparing intensive statin therapy with moderate statin therapy, not placebo, achieving only 33 mg/dL (0.85 mmol/L) greater LDL cholesterol reduction in the intensive treatment group (Table 1).

Taken together, MIRACL, PROVE IT, and A to Z demonstrate that the beneficial effects of statin therapy in ACS cannot be predicted entirely from the degree of LDL cholesterol reduction. <b>What other explanations are possible? All statins exhibit a variety of anti-inflammatory and antiproliferative effects commonly described as "pleiotropic" effects.10-13 The most widely examined inflammatory biomarker—high sensitivity C-reactive protein—is commonly measured in statin clinical trials. In the 2 successful ACS trials (MIRACL and PROVE IT), the difference in C-reactive protein between treatment subgroups was 34% and 38%, respectively, at trial completion. In the A to Z trial, the between-group reduction was much smaller (16.7%; Table 1). This finding suggests an intriguing hypothesis, specifically, that the early benefits of statin therapy are derived largely from the anti-inflammatory effects of the drugs, whereas the delayed benefits are lipid-modulated.</b>

These findings emphasize a critical principal of appropriate, evidence-based interpretation of clinical trials. It is hazardous to assume that similar agents always yield identical results. While a class effect for statins is likely, each agent requires careful testing in clinical trials to establish the extent of benefit and risk. These observations are even more important when applied to nonstatin LDL–cholesterol-lowering therapies. Because these agents, such as ezetimibe, have not demonstrated anti-inflammatory effects in the absence of concomitant statin administration,14 their value in reducing events cannot be assumed and must be tested in well-designed clinical outcome trials.

The myopathy rate in the A to Z trial, while low, is higher than observed in most other clinical statin trials. In trials using submaximal doses of pravastatin, lovastatin, fluvastatin, or simvastatin, myopathy has occurred rarely.8 Six studies treated patients with the highest dose of atorvastatin (80 mg/d), randomizing more than 10 000 patients, with no reported cases of myopathy (defined as 10 times the upper limit of normal creatine kinase levels with muscle symptoms) or frank rhabdomyolysis.5-7,15-17 The myopathy rate of 0.4% observed in the A to Z trial occurred despite patient selection criteria that sought to specifically exclude patients at greater risk.9 However, this rate is consistent with the reported 0.6% myopathy rate reported in a meta-analysis of the efficacy and safety of the 80-mg/d dose of simvastatin.18

The myopathy rate of the 80-mg/d dose of simvastatin observed in the A to Z trial and the previously reported meta-analysis are not particularly surprising. For many years following its introduction, the maximum dose of simvastatin approved by the Food and Drug Administration (FDA) was 40 mg/d. However, in 1997 the manufacturer undertook a development program to study 2 higher doses of simvastatin (80 mg/d and 160 mg/d).8, 19-20 Although a favorable report appeared in the medical literature,20 development of the 160-mg/d dose was abandoned due to high muscle toxicity.8, 19 Although never reported in the scientific literature, the financial community was informed that the rate of muscle-related symptoms was 5.7% for the 160 mg/d dose.19 The dose of 80 mg/d of simvastatin was eventually approved, but in 2002, the FDA product label was modified to include warnings about concomitant medications than inhibit cytochrome P450 3A4, the major metabolic pathway for simvastatin elimination.21 This warning was provoked by cases of rhabdomyolysis when simvastatin was administered with 3A4 inhibitors.21

There are several lessons to be learned from these events. The failure of the 160-mg/d dose of simvastatin and the enhanced toxicity that occurred with 3A4 inhibitors should probably have served as a warning that the 80-mg/d dose of simvastatin might border on a toxic threshold. Relatively minor differences in the rate of elimination, a low body mass index, mild renal insufficiency, or other unknown factors appear capable of pushing simvastatin blood levels into the toxic range. The failure to publish the actual results of studies using the 160-mg/d dose (negative publication bias) arguably prevented the medical and scientific community from fully appreciating the myopathic potential of high-dose simvastatin. In addition, the voluntary nature of the US postmarketing surveillance system may have compromised the ability of the FDA to recognize increased risk of the 80-mg/d dose. Indeed, it took several years to recognize that cerivastatin was associated with a 16- to 80-fold increase in risk of myopathy prior to its withdrawal.22

It must be emphasized that the cluster of myopathy events in the A to Z trial may be partially explained by chance alone. Although potentially alarming, 9 myopathic events in 2250 treated patients are insufficient to recommend withdrawal of the 80-mg/d dose of simvastatin. Fortunately, there is a larger ongoing trial randomizing 12 000 patients to either 80 mg/d or 20 mg/d of simvastatin.23 In addition, the FDA maintains a high degree of vigilance in this area and undoubtedly will subject high-dose simvastatin to additional scrutiny. If either FDA monitoring or ongoing clinical trials confirm that a regimen of 80 mg/d of simvastatin constitutes an unacceptable risk, this dosage level should be withdrawn by its manufacturer.

It is important to reassure practicing physicians and patients that the unfavorable risk-benefit relationship observed in the A to Z trial does not in any way diminish the value of intensive statin treatment in secondary prevention, including ACS patients. There was a trend toward reduced events in the A to Z trial, a finding that supports the lower is better concept. The increased myopathy rate applies only to a specific dose of a single agent and should not tarnish this remarkable class of drugs.24 It must also be emphasized that simvastatin in doses of up to 40 mg/d has shown excellent safety and efficacy in a series of clinical trials. For now, though, the 80-mg/d dose of simvastatin should be used with caution, particularly because other effective agents are available. Finally, in an era when criticism of selective reporting of positive trial results is common,25 the A to Z investigators are to be commended for their prompt and thorough reporting of a critically important major trial that did not meet its original objectives.


AUTHOR INFORMATION

Corresponding Author: Steven E. Nissen, MD, Department of Cardiology, Cleveland Clinic Foundation, 9500 Euclid Ave, Desk F15, Cleveland, OH 44195 (nissens~ccf.org).

Financial Disclosures: Dr Nissen has been a consultant to Merck, Astra Zeneca, Pfizer, Sankyo, Sanofi, Eli Lilly, Takeda, Novo Nordisk, Atherogenics, Lipid Sciences, GlaxoSmithKline, Hoffman LaRoche, Kos, and Wyeth. Dr Nissen also has directed clinical trials in collaboration with Astra Zeneca, Pfizer, Sankyo, Eli Lilly, Takeda, Atherogenics, and Lipid Sciences.

Editorials represent the opinions of the authors and THE JOURNAL and not those of the American Medical Association.

Author Affiliation: Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio.


REFERENCES

1. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4,444 patients with coronary heart disease. Lancet. 1994;344:1383-1388. MEDLINE
2. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009. ABSTRACT/FULL TEXT
3. Sever PS, Dahlof B, Poulter NR, et al, for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA). Lancet. 2003;361:1149-1158. MEDLINE
4. Heart Protection Study Collaborative Group. MRC/ BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals. Lancet. 2002;360:7-22. MEDLINE
5. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504. ABSTRACT/FULL TEXT
6. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711-1718. MEDLINE
7. Nissen SE, Tuzcu EM, Brown BG, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080. ABSTRACT/FULL TEXT
8. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003;289:1681-1690. ABSTRACT/FULL TEXT
9. de Lemos JA, Blazing MA, Wiviott SD, et al, for the A to Z Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292:1307-1316.
10. Kinlay S, Schwartz GG, Olsson AG, et al, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study Investigators. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation. 2003;108:1560-1566. ABSTRACT/FULL TEXT
11. Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as anti-inflammatory agents? Circulation. 2004;109(21 suppl 1):II18-II26. ABSTRACT/FULL TEXT
12. Waehre T, Yndestad A, Smith C, et al. Increased expression of interleukin-1 in coronary artery disease with downregulatory effects of HMG-CoA reductase inhibitors. Circulation. 2004;109:1966-1972. ABSTRACT/FULL TEXT
13. Rosenson RS. Pluripotential mechanisms of cardioprotection with HMG-CoA reductase inhibitor therapy. Am J Cardiovasc Drugs. 2001;1:411-420. MEDLINE
14. Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003;107:2409-2415. ABSTRACT/FULL TEXT
15. Pitt B, Waters D, Brown WV, et al, for the Atorvastatin versus Revascularization Treatment Investigators. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med. 1999;341:70-76. MEDLINE
16. Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia. Lancet. 2001;357:577-581. MEDLINE
17. Taylor AJ, Kent SM, Flaherty PJ, et al. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation. 2002;106:2055-2060. ABSTRACT/FULL TEXT
18. Davidson MH, Stein EA, Hunninghake DB, et al, for the Worldwide Expanded Dose Simvastatin Study Group. Lipid-altering efficacy and safety of simvastatin 80 mg/day: worldwide long-term experience in patients with hypercholesterolemia. Nutr Metab Cardiovasc Dis. 2000;10:253-256. MEDLINE
19. Available at: http://www.impostertrial.com/physician.htm. Accessed August 18, 2004.
20. Davidson MH, Stein EA, Dujovne CA, et al. The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day. Am J Cardiol. 1997;79:38-42. MEDLINE
21. Food and Drug Administration letter. Available at: http://www.fda.gov/cder/foi/applett...19766s51ltr.pdf. Accessibility verified August 20, 2004.
22. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539-540. FULL TEXT
23. MacMahon M, Kirkpatrick C, Cummings CE, et al. A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). Nutr Metab Cardiovasc Dis. 2000;10:195-203. MEDLINE
24. Topol EJ. Intensive statin therapy—a sea change in cardiovascular prevention. N Engl J Med. 2004;350:1562-1564. FULL TEXT
25. Olson CM, Rennie D, Cook D, et al. Publication bias in editorial decision making. JAMA. 2002;287:2825-2828. ABSTRACT/FULL TEXT

NEWS ANALYSIS:TECHNOLOGY
By Amy Tsao

New Tricks for Anticholesterol Drugs?
Merck and Bristol-Myers are racing to expand the use of these blockbusters before their versions lose patent protection in 2006
A new study has found that higher-than-usual doses of Zocor, a popular anticholesterol drug, provided no benefit to patients with extremely high risk for a heart attack. No doubt, Merck (MRK ), which makes Zocor and paid for the study that was reported in an item on the Journal of the American Medical Association's Web site on Aug. 31, anticipated a different outcome in this attempt to find a new use for Zocor. Yet because the drug wasn't studied in otherwise healthy patients with high cholesterol, it isn't expected to harm sales of Zocor, which is Merck's single biggest revenue-producing drug.

Despite this unsuccessful outcome, drug companies are likely to keep financing more studies of these cholesterol-fighting drugs. Known as statins, they're the biggest-selling prescription pills in pharmaceutical history. In 2004, global sales will total $26 billion, figures Shao Jing Tong, analyst at New York City-based Mehta Partners. "For such a big category, the effort [to study other uses] is obviously more intensive than for other categories," Tong says.

And with the looming prospect of statins going generic, getting as much as possible out of sales is critical. A decline in statin sales for Merck and Bristol-Myers Squibb (BMY ), the other key player in this market, is inevitable, so the motivation to find new uses is intense.

PRESSURE ON DOCTORS. In 2006, Merck's Zocor and Bristol's Pravachol will both lose patent protection in the U.S. How big are the stakes? Merck reported $6.3 billion in worldwide Zocor sales in 2003 and Bristol $2.8 billion for Pravachol. And the rest of the market -– namely Pfizer's (PFE ) Lipitor and Astra Zeneca's (AZN ) Crestor –- could also see sales slow as effective generics come out after competitors lose patent protection.

"There will be pressure for doctors to use Zocor and Pravachol when they become generic," says Hemant Shah, an individual industry analyst based in Warren, N.J. "That will put pressure on existing products." Pfizer reported $10.3 billion in Lipitor revenues in 2003, while Astra-Zeneca's Crestor, which was launched in 2003, is expected to be a multibillion-dollar drug in coming years.

Statins are already the subject of a variety of ongoing studies in cardiovascular-related ailments. Earlier-stage studies are testing the drugs' effectiveness in treating central-nervous-system disorders and autoimmune diseases.

DATA ADVANTAGE. In general, studies looking for alternative uses for approved drugs are undertaken as a calculated risk on the part of drug companies. They don't come cheaply, and it's always possible that results will be negative, as was the case with the recent Merck study. Another recent example in the statin field: In March, results of a study funded by Bristol-Myers Squibb comparing its Pravachol and Pfizer's Lipitor worked against Bristol.

Still, the potential upside outweighs the risks. And "one of the key benefits of having these studies, is it gets salespeople past the receptionist's desk [in the doctor's office]," says Sanford Bernstein analyst Richard Evans. Physicians often look to drug salespeople to "get up to speed on studies," he says. Certainly, companies are happier if the results of a study add to the case for prescribing one statin over another. But having have new data that doctors are curious about can give drug companies an edge.

The longer term hope, of course, is that statins may be found to be useful outside of cardiovascular-related disorders. Small studies have shown them to be effective in treating diseases such as multiple sclerosis, Alzheimer's, and Parkinson's. "Scientifically, it makes some sense," Tong says. "Statins decrease the cholesterol deposits in blood vessels, but that effect probably also happens in brain vessels and other areas."

GROWING BASE. The industry's ultimate goal is for new research to show ways of keeping the statin market growing. The government's recently lowered cholesterol guidelines will help by expanding the potential universe of people who might be prescribed the drugs. And sales could pick up if drugmakers figure out ways to reach the millions who should be but aren't yet taking statins. "The class can expand because only 30% of the patients who should be taking statins are doing it," Tong says.

At a minimum, it will take several years to fully test the drugs in new diseases. In the next two years, however, as the big names in the field become subject to generic competition, all of the statin makers will be busily trying to find the competitive edge.

NYT

August 31, 2004
Study Questions Value of Big Doses of Heart Drug
By DENISE GRADY

A study of a powerful cholesterol-lowering drug, Zocor, has surprised researchers by finding little or no benefit in greatly increasing the dose given to people who recently had a heart attack. People who took a high dose, 80 milligrams a day, also had an increased risk of muscle-related complications.

The study, to be published in the Sept. 15 issue of The Journal of the American Medical Association, was released early because it was presented yesterday at a cardiology meeting in Germany. The study was paid for by Merck, which makes Zocor.

Experts said that the findings suggested that some cholesterol-lowering drugs may be safer than others at high doses. The findings also raised concerns about the safety of the 80-milligram dose of Zocor, but researchers said that the more commonly used 40-milligram dose was safe and effective.

Zocor is the second-best-selling member of a class of drugs known as statins, which have been found to lower the risk of death, heart problems and strokes in people with high cholesterol or heart disease. Six statins are sold in the United States, and about 11 million Americans take them, though experts in heart disease say many more should. Recent studies have suggested that sharply lowering cholesterol with high doses of statins can offer increased protection.

As a result, federal health officials last month recommended that people at high risk of heart disease lower their cholesterol even more than had previously been advised - a policy that may lead even more Americans to use statins, and to take higher doses than in the past. The revised guidelines say that people at the highest risk should aim for an L.D.L. cholesterol level of less than 100; the previous limit was 130.

But the new findings on Zocor seem to run counter to those of other recent studies.

The experiment, which included 4,497 patients, set out to determine whether high doses of Zocor worked better than low ones at preventing death and cardiovascular complications in people who had suffered heart attacks.

One group, 2,265 patients, were assigned at random to aggressive treatment, meaning 40 milligrams of Zocor a day for 30 days and then 80 milligrams a day. A second group, 2,232 patients, took placebos for four months and then 20 milligrams of Zocor a day. They were followed for six months to two years. The researchers compared the two groups' rates of reaching what they called a "composite end point" that included death from heart disease, nonfatal heart attacks, strokes and readmission to the hospital for heart problems.

Although the high-dose patients appeared to fare slightly better over time, the difference between the groups never became large enough to be statistically significant. Moreover, nine patients in the high-dose group, 0.4 percent, and none in the low-dose group, suffered from myopathy, a muscle disorder estimated to affect one in 1,000 people who take statins.

Dr. James A. de Lemos, the principal author of the study and a cardiologist at the University of Texas Southwestern Medical Center, said that even though the difference between the groups was small, he considered the result to be in keeping with other recent studies.

"It supports the emerging paradigm, that lower cholesterol is better," he said. He added that the study also supported the practice of making sure that patients who have heart attacks start taking a statin before they leave the hospital.

"I don't advocate one drug over another," Dr. de Lemos said. "I think these aggressive approaches are likely to prevent substantial numbers of cardiovascular deaths and events, but we have to be alert for side effects."

Dr. Steven E. Nissen, a cardiologist at the Cleveland Clinic, who wrote an editorial accompanying the Zocor report, said in a telephone interview that the study suggests that not all statins are alike. He noted that 80-milligram doses of another statin, Lipitor, did not seem to cause muscle problems. He added that the dose of Zocor most commonly used, 40 milligrams a day, was safe and not associated with muscle problems.

"What's difficult or perhaps troubling is that we can't necessarily use these drugs interchangeably," Dr. Nissen said. "The lesson is that we have to test the drugs carefully in clinical trials."

Merck's stock dropped slightly yesterday, closing at $44.93, down 49 cents. But shares of other statin makers also decreased slightly.

Quick statins only marginally help heart patients
High-dose treatment offers limited benefits, study finds
The Associated Press
Updated: 5:52 p.m. ET Aug. 31, 2004

Putting patients with heart trouble on a high dosage of statin drugs quickly to lower their blood cholesterol levels offers only a marginal benefit compared to current treatment, a study said Monday.

Normally, patients at risk of another heart attack are first stabilized and put on low-cholesterol diets before introducing cholesterol-lowering drugs such as statins.

But in the study funded by Merck & Co. Inc., half the 4,500 patients were given a daily dose of 40 milligrams of simvastatin, which the company sells under the brand name Zocor, for 30 days and then raised to 80 milligrams daily. The drug was given within about four days of the initial heart "event."

The other patients were given a placebo for four months, then put on a 20-milligram dose of simvastatin.

While cholesterol levels dropped more sharply in the first group, the risks of suffering another heart attack, stroke, readmission to the hospital, or heart-related death were comparable in the two groups.

Among those who went on the drug regimen right away, 14 percent suffered another heart event, compared to 17 percent taking a placebo initially -- a difference that was not seen as statistically significant. Patients were followed for between six months and two years.

In addition, 0.4 percent of those on the heavier dose of simvastatin suffered from myopathy, a type of muscle pain and weakness, and statins can cause liver problems in a few cases.

Even so, the researchers said the findings favored quick use of statins.

“Until recently, little information was available about the timing of initiating statin drugs after a heart attack,” said researcher Dr. James de Lemos of the University of Texas Southwestern Medical Center, Dallas. “The findings from the ... trial suggest that statins can be initiated earlier and in dosages well above the typical starting dose,” he said, adding patients should be closely monitored for side effects.

An editorial accompanying the study, both of which were published in the online version of the Journal of the American Medical Association, commended the researchers for publishing the study findings even though they “did not meet its original objectives” -- in light of recent criticisms that bad news in some company-funded studies have been swept under the rug.

The study’s findings point to a cautious approach in using the 80-milligram simvastatin dose, though the 40-milligram dose appears to be safe and effective, wrote Steven Nissen of the Cleveland Clinic Foundation.
© 2004 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

URL: http://msnbc.msn.com/id/5868543/

"commended the researchers for publishing the study findings even though they “did not meet its original objectives”

???

I thought the "objective" of a study was to get that the truth. Uncover some data. Learn something. To try something, and see what happens. In that light, that's exactly what the study did. That's laudable. That's what science is.

But, do they mean that the "objective" of the study was to prove something that they wanted to prove? To gather some grist for their marketing mill? To prove something they already knew or hoped was true?

To me, that's not science. Business and marketing maybe, but not science.

No, you're right, it's not science, it's business!

The doc that did the Duke study wasn't out to prove LC worked. His hypothesis was that it would cause slower weight loss, increase in blood lipids, etc etc. He set out to prove his hypothesis....but a scientist publishes their work, regardless of the outcome. A businessman only publishes what is beneficial to them.