1 мар. 2012 г.

Report: Hundreds of thousands exposed to toxic compounds from metal-on-metal hip implants

Hundreds of thousands of patients may have been exposed to toxic chromium and cobalt particles as their metal-on-metal hip implants wear, according to a joint investigation by the British Medical Journal and BBC Newsnight.

Hundreds of thousands of patients may have been exposed to toxic compounds from metal-on-metal implants, according to an investigation by the British Medical Journal and BBC Newsnight, putting them at risk of developing cancer, cardiomyopathy, muscle and bone destruction and changes to their DNA.

The implants, including Johnson & Johnson's (NYSE:JNJ) DePuy ASR and Pinnacle, Smith & Nephew's (NYSE:SNN) Birmingham and Zimmer's (NYSE:ZMH) Durom, release particles of their chromium-cobalt alloy as the metal parts wear against each other, causing tissue and bone death and possibly exposing patients to the risk of developing cancer or even altering their DNA.

"Despite the fact that these risks have been known and well-documented for decades, patients have been kept in the dark about their participation in what has effectively been a large, uncontrolled experiment," according to the report.

Citing lax regulatory oversight both in Europe and the U.S., the report says that some 60,000 of the metal-on-metal devices have been implanted in England and Wales since 2003, noting that "the figure is closer to a million and likely to increase" in the U.S.

Metal-on-metal implants first hit the market in 1997, after being pioneered in Birmingham, England, by Dr. Derek McMinn in his garden shed. McMinn believed that the risk of metal ions being introduced into patients' bodies could be minimized with a design that kept the metal surfaces apart.

Midland Medical Technologies' Birmingham Hip Resurfacing device – Smith & Nephew acquired MMT for about $117 million in 2004 – was a popular but tightly controlled release. The company took pains to emphasize good technique and identification of good patient candidates for the device with its hand-picked coterie of surgeons. Marketed as the latest advance in hip replacement and targeted at younger, active patients who needed a hip that would last a whole lifetime, the implants instead put up 7-year failure rates of 11.8% for resurfacing models and 13.6% for full-hip replacements – compared with rates between 3.3% and 4.9% for implants made of other materials, according to the BMJ/BBC investigators.

And the initial restraint shown by MMT soon gave way to crushing demand for the devices, they wrote.

"As competition grew, the boundaries were pushed and the regulators were no match against the commercial pressure. Carefully crafted surgical innovations fell into the hands of the powerful multinationals and shareholder interests trumped patient safety," the investigator write.

Metal ions, genotoxicity and DePuy

There's uncertainty about just how much metal in the bloodstream constitutes a health threat. Cobalt and chromium ions have been shown to create genotoxic changes both in laboratory settings and in animals, according to the report; cobalt was linked to cardiomyopathy as early as 1966. Still, the investigators wrote, "the link to cancer is not proved."

The World Health Organization in 1990 listed hexavalent chromium as a proven carcinogen, trivalent chromium a potential carcinogen and cobalt ions a probable carcinogen.

But there's no doubt that some patients with metal-on-metal implants showed blood levels of ions drastically higher than normal. Human blood normally contains about 0.5 μg/L of cobalt; studies have revealed blood cobalt concentrations of more than 300 μg/L in patients with metal-on-metal implants – 600 times higher than normal.

Metal ion levels above 7 μg/L have been recorded in roughly 20% of patients with some metal-on-metal prostheses, according to the report, including the DePuy Pinnacle system the company promoted after the ASR recall. More than 300,000 Pinnacle prostheses have been implanted worldwide, according to the report.

"If it was the pharmaceutical industry developing a new chemical entity, it would be abandoned early on if it metabolized in the wrong bits of the liver," Nick Freemantle, professor of clinical epidemiology and biostatistics at University College London, told the investigators. "We shouldn't be in this position, where we don't know and there's so much uncertainty. The stability of a compound should have been ascertained before it was used widely in people. As yet, we don't know the consequences of this."

Officials at DePuy knew of the risks, according to the report.

"In addition to inducing potential changes in immune function, there has been concern for some time that wear debris may be carcinogenic. The mechanism is not known and only 24 local malignancies have been reported in patients with joint replacements. Also worrying is the possibility of distant effects. One study suggested a 3-fold risk of lymphoma and leukemia 10 years after joint replacement. The metal-to-metal total hip appears to be quite promising and in the laboratory the data is [sic] definitely in its favor. However, the ultimate test is the long-term human experience," according to an internal DePuy memo obtained by the investigation.

In 2009, Japanese surgeons contacted DePuy to report "generated metal debris between stem taper and head, and final necrosed tissue" with the Pinnacle device, according to a DePuy internal email. As late as 2010, senior DePuy engineers were still trying to ascertain why the implants were failing, 5 years after a spate of industry-wide re-designs aimed at reducing metal ion release.

A trial published in 2011 comparing metal-on-metal systems and conventional hip replacements made by Smith & Nephew was stopped after 2 years, when 20% of patients in the metal-on-metal cohort showed higher metal ion concentrations.

BMJ/BBC timeline: Metal-on-metal hip implants

1975: Study describes local tissue reactions caused by cobalt and chromium ions from metal-on-metal hips.
1988: Study shows human synoviocytes killed by cobalt in vitro.
1989: Metal-on-metal hip resurfacing designs start in Birmingham.
1990: WHO International Agency for the Research on Cancer lists trivalent chromium as a potential carcinogen and cobalt ions as a probable carcinogen.
1991: First metal-on-metal hip resurfacing device is implanted in Birmingham, England.
1994: Study shows dissemination of cobalt and chromium ions into lymph, liver, and spleen.
1996: Patients with metal-on-metal hips found to be at increased risk of cancer compared with those with metal-on-plastic hips.
1997: Birmingham Hip Resurfacing (BHR) implant comes onto the European market.
1998: Particles of cobalt and chromium shown to be toxic to monocytes in culture.
2000: NICE guidance on selection of prostheses for primary hip replacement and resurfacing sets a benchmark revision rate for conventional hip replacement of ≤10% at 10 years.
2003: Derek McMinn and Ronan Treacy publish paper showing positive results with BHR. This kickstarts the trend for larger heads in total hip replacement.
2004: McMinn, designer of the BHR, says, "Caution still needs to be exercised until longer-term results are available."
2004: One of DePuy's modified stems with a shortened trunnion is cleared by the FDA, which says the modified design "does not raise any new issues of safety or effectiveness."
2005: Internal DePuy memo reflects early concerns about health risks of wear debris from metal on metal hips. "In addition to inducing potential changes in immune function, there has been concern for some time that wear debris may be carcinogenic."
2006: MHRA Committee on Safety of Devices says there's growing concern over the biological risks of metal wear debris.
2006: The Dept. of Health's Committee on Mutagenicity concludes that "some metal-on-metal (those using cobalt-chromium) hip replacements may be associated with increased DNA-changes, and increased genotoxicity in patients." It says this "may present a potential risk of carcinogenicity in humans."
2007: Implantation of large-diameter metal-on-metal hips starts to increase rapidly in the U.K., and resurfacing peaks. Metal-on-metal hips accounted for 20% of market that year.
2007: U.K. expert advisory group chooses not to contra-indicate metal-on-metal hips in women of child-bearing age – even though metal ions had been detected in the umbilical cord and placental blood.
2007: The MHRA's Committee on Safety of Devices recommends that all patients sign a consent form setting out the risks associated with metal wear debris. But this recommendation is not widely communicated.
2008: Study shows 20% of patients with DePuy's Pinnacle hip system have metal ion levels over the upper limit accepted by occupational health experts.
2009: Japanese surgeons raise concerns with the design of DePuy's large diameter metal-on-metal system. They report seeing "generated metal debris between stem taper and head, and final necrosed tissue" and blame it on the poor connection between the 2.
2009: All joint replacement implants are re-classified as Class III devices in the European Union.
2010: In an internal email obtained by the BMJ, a senior executive at DePuy writes: "I feel the problem [with large diameter metal on metal] is emerging as more serious than first thought."
2010: DePuy recalls its ASR hip prostheses. Some studies show a failure of the total hip replacement secondary to adverse reactions to metal debris of 50% at 6 years.
2010: DePuy promotes Pinnacle – including metal-on-metal – as "an alternative for the majority of patients."
2011: Tony Nargol and his team warn the MHRA of failures with the Pinnacle implants.
2011: British Orthopaedic Assn. writes to surgeons to say that large diameter metal-on-metal total hip replacements should be "carefully considered and possibly avoided."
2011: A 2-year follow-up study of 144 patients shows an incremental increase in metal levels over the study period in a range of large-head metal-on-metal implants made by companies including Zimmer, DePuy, and Smith and Nephew.
2011: FDA writes to about 20 manufacturers to say that it is requiring post-marketing studies in cases where an implant's failure could have serious consequences. Companies would be expected to take blood samples from patients to measure metal ions.
2011: National Joint Register describes large-diameter metal-on-metal and resurfacing prostheses in some people as a "cause for concern."
2011: Trial comparing large-diameter Birmingham hip replacement with conventional hip is terminated after 2 years. Metal ion levels were raised above the MHRA advised safety level in 20% of the metal-on-metal group and in 1 patient in metal-on-polyethylene group (who had a metal-on-metal implant on the contralateral side).
2012: At the annual American Academy of Orthopedic Surgeons conference, manufacturers promote metal-on-metal products to the 40,000 attendees.

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