The strongly worded editorial, calling on AstraZeneca to retreat in its "unprincipled" marketing of rosuvastatin, says the "glittering arc of success" of chief executive officer Sir Tom McKillop has been "cast into shadow."

From the very beginning, notes the editorial, the marketing campaign behind rosuvastatin has been directed toward promoting the potency of the drug and its ability to provide greater reductions in LDL-C. Based on evidence presented to the FDA's Endocrinologic and Metabolic Drugs Advisory Committee, rosuvastatin reduced LDL-C 43% and 62% across the approved dose range, 5 mg and 40 mg, respectively.

Approved by the advisory panel in August 2003, rosuvastatin has been widely available to US physicians since mid-September. In just three weeks, the so-called "super-statin" had captured 2% of the global statin market. As the Lancet notes, that market is highly lucrative, with atorvastatin (Lipitor^®, Pfizer) leading the pack with annual sales in 2002 of $8 billion. According to several analysts, AstraZeneca is believed capable of capturing 20% of this market by 2007.

[AstraZeneca] has proceeded to push Galaxy into the realms of astrological rather than astronomical logic.

The Lancet editorial notes that the sales strategy for rosuvastatin is based on the Galaxy program, a consortium of clinical trials designed to investigate the efficacy of rosuvastatin in various clinical settings.

With no hard clinical end point trials yet completed, various surrogate end point studiesincluding Statin Therapies for Elevated Lipid Levels Compared across Doses to Rosuvastatin (STELLAR) and Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy (MERCURY I)have investigated the effectiveness of rosuvastatin to improve atherogenic lipid profiles.

The editorial states that while the premise that reducing elevated LDL-C and improving atherogenic lipid profiles will reduce the risk of cardiovascular morbidity and mortality is a compelling and familiar argument, the company has chosen to market rosuvastatin by "applying adventurous statistics to an overinterpreted syllogism." Moreover, AstraZeneca "has proceeded to push Galaxy into the realms of astrological rather than astronomical logic."

The Lancet takes issue with the soft end point trials, such as STELLAR and another study appearing in a promotional supplement of the American Journal of Cardiology in March 2003. The editorial states that critical appraisals of "weak data" are lacking and that other studies are blatant marketing "dressed up as research."

The recommendation to approve rosuvastatin has taken more than two years since AstraZeneca first submitted a new drug application (NDA) to the FDA. Originally, the company proposed to market the drug at doses ranging from 10 mg to 80 mg.

Safety concernsin particular, concerns about the risk of myopathy and rhabdomyolysis at the highest doseprompted the company to suspend the 80-mg dose, a fact not overlooked by the editorial.

Physicians must tell their patients the truth about rosuvastatinthat, compared with its competitors, rosuvastatin has an inferior evidence base supporting its safe use.

According to the Lancet, critics are still anxious about the 40-mg dose and have further concerns about findings of proteinuria and microscopic hematuria associated with rosuvastatin. The journal states that discussions about the efficacy of the statin subvert efforts to conduct large-scale outcome trials where they are needed most, in heart failure patients. Moreover, the editorial states there appears to be little clinical justification for rosuvastatin given the beneficial results of mortality end point trials for other statins.

"Since there are no reliable data about efficacy and safetyand AstraZeneca is facing an unusually acute commercial pressure to force rosuvastatin into the marketdoctors should pause before prescribing this drug," concludes the editorial. "Physicians must tell their patients the truth about rosuvastatinthat, compared with its competitors, rosuvastatin has an inferior evidence base supporting its safe use."

AstraZeneca has responded to the editorial by drafting an open letter to the Lancet, signed by CEO McKillop.

McKillop charges that while the Lancet has demanded physicians tell their patients the truth about rosuvastatin, no less is expected of the journal's editor.

According to McKillop, rosuvastatin is "an extensively studied and well-tolerated drug with a safety profile comparable to other marketed statins combined with a greater ability to get patients to their cholesterol goals than any other single product."

The letter notes that more than 200 000 patients have been treated worldwide with rosuvastatin, with 80% of patients reaching LDL-C target goals with the 10-mg dose of rosuvastatin.

I deplore the fact that a respected scientific journal . . . should make such an outrageous critique of a serious, well-studied, and important medicine.

The letter counters the charge that only soft end point trials are available, noting hard-outcome studies have not been requisite for other companies currently marketing commercially available statins. Moreover, McKillop writes that surrogate lipid end point studies are necessary, widely accepted, and form the basis of clinical decision-making.

"Outcomes data are rarely available for any new medicine at time of launch and have never been available for cholesterol-lowering and hypertensive drugs at this stage," writes McKillop. "Mandating outcomes data for any drug prior to approval would stifle innovation and needlessly delay the introduction of new therapeutic advances."

The letter concludes by stating, "Regulators, doctors, and patients, as well as AstraZeneca, have been poorly served by your flawed and incorrect editorial. I deplore the fact that a respected scientific journal like the Lancet should make such an outrageous critique of a serious, well-studied, and important medicine."

A number of lipid and atherosclerosis experts across the US reviewed the editorial for heartwire and were puzzled by the stance taken by the prestigious journal. According to Dr W Virgil Brown (Emory University, Atlanta, GA), the editorial is nonsense.

Lipitor went to 53% of the market without a single long-term clinical trial. How can you say this to AstraZeneca when its competitors have done exactly what it's now doing?

"The reason that it's nonsense is because there is a precedent for doing exactly what [AstraZeneca is] doing with every statin preceding [Crestor]," said Brown. "Lipitor went to 53% of the market without a single long-term clinical trial. How can you say this to AstraZeneca when its competitors have done exactly what it's now doing? No one raised this issue with atorvastatin, and Pfizer had far less data when it went to the FDA than when AstraZeneca did."

Another lipid expert, Dr Christie Ballantyne (Baylor College of Medicine, Houston, TX) agreed. Ballantyne told heartwirethat the Lancet never wrote a critical editorial when atorvastatin came to market, despite numerous outcome studies already supporting other statins.

"Yet Lipitor became, far and away, the best-selling statin in the world, with a two-to-one market share over Zocor, with no data at all and far less safety data than AstraZeneca had when it went to the FDA," said Ballantyne. "At that time, I didn't see any editorials in the Lancet, so I just can't understand where this came from."

Brown and Ballantyne both noted that the development program with rosuvastatin was the largest and most comprehensive in the statin class. Resubmitted information to the FDA included more than 12 500 patients treated with the statin in phase 2/3 clinical trials. Brown added that the database for rosuvastatin includes close to 4000 patients treated at the 20-mg and 40-mg doses, as well as several hundred patients who have been treated with rosuvastatin for more than one year.

While Brown admits the syllogism linking improvements in atherogenic lipid profiles to reductions in the risk of heart disease may be simplified, he adds that large outcome studies investigating rosuvastatin are ongoing.

"It's true that all the other statins have been out and in clinical use and have thousands of patients in clinical trials," said Brown. "AstraZeneca has set up the large clinical trials long term, and this is the path that every statin has followed to market. The research database, at this point in time, is as complete as any other statin approved after phase 3 trials."

Dr Scott Grundy (UT Southwestern, Dallas, TX), who chaired the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III), also commented on the editorial for heartwire.

I might surmise that AstraZeneca, a drug company, is a more acceptable target of criticism than is the FDA, a US government agency.

"In my view this editorial is really a criticism of the US FDA for approving rosuvastatin without evidence of clinical trial efficacy of benefit," said Grundy. "However, I might surmise that AstraZeneca, a drug company, is a more acceptable target of criticism than is the FDA, a US government agency."

Grundy told heartwire similar criticisms about a lack of hard clinical end point studies were leveled after the approval of atorvastatin. Only after the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) did these concerns disappear, he said.

"It should be noted, of course, that the kind of trials that led to the approval of simvastatin and pravastatin are no longer considered to be ethical, because of the known benefit of LDL lowering," said Grundy. "Therefore the bar for proof of efficacy has been raised to an impossibly high level for new statins. Any new statin must seek to find trials that test cholesterol lowering at the edges. It is by no means clear that they will prove to be efficacious beyond that which can be obtained with standard doses of statins."

Grundy said safety is obviously an important issue, but the FDA appeared satisfied with the data presented by the company during the approval process. He added that the FDA would have certainly been very cautious about approving rosuvastatin in light of the experience with cerivastatin (Baycol^®/Lipobay^®), a statin withdrawn in 2001 after reports of increased fatal rhabdomyolysis.

"AstraZeneca was required to provide a mass of data to the FDA on the safety of rosuvastatin," said Grundy. "Seemingly it convinced the FDA that this new statin is as safe as those statins already on the market. Further, it is by no means clear that a regular clinical trial will resolve the safety question. The greater toxicity of cerivastatin compared with other statins emerged only after many thousands of patients were treated."

While some are puzzled over the editorial, Grundy believes the message being sent is not necessarily to AstraZeneca but to the agency that regulates and monitors the marketing of these drugs.

"All of the drug corporations aggressively market their drugs in the US," Grundy told heartwire. "This too is a matter for the FDA to monitor. If a particular company gets out of line with current guidelines on marketing, it is called to task. Therefore, the editorial is again an oblique criticism of the FDA for allowing the type of marketing it does with statins and other drugs."

"I would have been happier with the editorial if it had directed its criticisms to its true targetthe FDA," continued Grundy. "This comment does not imply that I agree with these criticisms. It has been my experience that the FDA seeks to make balanced judgments when it comes to approval of new drugs, but I have no doubt that others look at the question from different angles."

You always have to show some caution with a new agent, but I don't think anybody has ever asked the pharmaceutical companies not to sell a new drug.

Ballantyne said he doesn't feel the "unprincipled campaign" marketing rosuvastatin is as aggressive as Pfizer's after atorvastatin was approved. Moreover, said Ballantyne, US physicians were blitzed with complimentary issues of the Lancet earlier this year when ASCOT was published, an issue that showcased Lipitor ads on the front and back promotional sleeve accompanying the journal.

Promotional efforts such as complimentary issues and free trial subscriptions sponsored by third parties skirt FDA regulations and should also be closely monitored for marketing infractions, said Ballantyne. Heartwire attempted to contact the Lancet about the complimentary issues but received no response.

Ballantyne said specifically targeting AstraZeneca is unfair as it creates an uneven playing field.

"You always have to show some caution with a new agent, but I don't think anybody has ever asked the pharmaceutical companies not to sell a new drug," he said.