ischemic stroke, statins, lipid-lowering agents, secondary prevention of stroke, stroke prevention
Research presented at this year's meeting of the American Academy of Neurology (AAN) and at the International Stroke Conference (ISC) continues to support the use of statins in patients with ischemic stroke of atherosclerotic origin, even as physicians await the results of a large randomized controlled trial investigating the potential role of statins in stroke patients without coronary heart disease. "Cholesterol is a risk factor for stroke, although it may not be the strongest risk factor," said Ralph L. Sacco, MD, professor of neurology and epidemiology at Columbia University. Sacco delivered a plenary presentation on cholesterol, statins, and stroke at the AAN meeting, which took place April 1 through 8 in San Diego. "Statins have a role in secondary stroke prevention," he said.IN-HOSPITAL INITIATIONSeveral studies support the administration of statins during hospitalization after an ischemic stroke or transient ischemic attack (TIA), suggesting such treatment can reduce patients' short-term mortality and improve the likelihood that patients will continue to take the medication after leaving the hospital. These results have important implications about the role neurologists should play in prescribing statins, said Nerses Sanossian, MD, a stroke neurologist at the University of California at Los Angeles (UCLA). "Neurologists are the ones who see these patients in the acute phase," Sanossian said. "We shouldn't leave it to the primary care doctors to start these patients on statins."In a 32-center retrospective study of 1256 patients hospitalized after ischemic stroke, investigators found that 48-hour in-hospital mortality rates were 80% lower in those given lipid-lowering agents than in those who did not receive statins, after adjustment for risk factors.1 That study, presented at the ISC, held from February 16 to 18 in Kissimmee, Florida, also found that patients treated with statins had a significantly shorter stay than those who did not receive the treatment."This study suggests an interesting association between lipid-lowering agents and mortality that needs to be investigated further," said Norrina Allen, a doctoral student in the Department of Epidemiology and Public Health at Yale University in New Haven, Connecticut, who presented the findings. "There's a potential that all acute stroke patients could be given statins as soon as they reach the hospitals."For a stroke patient, starting statin therapy in the hospital almost guarantees that he or she will still be taking the medication 3 months later, Sanossian and a team of UCLA researchers found in a prospective study presented at the AAN meeting.2 Of 92 patients treated with statins following ischemic stroke or TIA of atherosclerotic origin, 94% were still taking statins at 3 months. The study population also demonstrated significantly lower levels of mean low-density lipoprotein cholesterol (LDL-C) at 3 months than at baseline; 88% had LDL-C levels of less than 100 mg/dL (vs 36% at baseline) and 82% had non-high-density lipoprotein levels of less than 40 mg/dL (vs 46% at baseline), in keeping with national cholesterol guidelines."If neurologists start statins at the time of discharge, there's a very good chance that patients will continue taking them," Sanossian said.PLUSSES OF PREVIOUS USEThe database used in the in-hospital mortality study did not consistently note whether a patient was already taking statins before experiencing a stroke, and none of the patients in the UCLA study had a history of statin use. However, research from the University of Cincinnati suggests that previous statin use may decrease 90-day mortality in ischemic stroke patients.3In a retrospective review of 1678 patients' first ischemic stroke, the findings of which were presented at the AAN meeting, the 90-day mortality was significantly lower in 215 patients with hyperlipidemia who had been taking statins before their stroke than it was in a reference group of 1285 patients who had no history of hyperlipidemia or statin use. In 130 patients with hyperlipidemia who had not been taking statins, the 90-day mortality was slightly higher than in the reference group.The findings of the University of Cincinnati researchers were consistent with those of Columbia University researchers, including Sacco, who reported last summer that the 90-day mortality rate for first ischemic stroke patients who had been taking lipid-lowering agents before their stroke was significantly lower than the rate for patients not taking lipid-lowering agents (1.8% vs 10.6%).4 In that 650-patient study, which analyzed a subset of the Northern Manhattan Study population, the 57 patients taking lipid-lowering agents were significantly less likely to experience clinical worsening while in the hospital than those not taking lipid-lowering agents (6.3% vs 18.2%), but they were no less likely to suffer a severe stroke.STATINS AND THE ELDERLYResearch presented at the AAN meeting and the ISC also examined the use of statins in the elderly. The research primarily documented the treatment's safety although it did not conclusively demonstrate effectiveness of statins for secondary stroke prevention in at-risk older patients.Researchers in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) study analyzed a subgroup of 2400 hypertensive patients older than 65 years from a broader patient population of more than 10,000 persons who were randomly selected to receive a statin or placebo. They found no significant between-group difference in the number of reported serious adverse events during a mean follow-up of slightly more than 3 years.5 Results presented at the ISC further indicated no significant between-group differences in levels of creatine phosphokinase or alanine aminotransferase, suggesting that elderly statin users are at no greater risk for liver or muscle damage than are nonusers.Researchers from Pfizer, which manufactures atorvastatin (Lipitor), reviewed 50 published and unpublished trials and also found that rates of adverse events in patients treated with atorvastatin were similar to rates seen in patients treated with placebo and did not increase with dose (from 10 to 80 mg).6 Elevated levels of alanine aminotransferase and aspartate aminotransferase were seen in 3.2% patients receiving 80 mg of the drug, compared with 0.9% of patients receiving placebo, suggesting a possible increased risk of liver damage. Serious hepatobiliary adverse events occurred in 0.6% of 1698 patients in the 80-mg dose group and in 0.64% of 2042 patients in the 10-mg dose group. Creatine phosphokinase levels were very low (0% to 0.2%) and did not differ between groups; myalgia was reported in 3 patients in the 80-mg dose group and in 1 patient in the placebo group, and no cases of myopathy or rhabdomyolysis were reported in any groups.Elderly ASCOT-LLA patients treated with statins experienced an 18% lower incidence of fatal and nonfatal stroke than those taking placebo. This finding, although not statistically significant, contrasts with the Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) trial, published in 2002,7 which found that statin use had no effect on stroke risk in patients older than 70 years despite the fact that it significantly reduced the risk of heart disease. Neither the ASCOT-LLA analysis nor the Pfizer analysis reported new cancer diagnoses, which in the PROSPER study were found to be 25% higher among patients treated with statins than among patients receiving placebo.NEUROPATHY RISKA prospective study from the Czech Republic, however, added to the existing body of research suggesting that long-term treatment with statins may result in damage to the peripheral nervous system.8 Pavel Otruba, MD, and colleagues from the Department of Neurology at Palacky University in Olomouc, found statistically significant increases in F-wave mean latency of the peroneal and tibial nerves compared with baseline levels in 42 patients with hyperlipidemia treated with a 20-mg daily dose of simvastatin for 24 months. None of the patients reported subjective symptoms of polyneuropathy or myopathy.The Czech study's findings are consistent with those of a 2002 study from Odense University Hospital in Denmark,9 which found that the odds of receiving an idiopathic peripheral neuropathy diagnosis were 3.7 times higher for those with a history of statin use, 4.6 times higher for current users, and 26.4 times higher for those who had taken statins for 2 years or more compared with controls."STAY TUNED"Given that the vast majority of stroke patients do not have atherosclerosis, the most intriguing question about stroke and statins may be whether statin use can reduce the incidence of stroke in patients who do not have coronary artery disease. To this end, neurologists specializing in stroke are eagerly awaiting the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial,10 in which study participants have a history of TIA or stroke and have LDL-C levels between 100 and 190 mg/dL, but do not have coronary heart disease. The results of the 5-year multicenter study, which randomized more than 4700 patients to receive either 80 mg/d of atorvastatin or placebo, are expected to be announced later this year."Stay tuned for SPARCL," Sacco said.REFERENCES1. Allen NB, Brass LM, Cerese J, et al. Use of lipid-lowering agents during acute ischemic stroke decreases in-hospital mortality. Stroke. 2006;37:625.2. Sanossian N, Saver J, Liebeskind D, et al. Adherence rates and achievement of target cholesterol goals 3 months after hospital initiation of statins in stroke patients. Neurology. 2006;66(suppl 2):A25.3. Cho Y, Khoury J, Kleindorfer D, et al. Pretreatment with HMG-CoA reductase inhibitors reduces mortality after ischemic stroke in a population-based setting: Results from the Greater Cincinnati/Northern Kentucky Stroke Study. Neurology. 2006;66(suppl 2):A190.4. Elkind MS, Flint AC, Sciacca RR, Sacco RL. Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortality. Neurology. 2005;65:253-258.5. Poulter NR, Dahlof B, Sever PS, et al. Impact of atorvastatin on cardiovascular events in 2440 men and women aged 65 years and above: evidence from the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA). Stroke. 2006;37:695.6. Hey-Hadavi JH, Kuntze E, Luo D, et al. Tolerability of atorvastatin in a population aged greater than or equal to 65 years. Neurology. 2006;66(suppl 2):A26.7. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623-1630.8. Otruba P, Kanovsky P, Hlustik P. Treatment with statins and frequency of peripheral nervous system complications: results of a prospective study. Neurology. 2006;66(suppl 2):A84.9. Gaist D, Jeppesen U, Andersen M, et al. Statins and risk of polyneuropathy: a case-control study. Neurology. 2002;58:1333-1337.10. Amarenco P, Bogousslavsky J, Callahan AS, et al. Design and baseline characteristics of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) study. Cerebrovasc Dis. 2003;16:389-395.JORDANA BIEZE FOSTER is a freelance writer in Stow, Massachusetts and former editorial director of Applied Neurology.