Metal-on-Metal Hips: A Tale of Harm, Weak
Medical Device-Approval, and Lax Postmarket Scrutiny

Hip replacement, National Institutes of Health

Nearly 1 million metal-on- metal hips have been implanted in patients in the United States, making the US the world’s largest consumer of the implants. According to a BMJ/BBC Newsnight Investigation released today, the “risks associated with these devices have been known for decades, yet patients have been kept in the dark about their participation in what has effectively been a large uncontrolled experiment.” At issue are “leaky hips,” specifically, “release of metal ions that can seep into local tissue causing reactions that destroy muscle and bone and leaving some patients with long term disability,” writes Deborah Cohen, BMJ’s Investigations Editor. In a companion paper, Carl Heneghan, MD, director of the Centre for Evidence-Based Medicine, University of Oxford, Oxford, UK, and coauthors, point to the litany of safety warnings out on these implants for a decade or more.

Together, these reports point out:

  • internal memos deemed proprietary acknowledging safety issues dating back more than a decade;
  • lack of medium-to-long-term safety and reliability data on these devices;
  • uncertainty about safe levels of metal (cobalt and chromium) ion exposure;
  • design flaws;
  • a weak device regulatory approval process, seemingly more intent on rapid market entry, and not requiring clinical data submission prior to approval;
  • postmarketing databanks in the EU that alone are insufficient for flagging safety;
  • and despite all of this, exhibitors at a February 2012 American Academy of Orthopedic Surgery annual meeting, showcased metal-on-metal hips to thousands of attendees.

This story is hardly new, but what’s alarming is that the metal-on-metal hip story is emblematic of how thousands of medical devices like hip implants get out to market. FDA does not require clinical data submissions, but merely proof that the implants are “substantially similar” to other devices already out there through FDA’s 510(k) program.

Richard Deyo, MD, Professor of Evidence-Based Family Medicine, Oregon Health and Science University, Portland, OR, reviewed the report. In an email, Deyo wrote: “I think implanted medical devices should have much closer pre-approval scrutiny than they currently receive, and there is a need for much better post-marketing surveillance. The latter might uncover problems of this sort before too many patients are affected.”

As far as patients are concerned, Deyo wrote: “Patients may want to inquire as to the length of the track record for any implantable device. This is a situation where it’s not safe to assume that the latest is the greatest. It often takes years to learn about the durability of implants, and some new devices prove to be worse than older ones.”

Rita F. Redberg, MD, Professor of Medicine at the University of California San Francisco, told Patient POV:  ““We are dependent on foreign registries for data on hip implants and currently,there is no provision that would require collection and reporting of such data.” Redberg says we need more data in the  FDA premarket process, as well as more consistent and complete postmarketing surveillance. “A  US hip and knee registry would help,” Redberg said, adding that plans for such are moving very slowly.

Hip and knee replacement registries are further along outside of the United States. In 1999, Australia launched a mandatory, confidential hip and knee registry that generates detailed information on outcomes, implant performance, patient deaths, and revisions. Proponents say that it has been helpful in real-time quality control, in weeding out poorly performing implants, as well as pushing orthopods with less-than-optimal outcomes to improve their technique or stop doing implants. New Zealand similarly launched its registry in 1999.

In both Australia and New Zealand, individual surgeon data has not been discoverable, but this has been a sticking point for the US-based Association of Health Care Journalists and ProPublica, who have been fighting in the US to have the HHS National Practitioner Databank accessible at the provider level.

Patients need to think through who they should lobby to improve their odds of getting a safe, new hip, pacemaker, or new knee, should they need them. Thousands of devices become FDA approved through the 510(k) process, without clinical data submission. Sadly, I doubt most of us, including me, have tools available to make the best choice on where to go for a hip implant with a good track record and an orthopod with good outcomes. I haven’t found the websites of orthopedists very helpful.

A mandatory, real-time patient registry with uniform requirements would be a step in the right direction, but headway in this area has been slow. Putting safety first and insisting that industry submit clinical data before the FDA approves new devices is paramount. The 510(k) process needs to be abandoned and supplanted with clinical data reviewed by FDA. Postmarketing surveillance needs to be ramped up so that safety problems are flagged as early as possible. Comparative effectiveness research could also go a long way in evaluating the safety of implanted devices. Even though cost effectiveness research provisions are in place through the Accountable Care Act, orthopods have yet to contribute to the process.

An earlier version of this article misquoted Dr. Redberg. The corrected quote appears above.


Inattention to Drug Safety in the Elderly
Leaves Generations At Risk

This post originally appeared in a slightly different form in Scientific American’s guest blog on June 30, 2011.

My frail, 92-year-old mother was prescribed 80 mg of the cholesterol-lowering drug, or statin, simvastatin (Zocor) for years, possibly decades. She fell four times in the last four years of her life: the last fall was the least forgiving. Doctors diagnosed her with rhabdomyolysis and acute kidney failure; she was dead within 8 weeks.  She died in December 2007.

The MedlinePlus encyclopedia defines rhabdomyolysis as “the breakdown of muscle fibers and release of their contents (myoglobin) into the bloodstream.”[More specifically, myoglobin is the protein part of muscle fiber that transports oxygen through muscle.] In severe case, “the myoglobin breaks down into potentially harmful compounds, blocking the kidneys, causing damage such as acute tubular necrosis or kidney failure. Dead muscle tissue may be caused by any condition that results in damage to skeletal muscle, especially trauma.”

The FDA Safety Communication, issued on June 8, 2011, states that symptoms to watch for are: “muscle pain, tenderness or weakness, dark or red-colored urine, and unexplained fatigue” and be brought to the attention of a health professional. Rhabdomyolysis is a medical emergency. It is not uncommon after crush injuries, falls, and athletic feats.

FDA’s safety warning for high-dose simvastatin struck a chord in me because the 80 mg dose of simvastatin was the same given my mother.

FDA’s Simvastatin 80 mg Warning

FDA’s Drug Safety Communication on high-dose simvastatin to reduce the risk of muscle injury  state:

  1. Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drugs.
  2. Patients taking simvastatin 80 mg have an increased risk of myopathy compared to patients taking lower doses of this drug or other drugs in the same class.
  3. Muscle problems typically occur in the first year of use.
  4. FDA did not place any caveats on use of 80 mg in the elderly or in people who are high fall risks. It is well known that rhabdomyolysis occurs with falls.

FDA also applied the same restrictions to Vytorin, which combines 80 mg simvastatin with ezetimibe, and Simcor, which combines 80 simvastatin with niacin. FDA leaves the issue of people already on 80 mg simvastatin for one year or more to the discretion of physicians, pointing out that rhabdomyolysis cases are most likely to occur during the first year of taking a high dose. FDA is taking a major step to improve the public’s health. Whether FDA went far enough is debatable.

The consumer health advocacy group, Public Citizen considers 80 mg simvastatin unsafe and wants it off the market to protect the public. On its Worst Pills, Best Pills website  (subscribers only), it presses for a recall of 80 mg dose and urges consumers, no matter how long they have been on it, to ask their doctor for an alternative that is weaker.

According to FDA’s Safety  Communication, approximately 2.1 million patients in the US were prescribed a product containing 80 mg simvastatin in 2010.

An article in the Nov. 13, 2010 Lancet sounded an alarm that high-dose simvastatin could be hazardous. In a blinded randomized trial of more than 12,000 survivors of acute myocardial infarction, investigators found two (0·03%) cases of myopathy in patients taking 20 mg simvastatin daily, compared with 53 (0·9%) cases in the 80 mg group.

This finding could not be ignored. FDA pressed forward in further analyses. Even as my mother was in crisis, doctors told me that they were astounded that such a high-dose statin was given to a low-risk, frail, elderly woman.  By low-risk, she had no history of cardiovascular disease and she met the widely used and time-tested Framingham Risk Factor criteria. She did not smoke, had moderate, well-controlled hypertension, but a high cholesterol. I sensed deterioration months before she was diagnosed with rhabdomyolysis.  She walked everywhere.

The author and her mother celebrating her 90th birthday in the Canadian Rockies.

One night, she called me, saying: “All of a sudden I feel exhausted, like my legs won’t support me, and I keep stopping and sitting down. I just don’t think I can do it anymore.”

Prescribing Simvastatin in the Elderly

Who knew whether it was normal aging?  Her doctor did not think much of these changes.

There is no consensus on treatment in elderly patients, but many physicians worry that high doses are more dangerous in the elderly and that scientific data is scant. Rodney Hayward, MD, University of Michigan, professor of public health and internal medicine, told me that sometimes, fatigue and muscle weakness are attributed to aging, but that you must look at dosing. “Unfortunately, people don’t realize that an excessive dose might be causing loss of appetite, muscle problems, and not eating enough. The most common adverse event with the high-dose statins are the myopathies, pain in the muscles. And if the old are not doing well, the sensible thing is to taper down.”

Also, of critical importance, “as people age, the risks and benefits of people being on medicine change,” said Hayward. “Processing through the kidneys is increasingly less effective. You want to be aware of how many medications, and how many doses people are on, and reconcile that with the amount of benefit and risk.”

I thought that my mother had an eating disorder.  She ate very little; it was all low-fat, low cholesterol, and low salt. She was 5’ 1” and weighed about 105 pounds. Her refrigerator was pretty empty.

Rita Redberg, MD, director of women’s cardiovascular services, the University of California San Francisco, said: “Most trials of hyperlipidemia have not included enough women to determine gender-specific benefits and harms. Therefore, meta-analyses and systematic reviews become imperative.” But particularly glaring is the reality that most studies have never demonstrated a survival benefit for low-risk women like my mother who are on statins. Both Redberg and Hayward said that they know of no studies showing that low-risk people taken off statins are at increased risk for cardiac events.

Hayward, Redberg, and many other physicians argue that doctors should be far more cautious in prescribing medications for the elderly. “High-dose statins should almost never be used in the elderly,” said Hayward. “In fact,” he added: “I almost always use low doses of statins in people over 75 unless they have known heart disease, since most of the benefit of statins is achieved with low doses and there are good reasons to be concerned about the safety and tolerance of higher doses of statins in the elderly.” In particular, he stressed: “With stepped-up dosing, the risk for harm escalates disproportionally.” Moreover, he said:  “Most of the benefit from the simvastatin is in the initial dose. “

Other Factors in Overtreatment

Another issue of concern is whether overtreatment with high-dose statins could be directly related to how pharmaceutical companies promising very low levels of low-density lipoprotein (LDL) cholesterol (AKA “bad cholesterol,” Setting targets this low may be inappropriate for the elderly.

Also adding to the problem of overmedication are pay for performance (P4P) programs, which tie specific targets in cholesterol-lowering to payment. Target setting is controversial, yet widely practiced, and Hayward is hardly alone in his criticisms. One notable exception that may actually help keep the elderly healthy is that in HEDIS performance measures, people over age 75 are excluded from lipid-lowering targets.

Treatment Protocols for the Elderly

Arguments pressing for treating the elderly differently have been commonplace for decades because the elderly have been under-represented in clinical trials; hence, guidance on practice are not science based.

We are really in new terrain now, with an aging boom and more pills available for any symptom than could ever have been predicted.  The number of people in the oldest age group, namely age 85 and over, is projected to grow from 5.8 million in 2010, to 8.7 million in 2030, and 19 million by 2050. People age 75 and over were largely excluded from clinical trials and subgroup analyses by age are barely beginning.

This should be a compelling reason for FDA, the Centers for Medicare and Medicaid Services, and Congress to back drug safety initiatives in the elderly.  Many health researchers are also urging further study of potentially inappropriate medications (called PIMs) in elderly patients. Archives of Internal Medicine highlighted the problem in the June 13, 2011 issue, and there is a growing literature on it.

A recent study of elderly ICU survivors found that 85 percent were discharged with 1 or more potentially inappropriate medicines, with more than 50 percent in that group discharged with medications deemed more harmful than beneficial (Morandi et al, 2011). The authors press for more attention to appropriateness reviews, with the rationale for starting each therapy in the ICU, and discussion of when it can be stopped.

Brian Strom, MD, professor of public health and pharmacology, University of Pennsylvania, raises other issues.  “The problem is Congress and our research agencies, who fund so little work on the pharmacology of the aged and other demographic subgroups, and their risk of drug interactions. And, the phenomenally small, and shrinking by 60% (down to $5.1 million/year), amount of money being spent supporting (FDA’s} Centers for Education and Research and Therapeutics, who are charged with doing studies that industry would not fund, and with changing prescribing to be more rational.”

Caregiver Remorse

The entire experience of trying to find quality care for my mother was made especially difficult because of the dearth of good clinical practice guidelines and science guiding chronic care. I think it is way too much to ask family and caregivers to take this on. Now both my parents are dead. I see friends and family struggle under heavy odds, trying to get good quality care with physicians  practicing with little science.

This is where Congress, FDA, and the Centers for Medicaid and Medicare Services must step up, expand funding, and beef up post-marketing drug surveillance. A treasure trove of medication safety data is deemed proprietary, and even the FDA is restricted in the circumstances under which it can review the original data, according to Hayward. “Since the results of trials are often preferentially published, objective review of these data could improve the public’s health. “No one has the right to inspect this data except the FDA,” said Hayward. “Most of the trials data are industry supported and the industry can hide safety data,” he said, “but with public pressure, medication ineffectiveness and harm may be detected.”

Without well-funded research, subgroup analyses of the aged (ages 85-100), and postmarketing surveillance, the US is operating in too much darkness and uncertainty for the public’s health. Many generations of Americans will continue to suffer.