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EDITORIALS: Larry B. Goldstein Low LDL cholesterol, statins, and brain hemorrhage: Should we worry? Neurology 2007; 68: 719-720 [Full text] [PDF]

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Low LDL cholesterol, statins, and brain hemorrhage: Should we worry?

Eddie Vos, Paul de Groot, MD, PhD   (11 June 2007)

Reply from the Editorialist

Larry Goldstein, MD, FAAN, FAHA   (11 June 2007)

Low LDL cholesterol, statins, and brain hemorrhage: Should we worry?

Luca Mascitelli, Francesca Pezzetta   (1 April 2007)

Reply from the Editorialist

Larry B. Goldstein   (1 April 2007)

Low LDL cholesterol, statins, and brain hemorrhage: Should we worry? 11 June 2007
Eddie Vos, independent researcher 127, Courser Rd. Sutton (Qc) Canada J0E 2K0, Paul de Groot, MD, PhD Send Correspondence to journal: Re: Low LDL cholesterol, statins, and brain hemorrhage: Should we worry? vos{at}health-heart.org Eddie Vos, et al.	The editorial by Goldstein about brain hemorrhage asks whether we should worry about low cholesterol and the editorialist presents epidemiological data that indeed we should. [1] Further evidence comes from the J-LIT [2] study where hypercholesterolemic non-stroke patients from 6500 general practitioners were placed on simvastatin for 6 years. The cerebrovascular disease rate was found to be 1.7% in the highest octile for total cholesterol at baseline, >322 mg/dL (8.2 mM), which was the on-statin group of >280 mg/dL (7.2 mM).  On the other hand, the rate was 6.3%, 3.7x higher, in the bottom octile which was the group with baseline total cholesterol below 253 mg/dL (6.5 mM) an on-statin level of <160 mg/dL (4.1 mM).  This begs the question why one would want to further lower cholesterol. The editorialist dismisses the borderline significant doubled incidence of hemorrhagic stroke on simvastatin in the placebo controlled HPS study. [3] While the HPS finding was indeed a post hoc subgroup result, the editorialist arguably misrepresents the SPARCL [4] atorvastatin (Lipitor®) stroke study where the 66% increase in hemorrhaging stroke reached a probability of p=<0.025.  This was not post hoc as stated, but an endpoint reported in the abstract applying to the entire study population, not just a subgroup.  This is more ominous since hemorrhaging stroke was a conditional exclusion criterion with only 2% of participants suffering such stroke before study entry. SPARCL was disappointing. This study compared top dose atorvastatin vs. placebo which cannot be used to justify the editorialist's statement that ".. the data support the use of statins in patients with a history of cerebrovascular disease." Atorvastatin treatment resulted in more overall deaths, one more death from cardiac causes, 22 more hemorrhaging strokes (1 fewer fatal), 56 fewer ischemic strokes (18 fewer fatal). However, 18 more patients died on atorvastatin ".. from causes other than stroke before they could have a nonfatal stroke [sic]." Despite such disappointing results, the editorialist suggests "profound reductions in other major vascular events" in SPARCL. This is without noting that such combined non-fatal endpoint events may be related not to atorvastatin's cholesterol-lowering effect but its anti-inflammatory and nitroglycerin mimicking effect, reducing non-fatal angina driven hospital visits and subsequent surgical interventions. SPARCL supports the placebo controlled ASCOT [5] study where atorvastatin reduced angina by 40% while having zero effect on mortality. The editorialist should have presented the numbers needed to treat before suggesting benefit in stroke in an editorial about brain hemorrhage. The data consistently suggest harm from low or lowered cholesterol levels, and that most certainly includes the SPARCL study. References 1. Goldberg LB. Low LDL cholesterol, statins, and brain hemorrhage: Should we worry? Neurology. 2007 Mar 6;68:719-20. 2. Matsuzaki M, Kita T,Mabuchi H, et al. Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia. Circ J 2002;66:1087-95. 3.Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757–767. 4. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-59. 5. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-1158. Disclosure: The authors report no conflicts of interest.
Reply from the Editorialist 11 June 2007
Larry Goldstein, MD, FAAN, FAHA, Duke University Medical Center Durham, NC 27710 Send Correspondence to journal: Re: Reply from the Editorialist golds004{at}mc.duke.edu Larry Goldstein, MD, FAAN, FAHA	I thank Vos and de Groot for their comments. The purposes of my editorial1 were to put Dr. Bang et al.’s observational study [6] in perspective and to prompt thoughtful consideration of the potential relationship between recanalization therapy, low cholesterol, and hemorrhagic infarction. J-LIT was a prospective, open-label, uncontrolled, primary coronary heart disease cohort study of hypercholesterolemic Japanese patients. [2] Its applicability to non-Japanese populations is uncertain. Baseline lipid levels were weakly associated with major coronary events, the study’s primary outcome. With treatment, each 10 mg/dL decrease in total and LDL-cholesterol was associated with 11.3% and 15.8% reductions in coronary events. The J-LIT report referenced by Vos and de Groot did not include the cited data on cerebrovascular endpoints. Meta-analysis of 14 prospective randomized trials, however, found statin therapy was associated with a 17% reduction in fatal or nonfatal stroke (p < 0.0001), a 23% reduction in myocardial infarction or coronary death (p < 0.0001), and a 12% reduction in all-cause mortality (p < 0.0001) per mmol/L reduction in LDL-C. [7] Some of Vos and de Groot’s assertions regarding the SPARCL trial [8] are incorrect. Patients with hemorrhagic stroke (2% of those enrolled) could be included "if they were deemed by the investigator to be at risk for ischemic stroke or coronary heart disease." The analysis of outcome stroke subtype was post hoc. A further analysis found no relationship between LDL-C and hemorrhagic stroke in atorvastatin-treated patients. [9] SPARCL was neither designed nor powered to detect differences in overall or cause-specific mortality. The SPARCL publication provides the numbers needed to treat to prevent one stroke (n = 46, 95% CI 24 to 243), one major cardiovascular event (n = 29, 95% CI 18 to 75), or one revascularization procedure (n = 32, 95% CI 22 to 59) over 5 years. [8] The potential mechanisms of these benefits are not addressed by the trial data. Citing the cost of a therapy without considering its benefits is misleading. Cost-effectiveness analyses are complex and highly dependent on a series of assumptions. [10] Epidemiologic studies do generally find lower cholesterol levels are associated with the risk of hemorrhagic stroke whereas higher levels are associated with ischemic events. In contrast, numerous randomized controlled trials (including SPARCL) and meta-analyses support the benefit of lipid-lowering with statins in specific patient populations. I am, therefore, uncertain of the basis of their assertion that "all data consistently suggest harm from low or lowered cholesterol levels." As always, physicians need to balance benefits, risks, and costs when making therapeutic decisions. Disclosure: Steering Committee for the Stroke Prevention with Aggressive Reduction in Cholesterol (SPARCL) study supported by Pfizer and a consultant for Pfizer. 1. Goldstein LB. Low LDL cholesterol, statins, and brain hemorrhage: should we worry? Neurology 2007;68:719–720.[Free Full Text] 2. Matsuzaki M, Kita T, Mabuchi H, et al. Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia. Circ J 2002;66:1087–1095.[Medline] 3. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757–767.[Medline] 4. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549–559.[Abstract/Free Full Text] 5. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149–1158.[Medline] 6. Bang OY, Saver JL, Liebeskind DS, et al. Cholesterol level and symptomatic hemorrhagic transformation after ischemic stroke thrombolysis. Neurology 2007;68:737–742.[Abstract/Free Full Text] 7. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–1278.[Medline] 8. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549–559.[Abstract/Free Full Text] 9. Goldstein LB, Amarenco P, Szarek M, et al. Secondary analysis of hemorrhagic stroke in the stroke prevention by aggressive reductions in cholesterol levels (SPARCL) study. Neurology 2007;68:A183. 10. Goldstein LB. Is simvastatin cost-effective for reducing the risk of vascular events? Nat Clin Pract Neurol 2005;1:86–97.
Low LDL cholesterol, statins, and brain hemorrhage: Should we worry? 1 April 2007
Luca Mascitelli, Comando Brigata Alpina Julia 8 Via S. Agostina, Udine, 33100 Italy, Francesca Pezzetta Send Correspondence to journal: Re: Low LDL cholesterol, statins, and brain hemorrhage: Should we worry? lumasci{at}libero.it Luca Mascitelli, et al.	Bang et al found that lower LDL-cholesterol levels with or without statin treatment were strongly and independently related to a higher risk of symptomatic hemorrhagic transformation after recanalization therapy. [1] These findings, added to those of the industry-driven SPARCL trial, [2] should question the widely-believed assumption of beneficial effects of statin therapy in the prevention of stroke. In the SPARCL trial, [2] it was reported that, as compared with placebo, the use of high-dose statin in patients who had a stroke or TIA reduced the risk of nonfatal stroke from 11.8% to 10.4% over a period of 5 years, but it did so without improving survival (five more deaths in the statin arm), and with 66% increase in the relative risk of hemorrhagic stroke among the patients receiving high-dose atorvastatin. To the best of our knowledge, no statin trial has demonstrated a net reduction in all- cause mortality when studying primary or secondary prevention of stroke. What is the point of decreasing the number of events without decreasing overall mortality, when considering that statin therapy might increase the risk of hemorrhagic infarction, and when the harm caused by the side effects of statins is considered? It is very possible that the numbers of side effects are much larger in clinical practice where the drugs may be given to most patients usually excluded in randomized trials, in which ingenious criteria used for selecting the test individuals and generous limits for what is considered as normal laboratory results are usually used. [3] Furthermore, in the accompanying editorial, [4] Goldstein (from the Steering Committee for the SPARCL study) highlighting the beneficial effects of statins in reducing vascular events, discussed the global beneficial action of statins in the prevention of stroke. However, he did not mention any other statin-related side effects. We don’t share Goldstein’s optimism and think that concerns about efficacy and safety of statins remain. References 1. Bang OY, Saver JL, Liebeskind DS, et al. Cholesterol level and symptomatic hemorrhagic transformation after ischemic stroke thrombolysis. Neurology 2007; 68: 737-742. 2. Amarenco P, Bogousslavsky J, Callahan A 3rd, 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: 549-559. 3. Mascitelli L, Pezzetta F. Underestimated statins-related side effects. Lancet; in press. 4. Goldstein LB. Low LDL cholesterol, statins, and brain hemorrhage: should we worry? Neurology. 2007; 68: 719-720. Disclosure: The authors report no conflicts of interest.
Reply from the Editorialist 1 April 2007
Larry B. Goldstein, Duke University and Durham VA Hospital Box 3651, Duke University Medical Center, Durham, NC 27710 Send Correspondence to journal: Re: Reply from the Editorialist golds004{at}mc.duke.edu Larry B. Goldstein	Citing the report by Dr. Bang et al [1] and findings from the SPARCL trial [2], Drs. Mascitelli and Pezzetta feel that the results "...should question the widely believed assumption of beneficial effects of statin therapy in the prevention of stroke." They seem to be confusing the role of statins in preventing cardiovascular events (including stroke) and the risk of hemorrhagic and other complications of the treatment. As reflected in the recent meta-analysis of prospective trials cited in my editorial, statin therapy is associated with a 17% reduction in fatal or non-fatal stroke (rate ratio [RR] 0.83, 95% CI 0.78 to 0.88; p< 0.0001), a 23% reduction in myocardial infarction or coronary death (RR 0.77,95% CI 0.74 to 0.80; p< 0.0001), and a 12% proportional reduction in all-cause mortality per mmol/L reduction in LDL cholesterol (RR 0.88, 95% CI 0.84 to 0.91; p< 0.0001). [5] Thus, the available data do not support their concern or their contention that "...no statin trial [has] demonstrated a net reduction in all-cause mortality when studying primary or secondary prevention of stroke." The SPARCL trial was aimed at determining whether statin treatment would reduce the combined risk of fatal and non-fatal stroke in persons with recent (within 1-6 months) stroke or TIA, no evident coronary heart disease, and a baseline LDL-cholesterol between 100-190 mg/dL. [2] There was an overall 16% reduction (adjusted hazard ratio[HR] 0.84; 95% CI, 0.71 to 0.99; p = 0.03; unadjusted p = 0.05) in fatal and non-fatal stroke. Post hoc analysis showed that this benefit included a 22% reduction in ischemic stroke (HR 0.78, 95% CI 0.66 to 0.94) a 45% reduction in unclassified stroke (HR 0.55, 95% CI 0.21 to 1.40), but a 66% increase in hemorrhagic stroke (HR 1.66, 95% CI, 1.08 to 2.55). [2] The trial was neither designed nor powered to detect a reduction in all-cause mortality. The previously cited meta-analysis (primarily reflecting trials of patients without prior stroke) found no difference in hemorrhagic stroke associated with statin treatment (RR 1·05, 99% CI 0.78 to1·41; p=0.7). [3] The purposes of my editorial comment [4] were to both put Dr. Bang and colleague’s observational study into perspective and to prompt thoughtful consideration of the potential relationship between recanalization therapy, low cholesterol, and the risk of hemorrhagic infarction. Statin treatment can be associated with an overall reduction in stroke in both primary and secondary prevention populations. Fewer patients having strokes will result in fewer needing emergent recanalization. The potential for statin- related side effects should not be minimized, but needs to be balanced by the benefit of the treatment. References 5. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278. Disclosure: Dr. Goldstein reports his participation on the Steering Committee for the Stroke Prevention with Aggressive Reduction in Cholesterol (SPARCL) study supported by Pfizer. Dr. Goldstein is also a consultant for Pfizer.