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


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]

Worth emphasising 'no clear evidence'.

 The studies referenced are:
  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.


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]

 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.


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.

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.[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?

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., 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).
Click to zoom
(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
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