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:
- Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drugs.
- 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.
- Muscle problems typically occur in the first year of use.
- 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.
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.”
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.