June 30, 2011 | 10
My frail, 92-year-old mother was prescribed 80 mgs of the cholesterol-lowering drug, or statin, simvastatin for years. She fell four times in the last four years of her life: the last fall was the least forgiving. Doctors diagnosed her with rhabdomyolysis, a life-threatening condition, and acute kidney failure; she was dead within 8 weeks.
Source: Laura Newman
The MedlinePlus encyclopedia defines rhabdomyolysis as "the breakdown of muscle fibers and release of their contents (myoglobin) into the bloodstream." 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 Alert states that symptoms to watch for are: "muscle pain, tenderness or weakness, dark or red-colored urine, and unexplained fatigue" and should be brought to the attention of a health professional. Further, it advises doctors to inform patients taking that dose that they are at risk for rhabdomyolysis.
Rhabdomyolysis is a medical emergency. It is not uncommon after crush injuries, falls, and athletic feats. FDA’s safety warning that 80 mg simvastatin is linked to myopathy, issued on June 8, 2011, struck a chord in me because the 80 mg dose of simvastatin was the same given my mother.
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 women. 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 low-level, well-controlled hypertension, but a high cholesterol. I sensed deterioration months before she was diagnosed with rhabdomyolysis. Before she developed life-threatening rhabdomyolysis, she walked everywhere.
The Author and her mother in Canadian Rockies celebrating her 90th birthday. Source: Laura Newman
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." Who knew whether it was normal aging? Her doctor did not think much of these changes.
FDA’s Simvastatin 80 mg Warning
FDA’s Drug Safety Communication: New Restrictions, Contraindications, and Dose Limitations for 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 is taking a major step to improve the public’s health. Whether it is 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.
Prescribing Simvastin in the Elderly
Rodney Hayward, professor of public health and internal medicine at the University of Michigan, told me that sometimes, fatigue and muscle weakness are attributed to aging, when the culprit might be excess dosing. He said: "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 especially 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 ate like that for decades. 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, points out that many 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 statins at all for low-risk women like my mother, yet some doctors go so far as to put them on high-dose statins.
So one could argue that the benefit-risk ratio shifts towards harm in such women, particularly when they are given high-dose 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." People over age 75 are under-represented in clinical trials, leaving physicians in the dark as to safety.
Moreover, said Hayward: "With stepped-up dosing, the risk for harm escalates disproportionally. Most of the benefit from the simvastatin is in the initial dose. "
Factors in Overtreatment
Another issue of concern is whether overtreatment with high-dose statins has become widespread because of how heavy marketing, according to Hayward. Marketing of some statins promised achieving very low levels of low-density lipoprotein (LDL) cholesterol (a.k.a. "bad cholesterol"). It proved a valuable selling point. Setting targets this low may be inappropriate for the elderly, according to numerous pharmacoepidemiologists.
Also adding to the problem of overmedication are pay for performance (P4P) programs, which set specific targets in cholesterol-lowering to payment. Target setting is controversial because they may be too low for many individuals, yet they are widely used for assessing quality of care. One notable exception that may actually help keep the healthy elderly is that in HEDIS performance measures, people over age 75 are excluded from lipid-lowering targets.
Differences in the Elderly, in Women
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 (Zulman, Sussman, Chen, Cigalle et al., 2010; McMurd, Witham, Gillespie, 2005; Scott and Guyatt, ).
We are really in new terrain now, with an aging boom and more pills available for any symptom than could ever have been fathomed America’s shifting demographics in the United States, as evidenced by the most recent US Census Bureau report (Table left). The number of people in the oldest age group, namely age 85 and over, is rising, projected to grow from 5.8 million in 2010, to 8.7 million in 2030, and 19 million by 2050, according to the US Census Bureau. Not only have people age 75 and over been largely excluded from clinical trials, subgroup analyses in the aged have barely begun.
These should be compelling reasons 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 its 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, describes the issues this way: "The problem is Congress and our research agencies. They fund so little work on the pharmacology of the aged and other demographic subgroups, and their risk of drug interactions. And, there is phenomenally small, and shrinking by 60% (down to $5.1 million/year), amount of money being spent supporting the 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 for the elderly. 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 impossible odds, yet physicians who care for the elderly have little science to guide them.
This is where Congress, the Centers for Medicare and Medicaid Services, and the FDA must step up, expand funding, and beef up post-marketing drug surveillance. FDA has a treasure trove of safety data that has been deemed proprietary, some of it preferentially published, that 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 is industry-supported and the industry can hide safety data," he said, "but with public pressure, ineffectiveness and harm may be detected."
Without well-funded research and analyses of subgroups of the aged (age 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.
The aged take disproportionally more drugs than every group, and as a result are more at risk for drug-drug interactions. It will take a significant commitment from the federal government to marshall science and surveillance of drugs in this population.
Rhabdomyolysis. Accessed on June 27, 2011.
FDA Simvastatin 80 mg drug safety. Accessed on June 27, 2011.
Armitage et al. (2010) Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial, Lancet: 376(9753):1658-69. Epub 2010 Nov 8.
Morandi et al. Inappropriate Medications in Elderly ICU Survivors: Where to Intervene? Arch Intern Med.2011; 171: 1032-1034.
Risk Assessment Tool for Estimating Your 10-year Risk of Having a Heart Attack Ten-Year Cardiovascular Disease Risk Calculator. Third report from the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol. Downloaded on June 27, 2011.
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Scott IA, Guyatt GH. Cautionary tales in the interpretation of clinical studies involving older persons.Arch Intern Med. 2010 Jun 14;170(11):927.
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Vincent, Grayson K. and Victoria A. Velkoff, 2010, THE NEXT FOUR DECADES, The Older Population in the United States: 2010 to 2050, Current Population Reports, P25-1138, U.S. Census Bureau, Washington, DC.
Hamilton H, Gallagher P, Ryan C, Byrne S, O’Mahony D. Potentially Inappropriate Medications Defined by STOPP Criteria and the Risk of Adverse Drug Events in Older Hospitalized Patients. Arch Intern Med. 2011 Jun 13;171(11):1013-9
Schnipper J. Medication Safety: Are We There Yet?: Comment on "Potentially Inappropriate Medications Defined by STOPP Criteria and the Risk of Adverse Drug Events in Older Hospitalized Patients". Arch Int Med 2011 Jun 13;171(11):1019
About the Author: Laura Newman writes about medicine, health policy, and clinical outcomes research. She has a long-term interest in healthcare reform and what matters to patients. She has written news in health and medicine in peer-review journals, on the web, and for newsletters. Laura blogs at Patient POV, is active on twitter at @lauranewmanny, and she is especially interested in integrating patients into health reform efforts.
The views expressed are those of the author and are not necessarily those of Scientific American.
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