Letters
Author Affiliations: Laboratoire de Génétique de Maladies Rares, Laboratoire de Génétique Moléculaire, Centre Hospitalo–Universitaire de Montpellier, Institut Universitaire de Recherche Clinique, Université de Montpellier, Montpellier, France (Koenig); Département de Neurologie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France (Tranchant, Anheim). Corresponding Author: Michel Koenig, MD, PhD, Laboratoire de Génétique de Maladies Rares, Institut Universitaire de Recherche Clinique, 641 Avenue du Doyen Gaston Giraud, 34093 Montpellier Cedex 5, France (michel.koenig @inserm.fr). Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by the Agence Nationale de la Recherche/E-rare JTC 2011 Euro-SCAR (grant 2011-RARE-004-54 01 to Dr Koenig). Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication 1. Renaud M, Anheim M, Kamsteeg EJ, et al. Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study. JAMA Neurol. 2014;71(10):1305-1310. 2. Balreira A, Boczonadi V, Barca E, et al. ANO10 mutations cause ataxia and coenzyme Q10 deficiency. J Neurol. 2014;261(11):2192-2198.
“It is more likely that the ICH occurred because patients who stopped their statins on account of adverse effects also stopped their antihypertensive medication.”4 It is extremely common for patients who experience adverse effects of medication to stop all their pills, not knowing which is responsible for the problem. And finally, I noted that patients “with ICH in SPARCL had higher blood pressures, as would be expected.”4 Patients with ICH in SPARCL were 6 times more likely to have stage 2 hypertension at the last visit before the ICH.5 J. David Spence, MD, FRCPC Author Affiliation: Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Ontario, Canada. Corresponding Author: J. David Spence, MD, FRCPC, Stroke Prevention and Atherosclerosis Research Centre, 1400 Western Rd, London, ON N6G 2V2, Canada ([email protected]). Conflict of Interest Disclosures: None reported.
3. Fogel BL, Lee H, Deignan JL, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014;71(10): 1237-1246.
1. Flint AC, Conell C, Rao VA, et al. Effect of statin use during hospitalization for intracerebral hemorrhage on mortality and discharge disposition. JAMA Neurol. 2014;71(11):1364-1371.
4. Sheridan JT, Worthington EN, Yu K, Gabriel SE, Hartzell HC, Tarran R. Characterization of the oligomeric structure of the Ca(2+)-activated Cl- channel Ano1/TMEM16A. J Biol Chem. 2011;286(2):1381-1388.
2. Gonzalez-Castellon MA, Marshall RS. Statin use and brain hemorrhage: real risk or unfounded fear? JAMA Neurol. 2014;71(11):1353-1354.
5. Micol R, Ben Slama L, Suarez F, et al; CEREDIH Network Investigators. Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. J Allergy Clin Immunol. 2011;128(2):382-9.e1.
3. Amarenco P, Bogousslavsky J, Callahan A III, et al; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355 (6):549-559. 4. Spence JD. Statins do not cause intracerebral hemorrhage. Neurology. 2012; 79(11):1076-1077.
Statins and Intracerebral Hemorrhage To the Editor In an article1 and accompanying editorial2 about intracerebral hemorrhage (ICH) and statins, Flint et al1 and Gonzalez-Castellon and Marshall2 gave too much credence to the controversy about statins causing ICH. Most of this controversy is probably owing to misinterpretation of the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.3 Flint et al1 slightly misquoted my editorial about this topic, 4 suggesting that I attributed the increase in ICH to the high crossover rate in SPARCL. The full quote is below, followed by my comments for clarification. I wrote that the “apparent increase of [ICH] in the SPARCL trial, which was largely responsible for the idea that the risk of [ICH] is increased from statins, was largely an artifact of the intention-to-treat analysis. In that study, patients with a previous stroke were randomized to high-dose atorvastatin or placebo. If atorvastatin had been causally related to ICH, levels of [low-density lipoprotein] should have been lower in patients with ICH, but they were not.”4 It is not plausible for low-density lipoprotein levels not to be lower in a group of people taking 80 mg of atorvastatin compared with a group taking placebo. As I continued, the “problem with the intention-to-treat analysis was that a quarter of patients randomized to placebo were crossed over to statin, and the fact that the [low-density lipoprotein] levels were not lower in patients with ICH means that they were not taking statins.”4 The former is why the study underestimated the reduction of stroke with statins, not why there was an excess of ICH. 240
5. Goldstein LB, Amarenco P, Szarek M, et al; SPARCL Investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Study. Neurology. 2008;70(24, pt 2):2364-2370.
In Reply We appreciate the comments Dr Spence made in response to our article1 and the accompanying editorial.2 While our group is convinced by the arguments he has made in the quoted editorial piece regarding the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial results, it is important to recognize that controversy does persist in the literature when it comes to this issue. As evidence of ongoing controversy on the question of whether long-term high-dose statin therapy may increase intracerebral hemorrhage (ICH) risk, in our article, we cited editorials arguing both sides of the issue. Additionally, the American Heart Association/American Stroke Association guidelines on the management of ICH call out the increased rate of ICH among patients randomized to atorvastatin in SPARCL but go on to state that “there is [sic] insufficient data to recommend restrictions on use of statin agents … (Class IIb, Level of Evidence C).”3 Other authors have recommended the use of a Markov decision model to identify patients with a history of ICH in whom (the authors argued) statins should be avoided.4 While one meta-analysis has argued that no overall relationship between statin use and ICH risk can be found,5 another meta-analysis reported a relationship between lower lipid levels and higher ICH risk.6 On the specific issue raised by Dr Spence concerning crossovers in the SPARCL trial, it was our intent to refer to patients taking statins after assignment to placebo, as well as patients
JAMA Neurology February 2015 Volume 72, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
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Author Affiliations: Laboratoire de Génétique de Maladies Rares, Laboratoire de Génétique Moléculaire, Centre Hospitalo–Universitaire de Montpellier, Institut Universitaire de Recherche Clinique, Université de Montpellier, Montpellier, France (Koenig); Département de Neurologie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France (Tranchant, Anheim). Corresponding Author: Michel Koenig, MD, PhD, Laboratoire de Génétique de Maladies Rares, Institut Universitaire de Recherche Clinique, 641 Avenue du Doyen Gaston Giraud, 34093 Montpellier Cedex 5, France (michel.koenig @inserm.fr). Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by the Agence Nationale de la Recherche/E-rare JTC 2011 Euro-SCAR (grant 2011-RARE-004-54 01 to Dr Koenig). Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication 1. Renaud M, Anheim M, Kamsteeg EJ, et al. Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study. JAMA Neurol. 2014;71(10):1305-1310. 2. Balreira A, Boczonadi V, Barca E, et al. ANO10 mutations cause ataxia and coenzyme Q10 deficiency. J Neurol. 2014;261(11):2192-2198.
“It is more likely that the ICH occurred because patients who stopped their statins on account of adverse effects also stopped their antihypertensive medication.”4 It is extremely common for patients who experience adverse effects of medication to stop all their pills, not knowing which is responsible for the problem. And finally, I noted that patients “with ICH in SPARCL had higher blood pressures, as would be expected.”4 Patients with ICH in SPARCL were 6 times more likely to have stage 2 hypertension at the last visit before the ICH.5 J. David Spence, MD, FRCPC Author Affiliation: Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Ontario, Canada. Corresponding Author: J. David Spence, MD, FRCPC, Stroke Prevention and Atherosclerosis Research Centre, 1400 Western Rd, London, ON N6G 2V2, Canada ([email protected]). Conflict of Interest Disclosures: None reported.
3. Fogel BL, Lee H, Deignan JL, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014;71(10): 1237-1246.
1. Flint AC, Conell C, Rao VA, et al. Effect of statin use during hospitalization for intracerebral hemorrhage on mortality and discharge disposition. JAMA Neurol. 2014;71(11):1364-1371.
4. Sheridan JT, Worthington EN, Yu K, Gabriel SE, Hartzell HC, Tarran R. Characterization of the oligomeric structure of the Ca(2+)-activated Cl- channel Ano1/TMEM16A. J Biol Chem. 2011;286(2):1381-1388.
2. Gonzalez-Castellon MA, Marshall RS. Statin use and brain hemorrhage: real risk or unfounded fear? JAMA Neurol. 2014;71(11):1353-1354.
5. Micol R, Ben Slama L, Suarez F, et al; CEREDIH Network Investigators. Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. J Allergy Clin Immunol. 2011;128(2):382-9.e1.
3. Amarenco P, Bogousslavsky J, Callahan A III, et al; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355 (6):549-559. 4. Spence JD. Statins do not cause intracerebral hemorrhage. Neurology. 2012; 79(11):1076-1077.
Statins and Intracerebral Hemorrhage To the Editor In an article1 and accompanying editorial2 about intracerebral hemorrhage (ICH) and statins, Flint et al1 and Gonzalez-Castellon and Marshall2 gave too much credence to the controversy about statins causing ICH. Most of this controversy is probably owing to misinterpretation of the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.3 Flint et al1 slightly misquoted my editorial about this topic, 4 suggesting that I attributed the increase in ICH to the high crossover rate in SPARCL. The full quote is below, followed by my comments for clarification. I wrote that the “apparent increase of [ICH] in the SPARCL trial, which was largely responsible for the idea that the risk of [ICH] is increased from statins, was largely an artifact of the intention-to-treat analysis. In that study, patients with a previous stroke were randomized to high-dose atorvastatin or placebo. If atorvastatin had been causally related to ICH, levels of [low-density lipoprotein] should have been lower in patients with ICH, but they were not.”4 It is not plausible for low-density lipoprotein levels not to be lower in a group of people taking 80 mg of atorvastatin compared with a group taking placebo. As I continued, the “problem with the intention-to-treat analysis was that a quarter of patients randomized to placebo were crossed over to statin, and the fact that the [low-density lipoprotein] levels were not lower in patients with ICH means that they were not taking statins.”4 The former is why the study underestimated the reduction of stroke with statins, not why there was an excess of ICH. 240
5. Goldstein LB, Amarenco P, Szarek M, et al; SPARCL Investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Study. Neurology. 2008;70(24, pt 2):2364-2370.
In Reply We appreciate the comments Dr Spence made in response to our article1 and the accompanying editorial.2 While our group is convinced by the arguments he has made in the quoted editorial piece regarding the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial results, it is important to recognize that controversy does persist in the literature when it comes to this issue. As evidence of ongoing controversy on the question of whether long-term high-dose statin therapy may increase intracerebral hemorrhage (ICH) risk, in our article, we cited editorials arguing both sides of the issue. Additionally, the American Heart Association/American Stroke Association guidelines on the management of ICH call out the increased rate of ICH among patients randomized to atorvastatin in SPARCL but go on to state that “there is [sic] insufficient data to recommend restrictions on use of statin agents … (Class IIb, Level of Evidence C).”3 Other authors have recommended the use of a Markov decision model to identify patients with a history of ICH in whom (the authors argued) statins should be avoided.4 While one meta-analysis has argued that no overall relationship between statin use and ICH risk can be found,5 another meta-analysis reported a relationship between lower lipid levels and higher ICH risk.6 On the specific issue raised by Dr Spence concerning crossovers in the SPARCL trial, it was our intent to refer to patients taking statins after assignment to placebo, as well as patients
JAMA Neurology February 2015 Volume 72, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
jamaneurology.com
