We report the case of an 86-year-old man with a past history of coronary disease admitted to ourinternal medicine department for severe asthenia and weakness due to rhabdomyolysis. Three days earlier, he had been discharged from a gastroenterology unit with adiagnosis of amoxicillin–clavulanate-induced acute cholestatic hepatitis. A review of his drugs revealed that he had taken atorvastatin 10 mg daily in theprevious six years, without clinical or laboratory signs of myopathy. Atorvastatin was therefore stopped, with gradual improvement of therhabdomyolysis. All concomitant drug therapy needs to be reassessed in elderly patients, especially when they become acutely ill.
Statin myopathy, rhabdomyolysis, statin toxicity
Statin myopathy is a common concern for clinicians managing patients withdyslipidaemia. Well-known risk factors for statin toxicity include advanced age, female gender, hypothyroidism, diabetes, excessive alcohol consumption,concomitant use of drugs that increase statin blood concentration, a history of muscle complaints or elevated creatine kinase and history of renal or hepatic dysfunction[1]. However, the risk of statin toxicity may be easily overlooked when liver dysfunction occurs de novo in patients until then tolerant to statins, as exemplified by the present case report.
An 86-year-old man with a past history of coronary disease (coronary artery bypassgrafting and percutaneous transluminal coronary angioplasty, 6 and 4 years earlier, respectively) was admitted to our internal medicine department for severeasthenia and weakness following a lipothymic event. Three days earlier, he had been discharged from a gastroenterology unit with a diagnosis ofamoxicillin–clavulanate-induced acute cholestatic hepatitis. He had been able to ride his bicycle until the day before his first hospitalization, but now hehad become unable to get up and walk without help. At physical examination, he appeared an acutely ill elderly man, with jaundice, severe muscle weakness andbrown urine. Routine laboratory tests showed that – in comparison to those obtained at discharge – cholestasis indexes had improved, but cytonecrosisindexes and kidney function tests had deteriorated, with clear evidence of rhabdomyolysis (Table 1).
| First hospital stay | Readmission | |||||||
|---|---|---|---|---|---|---|---|---|
| Day 1 | Day 4 (discharge |
Day 1 | Day 4 | Day 5 | Day 8 | Day 14 | Day 22 (discharge) |
|
| Creatinine (mg/dl) |
1.44 | 2.09 | 1.45 | 2.19 | 3.02 | 1.72 | 1.59 | |
| Bilirubin (mg/dl, total) |
14.7 | 13 | 10.7 | 6.10 | 4.7 | 3.6 | 2.7 | |
| Direct | 14.3 | 10.8 | 6.40 | 2.7 | ||||
| AST (U/l) | 229 | 236 | 564 | 1,093 | 227 | 95 | ||
| ALT (U/l) | 154 | 138 | 188 | 338 | 244 | 119 | ||
| GGT (U/l) | 375 | 336 | 376 | 279 | 342 | 442 | ||
| ALP (U/l) | 3,486 | 3,209 | 2,320 | 1307 | ||||
| CPK (U/l) | 16,839 | 28,949 | 21,669 | 15,754 | 1,167 | 323 | ||
| Myoglobin (U/l) | >10,000 | >10,000 | >10,000 | >10,000 | 731 | 405 | ||
AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; CPK, creatine phosphokinase
Table 1 - Laboratory tests
The patient had no history of recent crush injuries, immobilization, seizure,extreme exertion, hyperkinetic states, alcoholism, electrolyte abnormalities or hypothyroidism. He had been prescribed amoxicillin–clavulanate (1 g twice daily for 7 days) by his general practitioner for lymphoedema, although two months earlier he had had malaise, not better specified, after having received thesame drug for bronchitis. A review of his drug therapy revealed that he had consumed atorvastatin 10 mg daily in the previous six years, without any clinical or laboratory signs of myopathy. Atorvastatin was therefore promptly stopped, with gradual improvement first of laboratory indexes and later of clinical conditions. After a hospital stay of approximately 3 weeks, he was able to eat completely independently, to seat himself and to walk shortdistances with assistance.
Statins are remarkably safe and effective in preventing cardiovascular complicationsand death and have become the most prescribed class of drugs worldwide. Clinical trials suggest that muscle injury is uncommon with statin therapyalone, with estimated frequencies of 2–11% for myalgias, 0.5% for myositis and <0.1% for rhabdomyolysis. However, clinical trials, based on patients selected for being at low risk for drug-related complications, may underestimate the true prevalence of statin myopathy in clinical practice[2]. Moreover, the onset of muscle symptoms is usually within weeks to months after the initiation of statin therapy, but may occur any time during treatment[3]. Clinicians should pay particular attention to patients’ vulnerability to acute or chronic renal failure, obstructive liver disease and when statins extensively metabolized by cytochrome P-450 3A4 (lovastatin, simvastatin, atorvastatin) are administered together with drugs that interfere with CYP3A4[4].
Amoxicillin–clavulanate liver injury tends to occur more often in elderly male patients and is almost always associated with comorbidities and/or polytherapy concomitant medications with known potential for hepatic adverse effects[5].
In this case, it was certainly predictable, because drug therapy needs to befrequently and carefully reassessed in elderly patients, especially when they become acutely ill.
In turn, if statin treatment is not interrupted despite the presence of acute severe cholestasis, rhabdomyolysis is not unexpected.
In our opinion, the two factors that led to this potentially very risky situation were (a) the false confidence created by this gentleman tolerating atorvastatin well over the years and (b) the lack of attention paid by sub-specialists to the complexities of drug therapy in elderly patients who present with multiple conditions.
The use of statins in the very elderly is still a matter of debate. The Heart Protection Study, the PROSPER study and the SAGE study illustrate the benefit of statin treatment on coronary or surrogate end points in higher-risk elderly patients, although the data are still somewhat controversial, particularly for individuals >80 years of age. Very elderly people are likely to suffer comorbidities, possibly of more immediate importance than future cardiovascular events. In such circumstances, prescribing a statin should not be a high priority, particularly when treatment with multiple drugs is ongoing or when adherence is an issue.
In conclusion, this case warns us that physicians should be able to update theirpractice based on experience and learning and never underestimate the effect of intercurrent events (new diseases, introduction of new drugs), even in patient swho have demonstrated good tolerance to statins over the years.