Optimal LDL Cholesterol < 70 MG/DL

OPTIMAL LDL CHOLESTEROL < 70 MG/DL, SCIENTIFIC UPDATE 1/30/08, CHARLES J. GLUECK MD, DIRECTOR ALLIANCE CHOLESTEROL CENTER. Phone 513-585-7800, Fax 513-585-7950, address 3200 Burnet Avenue, Cincinnati OH, 45229, email glueckch@healthall.com 

2/27/08 update

MAJOR FINDINGS:

In primary prevention (patients with no previous heart attack or stroke) and in secondary prevention (patients with previous heart attack and stroke), study after study after study, placebo-controlled, has shown that lowering LDL cholesterol with statin drugs reduces coronary heart disease and stroke morbidity and mortality. Moreover, the greater the lowering the LDL cholesterol, the greater the reduction in morbidity and mortality. Substantial reductions in morbidity also inevitably must improve the quality of life, reducing the adverse effects of heart and stroke events on everyday life. Beyond these findings, multiple studies have also shown that when LDL cholesterol is lowered to 70 mg/dl or more, regression of the atherosclerotic lesion can be demonstrated, and this regression is associated with a reduction in coronary heart disease and stroke morbidity and mortality.

How low should cholesterol go?

The primary and secondary prevention and atherosclerosis regression studies below in aggregate suggest that for optimal effects, LDL cholesterol should be lowered well below 100 mg/dl, to levels around 70 mg/dl.

IS THERE AN ASYMPTOTIC LIMIT FOR LDL AT WHICH  CARDIOVASCULAR EVENT RATES APPROXIMATE ZERO?

The LDL level at which cardiovascular event rate may approach ZERO is estimated to be ~ 60 mg/dl for primary prevention (no previous clinical coronary disease), and 30 mg/dl for secondary prevention (previous clinical coronary disease).

• “Primitive” hunter-gatherer populations: total cholesterol 100-150 mg/dl,  (estimated) LDL 50-75 mg/dl.
   
• Neonates’ LDL 30-70 mg/dl.
   
• Familial hypobetalipoproteinemia: LDL cholesterol 30-40 mg/dl, associated with longevity, and life expectancy 15 years longer than their birth cohort. Atherosclerotic coronary and cerebrovascular disease almost never occurs in this common inherited disorder.
   
• Threshold for progression of atherosclerosis estimated to be approximately 70 mg/dl 
   
• REVERSAL STUDY: 654 cases with symptomatic coronary disease and baseline stenosis ≥ 20%, randomized to Lipitor 80 mg or Pravachol 40 mg. Coronary atherosclerosis (by IVUS) halted in Lipitor group where 48% reduction in LDL led to mean LDL on treatment of 79 mg/dl. Pravachol group had 28% decline in LDL to a mean of 110 mg/dl. There was a 0.4% regression of atheroma volume in the Lipitor group vs 2.7% mean progression in the Pravachol group over 18 months. High specificity CRP was reduced by 36% in the Lipitor group vs 5% decrease in the Pravachol group.
   
• ASAP STUDY: Lipitor 80 mg vs Zocor 40 mg, 325 cases with familial hypercholesterolemia. Carotid intimal-medial thickness (IMT) regressed 0.031 mm over 2 years in the Lipitor group vs 0.036 mm progression in Zocor group.
   
• ARBITER STUDY: Lipitor 80 mg vs 40 mg Pravachol, 161 cases with baseline LDL = 150 mg/dl. Lipitor reduced LDL by 50% to 76 mg/dl vs 110 mg/dl on Pravachol. Carotid IMT regressed 0.038 mm in Lipitor group vs mean progression of 0.026 mm in Pravachol group.
   
• HEART PROTECTION STUDY: 3500 cases with LDL <100 mg/dl before treatment, with mean LDL of 97 mg/dl reduced to 65 mg/dl on Zocor 40 mg. This was associated with 25% reduction in CHD events.
   
• PROVE-IT-TIMI: 4162 acute coronary symptom cases with pre-treatment total cholesterol ≤ 200 mg/dl to Lipitor 80 mg or Pravachol 40 mg. On Lipitor, 51% fall in LDL to 62 mg/dl, vs 95 mg/dl (22%) decrease on Pravachol. After 2 years, 16% reduction in adverse CHD events, 28% reduction in CHD death in Lipitor group. In a retrospective analysis, there were lower clinical coronary heart disease events in patients who achieved LDLC <60 or <40 mg/dl compared with those in the 80-100 mg/dl range. LDL <60 or < 40, well below current guidelines, were not associated with adverse safety outcomes. Hence,  do not reduce statin dose if LDL levels fall below the 70 mg/dl goal.
   
• TNT: 10,001 cases with stable coronary heart disease, all started on Lipitor 10 mg, and after run in period, half to 80 mg, half remained on 10 mg. LDL remained at 101 mg/dl in the case on 10 mg, and fell to 77 mg/dl on the Lipitor 80 mg. The reduction in CHD events 22% (p<.01), 27% reduction in stroke (p<.01).

An increasing amount of data from primary prevention, secondary prevention, and atherosclerosis regression studies suggest that to provide optimal results in terms of lowering coronary heart disease events and /or stopping the progression of or reversing atherosclerotic lesions, LDL cholesterol should be lowered to well under 100 mg/dl, and optimally to <80 mg/dl.

Prove-it (Cannon P, et al, New Eng J Med 2004;350:15)

In patients hospitalized for acute coronary syndrome (n=4162), half randomized to Lipitor 80 mg/day, half to Pravachol 40 mg/day. Primary endpoint wad composite of death from any cause, MI, unstable angina, revascularization, and stroke. Mean followup 24 months.

Median cholesterol on Pravachol 95 mg/d, and 62 mg/dl on Lipitor. There was a 16% reduction in the hazard ratio in favor of Lipitor (p =.005), 95% CI 5% to 26%. Conclusion: Patients with acute coronary syndrome benefit from early and continued lowering of LDL cholesterol levels to < than the current target of 100 mg/dl, and probably to < 80 mg/dl.

Heart Protection Study (HPS) ¹

Lower LDL cholesterol is associated with a lower risk of cardiovascular disease. The purpose of the Heart Protection Study (HPS) was to investigate whether lowering LDL cholesterol with simvastatin (brand name Zocor®) reduced the development of vascular disease irrespective of initial LDL concentrations. The researchers studied 20,536 patients in the United Kingdom with coronary disease, other occlusive arterial disease, or diabetes. Patients were randomly assigned to receive either 40mg of simvastatin per day or a placebo.  The average compliance was 85%, and 17% of the patients were already taking statins not related to the study.

Among the findings was that patients taking simvastatin showed in a first non-fatal or fatal stroke compared to the placebo group (444 [4.3%] vs 585 [5.7%]; p<0.0001). Additionally, patients taking simvastatin showed a lower frequency of first non-fatal or fatal heart attack (8.7% vs 11.8%, p<.0001).  Overall, patients taking simvastatin had a 24% reduction in the  first occurrence of any of the studied major vascular events. Importantly, patients who entered the study with LDL cholesterol < 100 mg/dl before receiving Zocor had a reduction in cardiovascular events which was essentially as great as patients whose baseline LDL cholesterol was 130 or 160 mg/dl. This focused attention on lowering LDL cholesterol to ~80 mg/dl (as in this group) for optimal prevention of cardiovascular events.
 
This reduction in major vascular events was not significant in the first year of the study, but it was significant in each of the following four years. Furthermore, this reduction was seen in each subcategory (based on the type of vascular disease in their history) of patients studied.

There are several important messages from this study. Adding simvastatin to an existing treatment (17% were already on statins) safely produces large additional benefits over a wide range of cholesterol ranges. Taking 40 mg of simvastatin daily reduced the rates of heart attack, stroke, and revascularization by roughly 25%.Because of 15% non-compliance in this study, the true reduction could be as large as 33%. Although treatment with simvastatin produced significant benefits, the size of the five-year benefit depends on the overall risk for vascular disease rather than only cholesterol concentrations.  That is, lowering cholesterol is likely to decrease the risk of a vascular event but the amount of reduction depends largely on other factors such as smoking, obesity, and genetic predisposition, rather than cholesterol concentrations alone.

MIRACL Study ²

During the early time after an acute coronary syndrome—unstable angina (chest pain due to a blockage in the heart) or sudden heart attack—patients have the highest rate of death or recurrent ischemic (blockage) events.  This study investigated whether 80 mg daily of atorvastatin (brand name Lipitor®), started 1-4 days after an acute coronary event, reduced the risk of death or non-fatal ischemic events.  Patients at 122 clinical centers in Europe, North America, South Africa, and Australasia (n =3086) were randomly divided into two groups, receiving either 80 mg of atorvastatin per day or a placebo.  Patients were followed for 16 weeks after the occurrence of an acute coronary syndrome.  The significant finding was that patients in the atorvastatin group had a lower occurrence of recurrent ischemic events in the first 16 weeks after the appearance of acute coronary syndrome.

Anglo-Scandinavian Clinical Outcomes Trial (ASCOT) ³

Hypertension (high blood pressure) and elevated cholesterol are two of the most common risk factors for heart disease and stroke, which are major causes of death worldwide. Lowering blood pressure and cholesterol are important in controlling these conditions. The ASCOT study included 19,342 patients randomized into one of two antihypertensive regimens.  A total of 10,305 patients were randomly selected from these groups and placed in a lipid-lowering group which consisted of 10 mg of atorvastatin daily or placebo.  The atorvastatin and placebo groups of the lipid-lowering arm had identical initial cholesterol levels and blood pressure. Patients were followed for a median of 3.3 years.  The atorvastatin group had a 35% relative reduction in the LDL compared to the placebo group.  Fatal heart attack and fatal coronary heart disease were 36% lower in the atorvastatin group.  There were also significant (29%) reductions in total coronary events and a 27% reduction in fatal and non-fatal strokes.  In the atorvastatin group, LDL cholesterol levels were about 80 mg/dl on therapy, again providing emphasis on lowering LDL to well below 100 mg/dl.

Reversing Atherosclerosis with Aggressive Lipid Lowering  (REVERSAL) ⁴

This recent study compared the effectiveness of atorvastatin and pravastatin in the reversal in atherosclerosis.  Five hundred and two patients diagnosed with coronary heart disease and with LDL cholesterol around 150 mg/dl were treated with either atorvastatin  or pravastatin (brand name Pravachol®). Intravascular ultrasound was used to assess atherosclerotic plaque status at pre-treatment baseline and after 18 months on therapy. The group treated with atorvastatin showed a median 0.4% reduction in plaque volume (the total plaque in a given section of an artery) while the pravastatin group had a median 2.7% increase in total plaque volume.  Additionally, 97% of the patients taking atorvastatin reached the recommended LDL levels (≤100 mg/dL) while 67% of pravastatin patients reached this level.  On atorvastatin, LDL cholesterol was lowered to around 80 mg/dl, while on pravastatin, to 110 mg/dl.      

Regression Growth Evaluation Statin Study (REGRESS) ⁵

Restenosis (re-narrowing) after a type of angioplasty called percutaneous transluminal coronary angioplasty (PTCA) is one limitation of the long-term success of this procedure.  In previous studies statins have failed to prevent restenosis.  However their lack of success in the past may have been due in part to the fact that the studies did not allow a long enough follow-up time.  Also, a better understanding of restenosis has led to a better evaluation of it.  The REGRESS study investigated the efficacy of pravastatin in reducing restenosis after PTCA. The study considered 221 patients who had undergone PTCA.  Patients were randomly selected to receive pravastatin or placebo.  The pravastatin group showed a lower percentage of the artery blocked—based on the ratio of blockage to artery diameter (32% vs 45%).  In addition, pravastatin provided a 7% reduction in clinical restenosis over placebo.  Pravastatin, therefore, is an effective treatment to prevent restenosis after PTCA.

Effect of aggressive lipid lowering on progression of atherosclerosis after coronary artery bypass graft (CABG) ⁶

This follow-up study investigated the difference between moderate LDL lowering therapy and aggressive LDL therapy on the progression of athersclerosis.  Four hundred and two patients were randomly assigned into the two treatment groups (aggressive and moderate).  The aggressive group received 75-80 mg of lovastatin daily and the moderate group received 2.5-5 mg of lovastatin.  Patients in the aggressive group showed average LDL levels of 92-97 mg/dL (a 40% decrease from baseline) while patients in the moderate group had levels of 131-135 (a 12% decrease).  More significantly, patients treated with the aggressive treatment had less atherosclerosis than the moderately treated group.  Athersclerosis was measured by minimum lumen diameter or by the average change in maximum arterial stenosis. This study, like the Heart Protection Study and the Reversal study demonstrates that at in patients with CABG there are clear benefits to receiving aggressive LDL lowering therapy with a goal of lowering LDL cholesterol to below 100 mg/dl. 

Arterial Biology for the Investigation of the Treatment of Effects of Reducing Cholesterol (ARBITER) ⁷

This study further assessed the question of whether lowering LDL cholesterol to well under 100 mg/dl will have benefits above and beyond lowering levels to 100 mg/dl. This study compared pravastatin and atorvastatin, at different doses, on carotid intima-media thickness (CIMT) which is a measure commonly used as a surrogate for vascular atherosclerosis. One hundred and sixty one patients with known cardiovascular disease were randomly divided into a pravastatin (40mg/d) group (n=82) and an atorvastatin (80 mg/d) group (n=79).  After one year the average LDL in the pravastatin group was 110 mg/dL and was 76 mg/dL in the atorvastatin group.  The CIMT was stable in the pravastatin group while the atorvastatin group showed a regression in CIMT over 12 months.  An aggressive reduction in LDL is an efficient way to induce the regression of atherosclerosis which may in turn lead to fewer coronary events.

Pravastatin in the secondary prevention of cardiovascular events in patients with kidney insufficiency ⁸

Since statins have been overwhelmingly shown to reduce cardiovascular disease in the general population, this study investigated the ability of statins to reduce cardiovascular events in patients with renal insufficiency (when the kidneys lose their ability to remove waste from the body).  There were 1711 participants in this study who were identified as having chronic kidney insufficiency by having a creatinine clearance of ≤75 mL/min.  Patients were given either pravastatin or placebo.  Pravastatin was associated with a lower occurrence of major coronary events but there was not a difference in total mortality between the two groups.  The incidence of side effects was similar in patients receiving pravastatin to those receiving placebo.  A significant finding is that patients will see the observed benefits whether or not they have kidney insufficiency and regardless of its severity.  Pravastatin is therefore a safe and effective method of secondary prevention for patients who have mild chronic kidney insufficiency.

Fluvastatin and prevention of cardiac events after a successful, first percutaneous coronary intervention ⁹  (LIPS study)

Percutaneous coronary intervention (PCI) is effective for short-term improvement in ischemic symptoms but has less long-term efficacy.  Sixty percent of patients are free of a major adverse cardiac event (MACE) 5 years after PCI and only 33% after 10 years.  The goal of this study was to assess whether fluvastatin reduces major cardiac events.  A total of 1677 patients at 77 centers in Europe, Canada, and Brazil were studied.   Eight hundred and forty four patients with unstable angina or silent ischemia after their first PCI were randomly assigned to receive 80 mg/d of fluvastatin and 833 a placebo. After a median follow-up time of 3.9 years 21.4% of the patients in the fluvastatin group had a MACE, compared to 26.7% in the placebo group.  Also, there was a longer time before a MACE in the fluvistatin group.  This study suggests that patients with average cholesterol levels will benefit from fluvistatin treatment after the first successful PCI.  The LIPS study has also shown that patients treated with a stent and fluvistatin show a 28% reduction in MACE. 

Atorvastatin versus simvastatin on atherosclerosis progression (ASAP) study ^10,11

The purpose of the ASAP study was to assess the difference of aggressive versus traditional cholesterol treatment on the progression of atherosclerosis in patients with familial high cholesterol.  Three hundred and twenty five patients with a family history of high cholesterol were randomly divided into an aggressive group (atorvastatin) and a traditional treatment group (simvastatin).  After two years of treatment, the progression of atherosclerosis was compared between the two groups.  In one test, the levels of hs-CRP were lower in patients taking atorvastatin compared to simvastatin.  hs-CRP is a good marker of inflammation in atherosclerotic vascular disease.  In another test—a measurement of the carotid intima media thickness—the atorvastatin group showed a regression of atherosclerosis, whereas the simvastatin group did not.  These results show that aggressive lowering of LDL was accompanied by a regression of atherosclerosis in the carotid artery but conventional LDL lowering by simvastatin did not show any benefit.

The Benefit of Aggressive Lipid Lowering ¹² (AVERT study)

This study examined 341 patients with stable coronary heart disease (CHD).  They were randomly assigned to receive atorvastatin (80 md/d) and conventional treatment or angioplasty followed by usual care.  The differences in LDL and subsequent ischemic events were compared between the two groups.  The atorvastatin/conventional treatment group showed a 48% decrease in LDL compared to an 18% decrease following angioplasty.  The atorvastatin group had fewer ischemic events (13% vs 21%, p=.048) and a longer time before the first ischemic event (p=.027) when compared with the angioplasty group.  Therefore aggressive lipid lowering is beneficial in patients with existing CHD.

Aggressive LDL lowering provides the greatest reduction in carotid atherosclerosis ¹³

The purpose of this study was to investigate the effects on atherosclerosis of lowering LDL well below the current recommended level of 100 mg/dL.  The investigators used the carotid intima media thickness (CIMT) as an indicator of atherosclerosis progression.  The study compared the effects of pravastatin (40 mg/d) and atorvastatin (80mg/d) among 161 patients.  The final LDL level was directly correlated with the amount of CIMT regression.  Sixty-one percent of subjects with final LDL levels of < 70 mg/dL showed a regression whereas only 29% of those with final LDL of ≥ 114 mg/dL.  The amount of atherosclerotic regression is directly related to absolute LDL level.  The investigators recommend a lower National Cholesterol Education Program guideline. 

The relation between atherosclerotic progression and cholesterol levels ¹⁴

This study assessed the long-term (average of 18.3 months) progression or regression of atherosclerotic plaque in the left main coronary artery (LMCA) by intravascular ultrasound (IVUS).  IVUS studies were performed on the LMCA of 60 patients.  LDL and plaque progression were positively correlated (i.e. the more LDL, the more plaque).  The researchers calculated that LDL levels below 75 mg/dL would not predict any progression of atheroclerosis (i.e. it would be essentially stopped, but not necessarily regress). Also, there was an negative correlation between HDL and plaque (i.e. more HDL less plaque).  Therefore lower LDL (at least below 75 mg/dL) and higher HDL slows or halts progression of atherosclerosis. This study is particularly useful because unlike other similar studies it examined the effects of HDL cholesterol on atherosclerotic plaque. 

TNT. Intensive lipid lowering with Atorvastatin in patients with stable coronary disease. ¹⁵

10,001 cases with stable coronary heart disease, all started on Lipitor 10 mg, and after run in period, half to 80 mg, half remained on 10 mg. LDL remained at 101 mg/dl in the half on 10 mg, fell to 77 on the 80 mg. Reduction in CHD events 22% (p<.01), 27% reduction in stroke (p<.01).

ASTEROID: Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. ¹⁶

507 cases had baseline IVUS and received Crestor, 40 mg/day. After 24 months, 349 patients had evaluable serial IVUS examinations. Mean ± SD baseline LDL of 130 ± 34 fell to 61 ± 20 mg/dl, a mean reduction of 53.2% (p <.0001). HDL increased by 14.7%. This resulted in significant regression of atherosclerosis for all 3 prespecified IVUS measures of disease burden.

METEOR:

Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 2007;28:297:1344)

Crouse JR 3rd, Raichlen JS, Riley WA, Evans GW, Palmer MK, O'Leary DH, Grobbee DE, Bots ML; METEOR Study Group.

CONTEXT: Atherosclerosis is often advanced before symptoms appear and it is not clear whether treatment is beneficial in middle-aged individuals with a low Framingham risk score (FRS) and mild to moderate subclinical atherosclerosis. OBJECTIVE: To assess whether statin therapy could slow progression and/or cause regression of carotid intima-media thickness (CIMT) over 2 years. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled study (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin [METEOR]) of 984 individuals, with either age (mean, 57 years) as the only coronary heart disease risk factor or a 10-year FRS of less than 10%, modest CIMT thickening (1.2-<3.5 mm), and elevated LDL cholesterol (mean, 154 mg/dL); conducted at 61 primary care centers in the United States and Europe between August 2002 and May 2006. INTERVENTION: Participants received either a 40-mg dose of rosuvastatin or placebo. MAIN OUTCOME MEASURES: Rate of change in maximum CIMT (assessed with B-mode ultrasound) for 12 carotid sites; changes in maximum CIMT of the common carotid artery, carotid bulb, and internal carotid artery sites and in mean CIMT of the common carotid artery sites. CIMT regression was assessed in the rosuvastatin group only. RESULTS: Among participants in the rosuvastatin group, the mean (SD) baseline LDL cholesterol level of 155 (24.1) mg/dL declined to 78 (27.5) mg/dL, a mean reduction of 49% (P<.001 vs placebo group). The change in maximum CIMT for the 12 carotid sites was -0.0014 (95% CI, -0.0041 to 0.0014) mm/y for the rosuvastatin group vs 0.0131 (95% CI, 0.0087-0.0174) mm/y for the placebo group (P<.001). The change in maximum CIMT for the rosuvastatin group was -0.0038 (95% CI, -0.0064 to -0.0013) mm/y for the common carotid artery sites (P<.001), -0.0040 (95% CI, -0.0090 to 0.0010) mm/y for the carotid bulb sites (P<.001), and 0.0039 (95% CI, -0.0009 to 0.0088) mm/y for the internal carotid artery sites (P = .02). The change in mean CIMT for the rosuvastatin group for the common carotid artery sites was 0.0004 (95% CI, -0.0011 to 0.0019) mm/y (P<.001). All P values are vs placebo group. Overall, rosuvastatin was well tolerated with infrequent serious adverse cardiovascular events (6 participants [0.86%] had 8 events [1.1%] over 2 years). CONCLUSIONS: In middle-aged adults with an FRS of less than 10% and evidence of subclinical atherosclerosis, rosuvastatin resulted in statistically significant reductions in the rate of progression of maximum CIMT over 2 years vs placebo. Rosuvastatin did not induce disease regression. Larger, longer-term trials are needed to determine the clinical implications of these findings.
Thavendiranathan P, et al: Primary prevention of cardiovascular diseases with statin therapy-a meta-analysis of randomized controlled trials. Arch Intern Med 2007;2307-13. In patients without antecedent cardiovascular disease, statin therapy decreases the incidence of major coronary and cerebrovascular events and revascularizations (quality of life, morbidity), but not coronary heart disease or overall mortality.

References.

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