PLAC and statins

Combined treatment, using half the dose of simvastatin, led to greater reduction of Lp-PLA2 mass level total cholesterol and LDL-C, compared to monotherapy with simvastatin. 

Due to the steady decline of target levels of LDL-C, which leads to prescribing high doses of statins (and it is not always possible because of the presence of co-morbidities), combination therapy with statin and ezetimibe is a reliable alternative, which allows not only to largely reduce LDL-C but also to significantly reduce such important participants of atherosclerosis process and markers of inflammation, as Lp-PLA2 and CRP.

Read more

The Case for Statins (with commentary) - 5 COMMENTS ARE WELCOME ON THIS SPECIFIC STUDY

Conclusions, Recommendations, Future Directions

There is persuasive evidence that statins have beneficial effects extending beyond reduction of major coronary event rate and all-cause mortality. Clinical and experimental data show that statins reduce stroke, particularly in patients with established vascular disease and among patients with a high burden of vascular risk factors. Other studies in animal models of stroke suggest that statins may also possess neuroprotective properties that may be important during cerebral ischemia.^[37,38] 

Comments

The preceding comments suggest that lifestyle changes - if consistent and possibly severe - can also do this

The effects of statins on stroke are at variance with epidemiological studies and suggest that statins reduce stroke through cumulative improvements in a number of different components of atherosclerosis including effects on the endothelium, thrombosis, plaque stability, and through anti-inflammatory effects.

More information is needed before statin therapy can be recommended as a specific indication for secondary or primary prevention of stroke.^[6,20]Results of the ongoing Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial^[44] will provide additional information about the role of statins in the minority of patients with prior stroke but no history of coronary heart disease, other occlusive arterial disease, or diabetes. However, considering the discussion above, therapy guided by National Cholesterol Education Program (NCEP) guidelines^[45,46] may have a large impact in stroke reduction. Questions remain as to how low LDL targets should be in specific populations, and the guidelines will probably change as data from large studies such as HPS^[18,21] and ASCOT^[19] are considered. Future studies that look at stroke as a primary end point for statin therapy will further clarify possible expanded indications for statin therapy.

Reprint Address

Address for correspondence: Neil L. Coplan, MD, Cardiology Division, 100 East 77th Street, New York, NY 10021

Prev Cardiol. 2005;8(2):98-101. © 2005 Le Jacq Communications, Inc. 

Nenad Trubelja, MD; Carl Vaughan, MD; Neil L. Coplan, MD

DISCLOSURES 

Prev Cardiol. 2005;8(2):98-101. 

Read more BUT you may have to log in which is why the whole article is here in the blog

The Case for Statins (with commentary) - 4 COMMENTS WELCOME AS LONG AS THEY ARE SPECIFIC TO THE ABSTRACT

Plaque Stabilization and Decreased Plaque Thrombogenicity

Experiments have demonstrated that cholesterol reduction is accompanied by favorable alterations in a number of mediators of plaque stability.^[39,40]Studies have shown that statins decrease macrophage number, reduce expression of tissue factor, adhesion molecules, and matrix metalloproteinases within plaque.^[39] The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors also reduce the oxidation of LDL, macrophage uptake of LDL,^[24,25] and reduce monocyte adhesion to endothelium.^[25] Lipid lowering with statins results in increased smooth-muscle cell content (a surrogate of plaque stability) and decreased collagen degradation (which may further enhance plaque stability).^[39] Clinical studies support these experimental observations and provide further evidence that statin therapy may be associated with plaque stabilization. Statins may also inhibit atherogenesis through the inhibition of vascular smooth-muscle cell proliferation and migration, and thus attenuate plaque growth and new lesion formation.^[41]

^Comment:

<sup>Plaque stabilisation may also be achieved through diet:

"</sup>While plaque stabilization mainly focuses on repairing the endothelial cap and strengthening collagen content, plaque regression mainly focuses on aggressive lipid management to remove necrotic components and restore normal endothelial function of the arterial wall. Plaque stabilization has already been proven to reduce clinical events and studies with statins, HDL-C increasing agents, anti-thrombotic agents, ACE inhibitors, calcium antagonists, oral anti-oxidants, and diet modifications have shown that reduction in clinical events need not be reflected by reduced plaque volume. The major studies supporting plaque stabilization included MIRACL, PACT, CURE, HOPE, and Lyon Diet Heart Study."

Source

If using exercise though, care must be taken:

"Sudden rupture of a vulnerable plaque may occur spontaneously without obvious triggers. By contrast, it may follow a particular event, such as extreme physical activity (especially in someone unaccustomed to regular exercise), severe emotional trauma, sexual activity, exposure to illicit drugs (cocaine, marijuana, amphetamines), exposure to cold, or acute infection (106–114)."

Source

Another factor which may contribute toward decreased risk for stroke with statin therapy is the effect of statins on platelets and the endogenous balance of thrombosis/thrombolysis.^[40] Statin therapy decreases platelet activation and aggregation, and thereby may decrease the propensity toward thrombosis.^{[10,23,42,43]} 

Comment

This can definitely be reduced through diet

Here's how

Also:

"Diets such as Mediterranean diet, high in omega-3 polyunsaturated fatty acids (PUFA), and vegetarian diets have inverse relationships with CVD. Dark chocolate, foods with low glycemic index, garlic, ginger, omega-3 PUFA, onion, purple grape juice, tomato, and wine all reduce platelet aggregation. Dark chocolate and omega-3 PUFA also reduce P-selectin expression. In addition, dark chocolate reduces PAC-1 binding and platelet microparticle formation. Berries inhibit platelet function (PFA-100)."

https://www.ncbi.nlm.nih.gov/pubmed/24497119

"Coffee drinking decreases platelet aggregation, and induces a significant increase in phenolic acid platelet concentration. The antiplatelet effect of coffee is independent from caffeine and could be a result of the interaction of coffee phenolic acids with the intracellular signalling network leading to platelet aggregation."

https://www.ncbi.nlm.nih.gov/pubmed/18439332

Statin therapy inhibits tissue factor expression by macrophages, which plays an integral role in blood coagulation and is an important determinant of plaque thrombogenicity.^[23,25] There also may be a reduction in plasminogen activator inhibitor activity, which would facilitate fibrinolysis.^[23] All of these factors may contribute toward decreased risk for stroke seen in the statin studies. These statin effects may lead to decreased thrombus formation and thereby influence the development of clinical activity related to atherosclerotic plaque.

The Case for Statins (with commentary) - 3 COMMENTS ARE WELCOME ON THIS SPECIFIC STUDY

Endothelial Dysfunction

Endothelial dysfunction is a risk factor for cerebrovascular events.^[30,31]Statin therapy has been shown to improve endothelial function,^{[25,32,33,34]}and there is evidence suggesting that statin therapy is accompanied by increased nitric oxide (NO) bioavailability.^[5,35,36] NO modulates endothelial function, affecting both vascular tone and maintenance of a thromboresistant interface between the bloodstream and the vessel wall.^[36]

LOW INTENSITY RESISTANCE TRAINING CAN DO THIS


Improvement in endothelial function may, then, be a contributing mechanism to the decreased incidence of stroke observed in patients on statins. For example, studies in a murine experimental model of ischemic stroke show that prophylactic statin therapy enhances cerebral blood flow, reduces infarct size (by approximately 30%), and improves neurologic outcome in normocholesterolemic animals.^[37] In this animal model, statin therapy directly upregulated brain endothelial type III NO synthase activity without altering expression of neuronal NO synthase. This effect was independent of change in cholesterol level and was reversible by cotreatment with mevalonate or geranylgeranylpyrophosphate. These observations highlight important cholesterol-independent actions of statins and underscore the potential biologic relevance of intermediates in the cholesterol biosynthetic pathway. In a similar study, atorvastatin has been shown to reduce stroke size in normocholesterolemic mice through cholesterol-independent mechanisms.^[38]

The Case for statins (with commentary) - 2 COMMENTS WELCOME IF RELEVANT TO THE STUDY

Anti-Inflammatory Actions of Statins

There is not a strong epidemiological association between hyperlipidemia and stroke. Studies that show statin therapy is associated with reduced incidence of stroke may be due to the effect of statins on factors such as inflammation. Engstrom et al.^[26] demonstrated that patients with hyperlipidemia and elevated inflammatory markers (such as fibrinogen and haptoglobin) are at increased risk for ischemic stroke over long-term follow-up, but in the absence of these inflammation-sensitive proteins, hyperlipidemia was not a risk factor for stroke. 

Comment:

Important to remember this and have these other areas checked. No inflammation-sensitive proteins...not a risk factor

Statin therapy suppresses T-cell activation and inhibits the release of proinflammatory cytokines^[5,24,25]that are critical mediators of inflammatory and immunological responses in the brain and are produced by neurons, glial cells, and the endothelium.^[26]Statin therapy also influences C-reactive protein levels, which is another important marker of inflammation that also appears to be an independent risk factor for the development of ischemic stroke.^[27,28,29] Statin therapy reduces C-reactive protein level independent of its effect on serum LDL cholesterol. For example, in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS),^[29] lovastatin appeared to be highly effective in reducing the risk of acute coronary events in participants with elevated C-reactive protein levels but no hyperlipidemia. 

Comment

Cholesterol not seen as the important marker

Therefore, statins may be more effective in reducing cardiovascular events in patients with a high compared with low C-reactive protein level.<sup>[29]

This may all be done without statins and with greater knock-on effects</sup>

The case for statins - 1 (with commentary) COMMENTS WELCOME IF RELEVANT TO THIS STUDY

THIS IS THE ORIGINAL PUBLICATION

Epidemiological studies have not demonstrated a clear relationship between stroke risk and hypercholesterolemia. Clinical trials using statins have demonstrated a reduction in stroke, in particular, in patients with established coronary artery disease. 

Commentary: this reduction in stroke tends to use RRR and when ARR the difference is minor. Even then this assumes no other changes in contributory factors to stroke such as stress, weight,blood pressure etc. This assumption of ceteris paribus is unrealistic and even if provided for through probability estimates, these are at best, guess work. Why would statins be more effective in those whose immune system is already compromised?

The disparity between epidemiological and clinical studies suggests hypercholesterolemia is a true risk factor for stroke that evaded detection in epidemiological studies, or that statins possess other properties that render them useful in stroke prevention. These effects have been loosely termed "pleiotropic" in the lipid literature and revolve around putative effects of statins on endothelial function, inflammation, thrombosis, plaque stability, and immune regulation. 

Pleiotropic: Producing or having multiple effects from a single gene. For example, the Marfan gene is pleiotropic, potentially causing such diverse effects as long fingers and toes (arachnodactyly), dislocation of the lens of the eye, and dissecting aneurysm of the aorta.

Key development:

The effect of statins on:

endothelial function

inflammation

thrombosis

plaque stability

immune regulation

Questions remain as to the mechanisms of benefit of statin therapy in stroke prevention, the role of statins in the primary prevention of stroke, and the role of statins in modulating the immune system in the brain.

Hypercholesterolemia is a risk factor for coronary artery disease (CAD). Numerous clinical studies have shown that low-density lipoprotein (LDL) cholesterol plays a major role in the pathogenesis of CAD;^[1,2] 

Neither of the links work but the studies referenced are:

1. LaRosa JC, Hunninghake D, Bush D, et al. The cholesterol facts: a summary of the evidence relating dietary fats, serum cholesterol, and coronary heart disease. Circulation. 1990;81:1721-1733.
2. Gould AL, Rossouw JE, Santanello NC, et al. Cholesterol reduction yields clinical benefit. Circulation. 1998;97:946-952.

However, based on epidemiological studies, there is no clear evidence for a relation between stroke risk and hypercholesterolemia.^[3,4]

<sup>Worth emphasising 'no clear evidence'.

The studies referenced are:</sup>

1. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective studies. Lancet. 1995;346:1647-1653.
2. Iso H, Jacobs DR Jr, Wentworth D, et al., for the MRFIT Research Group. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med. 1989;320:904-910    
3. Keeping the epidemiological studies in mind, it seems paradoxical that recent CAD prevention trials indicate that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are associated with a significant reduction in stroke risk.^{[5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]} 

'Significant reduction in stroke risk"

That's important. Do statins lead to a SIGNIFICANT REDUCTION? What do the studies say?

The links are not working (it is an old article) but here are the studies:

1. Di Napoli P, Taccardi AA, Oliver M, et al. Statins and stroke: evidence for cholesterol-independent effects. Eur Heart J. 2002;23:1908-1921.
2. Crause JR, Byrington RP, Maria H, et al. Reductase inhibitor monotherapy and stroke prevention. Arch Intern Med. 1997;157:1305-1310.
3. Bucher HC, Griffith LE, Guyatt GH. Effect of HMG-CoA reductase inhibitors on stroke. A meta-analysis of randomized controlled trials. Ann Intern Med. 1998;128:89-95.
4. Hebert PR, Gazioano JM, Chan KS, et al. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA. 1997;278:313-321.
5. Blauw GJ, Lagaay AM, Smelt AH, et al. Stroke, statins, and cholesterol. A meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors. Stroke. 1997;28:946-950.
6. Vaughan CJ, Delanty N, Basson CT. Statin therapy and stroke prevention. Curr Opin Cardiol. 2001;16:219-224.
7. Crouse JR. Effects of statins on carotid disease and stroke. Curr Opin Lipidol. 1999;10:535-541.
8. Hankey GJ. Role of lipid-modifying therapy in the prevention of initial and recurrent stroke. Curr Opin Lipidol. 2002;13:645-651.
9. Hess DC, Demchuk AM, Brass LM, et al. HMG-CoA reductase inhibitors (statins): a promising approach to stroke prevention. Neurology. 2000;54:790-796.
10. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.
11. Sacks FM, Pfeffer MA, Moye LA, et al., for the Cholesterol and Recurrent Events Trial investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.
12. White HD, Simes RJ, Anderson NE, et al. Pravastatin therapy and the risk of stroke. N Engl J Med. 2000;343:317-326.
13. Schwartz GG, Olsson AG, Ezekowitz MD, et al., for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711-1718.
14. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7-22.
15. 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.

For example, the Cholesterol and Recurrent Events (CARE) trial^[15] showed that pravastatin significantly reduced the prespecified end point of stroke by 31%. 

Sacks FM, Pfeffer MA, Moye LA, et al., for the Cholesterol and Recurrent Events Trial investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.

Here is the link

From the study:

Stroke, a specified end point in the CARE trial,17 was reduced significantly (by 31 percent) in the pravastatin group. A reduction in cerebrovascular end points was found in post hoc analyses of data from several previous trials conducted in hypercholesterolemic populations.8,10,22,23 A meta-analysis of trials of pravastatin in patients with atherosclerosis showed a significant, 62 percent reduction in stroke.10 Dietary therapy that replaced saturated fat with polyunsaturated fat reduced the incidence of stroke by 45 percent (P = 0.055).22 

62% reduction!

That 62% reduction came from here:

Byington RP, Jukema JW, Salonen JT, et al. Reduction in cardiovascular events during pravastatin therapy: pooled analysis of clinical events of the Pravastatin Atherosclerosis Intervention Program. Circulation 1995;92:2419-2425

LINK IS HERE

Extract:

Methods and Results Clinical data from four atherosclerosis regression trials that evaluated pravastatin were pooled for a predetermined analysis of the effect of that agent on the risk of coronary events. All trials were double-masked, placebo-controlled designs that used pravastatin as monotherapy for 2 to 3 years. The 1891 participants in the trials had evidence of atherosclerosis and mildly to moderately elevated lipid levels. For fatal or nonfatal myocardial infarction, there was a 62% reduction in events attributable to pravastatin (P=.001). This effect was evident in younger and older patients, men and women, and patients with and without histories of hypertension and prior infarction. There was a 46% reduction in all-cause mortality (P=.17), which, although not statistically significant, is consistent with the results of other statin trials. There also was a 62% reduction in the risk of fatal or nonfatal stroke (P=.054). 

Of note, stronger stroke reduction effect was noted in secondary coronary artery prevention trials than primary coronary artery prevention trials.^[6,8,20]

<sup>Crause JR, Byrington RP, Maria H, et al. Reductase inhibitor monotherapy and stroke prevention. Arch Intern Med. 1997;157:1305-1310.

Hebert PR, Gazioano JM, Chan KS, et al. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA. 1997;278:313-321.

Corvol J, Bouzamondo A, Siror M, et al. Differential effects of lipid-lowering therapies on stroke prevention. Arch Intern Med. 2003;163:669-676.</sup>

In addition, randomized trials show that stroke reduction occurs over a wide range of initial lipid levels.^[6,9,18,19] 

This is an important point as lipid levels would almost seem to be irrelevant and therefore the statin positive effect is NOT the 'lipid lowering effect' that is often trumpeted.

Here are the studies:

Crause JR, Byrington RP, Maria H, et al. Reductase inhibitor monotherapy and stroke prevention. Arch Intern Med. 1997;157:1305-1310.

Blauw GJ, Lagaay AM, Smelt AH, et al. Stroke, statins, and cholesterol. A meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors. Stroke. 1997;28:946-950.

Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7-22

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.

Article continued.....

The Heart Protection Study (HPS)^[18,21](which included over 20,000 patients) and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)^[19] study (which included over 10,000 patients) provide strong support for the role of statin therapy in reducing risk of stroke in patients with average or relatively low LDL cholesterol levels. 

Commentary:

Statins reduce cholesterol levels.
These studies apparently show a benefit of reducing ALREADY RELATIVELY LOW LDL LEVELS and this reduces stroke risk

What of the studies showing low cholesterol is a risk?

The studies cited are:

1. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7-22.
2. 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.

This one is here

Let us have a look:

BACKGROUND:

The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome. No study, however, has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease (CHD) in hypertensive patients who are not conventionally deemed dyslipidaemic. (Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle.)

METHODS:

Of 19342 hypertensive patients (aged 40-79 years with at least three other cardiovascular risk factors) randomised to one of two antihypertensive regimens in the Anglo-Scandinavian Cardiac Outcomes Trial, 10305 with non-fasting total cholesterol concentrations 6.5 mmol/L or less were randomly assigned additional atorvastatin 10 mg or placebo. These patients formed the lipid-lowering arm of the study. We planned follow-up for an average of 5 years, the primary endpoint being non-fatal myocardial infarction and fatal CHD. Data were analysed by intention to treat.

FINDINGS:

Treatment was stopped after a median follow-up of 3.3 years. By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50-0.83], p=0.0005). This benefit emerged in the first year of follow-up. There was no significant heterogeneity among prespecified subgroups. Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0.73 [0.56-0.96], p=0.024), total cardiovascular events (389 vs 486, 0.79 [0.69-0.90], p=0.0005), and total coronary events (178 vs 247, 0.71 [0.59-0.86], p=0.0005) were also significantly lowered. There were 185 deaths in the atorvastatin group and 212 in the placebo group (0.87 [0.71-1.06], p=0.16). Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months, and by 1.1 mmol/L after 3 years of follow-up.

INTERPRETATION:

The reductions in major cardiovascular events with atorvastatin are large, given the short follow-up time. These findings may have implications for future lipid-lowering guidelines.

COMMENT

Total of 6.5 mmol is not that high and neither is the statin dose and nor is the actual reduction so the results are surprising

1. Collins R, Armitage J, Parish S, et al. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004;363:757-767.

In HPS, larger numbers of subjects suffered a stroke than in any previous cholesterol-lowering trial. The results demonstrate that statin therapy rapidly reduces the incidence not only of coronary events, but also of ischemic strokes (with no apparent effect on cerebral hemorrhage), even among individuals who do not have high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of ischemic strokes by approximately 25%. HPS also provides definitive evidence that statins are beneficial for patients with preexisting cerebrovascular disease, even if they do not already have coronary disease.<sup>[21]

The study:

Collins R, Armitage J, Parish S, et al. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004;363:757-767

This looks pretty convincing - and yet the study is 13 years old. What happened?</sup>

These findings, coupled with the observation that lipid lowering by other means (e.g., fibrates, resins, or diet) has no impact on stroke incidence,^[6,7,21,22] suggest that statins may be unique among lipid-lowering drugs in relation to stroke reduction. 

Comment:

This is VERY significant. 
Lipid lowering by diet has NO impact on stroke incidence?
Wouldn't a diet also affect inflammation?

Here are the studies:

Crause JR, Byrington RP, Maria H, et al. Reductase inhibitor monotherapy and stroke prevention. Arch Intern Med. 1997;157:1305-1310.

Bucher HC, Griffith LE, Guyatt GH. Effect of HMG-CoA reductase inhibitors on stroke. A meta-analysis of randomized controlled trials. Ann Intern Med. 1998;128:89-95.

Collins R, Armitage J, Parish S, et al. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004;363:757-767.

Atkins D, Psalty BM, Koepsell D, et al. Cholesterol reduction and the risk for stroke in men: a meta analysis of randomized, controlled trials. Ann Intern Med. 1993;119:136-145.

Comment:

from the fourth study:

Two prior meta-analyses using trials of diet, bile acid resins, fibric acid derivatives, and niacin have shown a nonsignificant decrease in the relative risk for nonfatal stroke, a nonsignificant increase in the relative risk for fatal stroke, and no effect on total stroke incidence.6,7 Both analyses suggested that the inability to demonstrate a significant reduction in overall stroke rates was due to a degree of cholesterol reduction achieved in these trials (about 10%) that may have been inadequate to reverse established cerebrovascular disease and to an offset in the beneficial effects of cholesterol reduction by an increase in hemorrhagic stroke, which carries the higher case-fatality rate.

Let's check the references cited:

Atkins D, Psaty BM, Koepsell TD, Longstreth Wt, Jr, Larson EB. Cholesterol reduction and the risk for stroke in men: a meta-analysis of randomized, controlled trials. Ann Intern Med. 1993;119:136–45.[PubMed]

Quote:

"Lowering serum cholesterol through modified diets or medications does not reduce stroke mortality or morbidity in middle-aged men. Clofibrate appears to increase the risk for fatal strokes, but the mechanism for this effect is unknown."

Note: MEDICATION - that was NOT what the previous study (that cited this) said!

7. Hebert PR, Gaziano JM, Hennekens CH. An overview of trials of cholesterol lowering and risk of stroke. Arch Intern Med. 1995;155:50–5. [PubMed]

Quote:

" no benefit of cholesterol lowering on the risk of stroke"

That is NOT what the study that cites this, says!

Statins have more robust effects on LDL cholesterol reduction than other lipid-modifying agents; therefore, the effects may reflect better LDL cholesterol reduction. However, the disparity between epidemiological and clinical studies may indicate additional biologic effects of statins that contribute to stroke reduction.^[5,6,23] 

The studies:

1. Di Napoli P, Taccardi AA, Oliver M, et al. Statins and stroke: evidence for cholesterol-independent effects. Eur Heart J. 2002;23:1908-1921.
2. Crause JR, Byrington RP, Maria H, et al. Reductase inhibitor monotherapy and stroke prevention. Arch Intern Med. 1997;157:1305-1310.
3. Rosenson RS, Tangney C. Antiatherothrombotic properties of statins: implication for cardiovascular event reduction. JAMA. 1998;279:1643-1650.

These effects have been loosely termed "pleiotropic" in the lipid literature.^[10,24,25]

Vaughan CJ, Delanty N, Basson CT. Statin therapy and stroke prevention. Curr Opin Cardiol. 2001;16:219-224.

Vaughan CJ. Prevention of stroke and dementia with statins: effects beyond lipid lowering. Am J Cardiol. 2003;91:23B-29B.

Vaughan CJ, Gotto AM Jr, Basson CT. The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol. 2000;35:1-10.

Pleiotropic effects which may be contributing to the decreased incidence of stroke in patients on statin therapy include atherosclerotic plaque stabilization, decreased inflammation, improvement in endothelial function, and altered thrombogenicity (Figure 1).

(Enlarge Image)

The aorta and carotid are pericerebral arteries that may contain a significant burden of atherosclerotic plaque. Plaque at these sites may become unstable through macrophage elaboration of matrix metalloproteinases that weaken the fibrous skeleton of plaque, making disruption more likely. Plaque disruption is accompanied by thrombosis that predisposes to artery-to-artery thromboembolism and stroke. Statins have a number of putative effects that may stabilize aortic and carotid plaque. 

COMMENT

So this is going to explain HOW statins stabilise plaque

These include effects on plaque lipid content, macrophage activation, protection of the endothelium through enhanced nitric oxide (NO) bioavailability, anti-inflammatory, and antithrombotic actions