Population Characteristics and Study Quality of Included Trials , by Combination Therapy Agent and Potency Comparison Long-Term Clinical Outcomes We found insufficient evidence to compare long-term clinical outcomes ( mortality , acute coronary events , cerebrovascular events , and revascularization procedures ) for all combination therapy and statin intensity comparisons .
Figure 1 presents an evidence map of studies that evaluated these
Atherosclerotic cardiovascular disease ( ASCVD ) affects more than 15 million Americans ( 1 ) and is the leading cause of death for both men and women in the United States ( 2 ) .
Trials have demonstrated reductions in low-density lipoprotein ( LDL ) cholesterol levels ( 3 ) and decreased ASCVD risk with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ( statin ) monotherapy ( 4 ) .
Over the past decade , statins have often been used in combination with other lipid-modifying agents .
Recently , several high-profile r and omized , controlled trials ( RCTs ) have evaluated add-on therapy ( 57 ) , wherein statin monotherapy is compared with the combination of the same statin dose and another lipid-modifying agent .
Add-on combination therapy can lead to superior lipid outcomes , but studies have not shown decreased rates of cardiovascular death , myocardial infa rct ion , revascularization , or stroke ( 57 ) .
Therefore , the 2013 American College of Cardiology ( ACC ) and American Heart Association ( AHA ) guidelines recommend moderate- or high-intensity statin monotherapy as the first-line strategy for ASCVD risk reduction among patients with LDL cholesterol levels of 4.91 mmol/L or greater ( 190 mg/dL ) , preexisting ASCVD , diabetes mellitus ( DM ) , or estimated 10-year ASCVD risk of 7.5 % or greater ( 8) .
Adverse effects are more common with higher-intensity statin regimens ( 9 ) , and musculoskeletal adverse events occur frequently among patients with the C variant in the SLCO1B1 gene ( 10 ) .
The 2013 ACC/AHA guidelines suggest that clinicians consider moderated combination therapy with a lower-intensity statin and another lipid-modifying medication among high-risk patients ( LDL cholesterol level 4.91 mmol/L [ 190 mg/dL ] , preexisting ASCVD , or DM ) who are intolerant of or unresponsive to statins ( evidence grade E : expert opinion ) ( 8) .
Yet , it is unclear whether this strategy results in similar ASCVD risk reductions and fewer adverse effects compared with higher-intensity statin monotherapy .
A 2009 systematic review that examined these questions found insufficient evidence to weigh benefits and risks of moderated combination therapy ( 12 ) .
We aim ed to compare the effectiveness , safety , and tolerability of moderated combination therapy of statin with another lipid-modifying medication ( bile acid sequestrant , ezetimibe , fibrate , niacin , or -3 fatty acid ) with those of higher-intensity statin monotherapy among high-risk patients .
We sought to compare the long-term clinical benefits and short-term lipid effects of moderated combination therapy with those of higher-intensity statin monotherapy , as well as to determine whether these regimens differ in rates of adherence and harms .
Given the recent release of the 2013 ACC/AHA guidelines ( 8) , we narrowed the scope of this manuscript to focus on evidence most relevant to high-risk population s for whom combination therapy might be considered .
Prior studies have suggested schemes to group statins on the basis of their reported LDL cholesterol reduction ( 17 , 18 ) , which are similar to the strategy used by the ACC/AHA committee ( 8) .
Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double-blind randomised trial
Summary Background Lowering of LDL cholesterol reduces major vascular events , but whether more intensive therapy safely produces extra benefits is uncertain . We aim ed to establish efficacy and safety of more intensive statin treatment in patients at high cardiovascular risk . Methods We undertook a double-blind r and omised trial in 12 064 men and women aged 18–80 years with a history of myocardial infa rct ion . Participants were either currently on or had clear indication for statin therapy , and had a total cholesterol concentration of at least 3·5 mmol/L if already on a statin or 4·5 mmol/L if not . R and omisation to either 80 mg or 20 mg simvastatin daily was done central ly using a minimisation algorithm . Participants were assessed at 2 , 4 , 8 , and 12 months after r and omisation and then every 6 months until final follow-up . The primary endpoint was major vascular events , defined as coronary death , myocardial infa rct ion , stroke , or arterial revascularisation . Analysis was by intention to treat . This study is registered , number IS RCT N74348595 . Findings 6031 participants were allocated 80 mg simvastatin  daily , and 6033 allocated 20 mg simvastatin daily . During a mean follow-up of 6·7 ( SD 1·5 ) years , allocation to 80 mg simvastatin produced an average 0·35 ( SE 0·01 ) mmol/L greater reduction in LDL cholesterol compared with allocation to 20 mg . Major vascular events occurred in 1477 ( 24·5 % ) participants allocated 80 mg simvastatin versus 1553 ( 25·7 % ) of those allocated 20 mg , corresponding to a 6 % proportional reduction ( risk ratio 0·94 , 95 % CI 0·88–1·01 ; p=0·10 ) . There were no apparent differences in numbers of haemorrhagic strokes ( 24 [ 0·4 % ] vs 25 [ 0·4 % ] ) or deaths attributed to vascular ( 565 [ 9·4 % ] vs 572 [ 9·5 % ] ) or non-vascular ( 399 [ 6·6 % ] vs 398 [ 6·6 % ] ) causes . Compared with two ( 0·03 % ) cases of myopathy in patients taking 20 mg simvastatin daily , there were 53 ( 0·9 % ) cases in the 80 mg group . Interpretation The 6 % ( SE 3·5 % ) reduction in major vascular events with a further 0·35 mmol/L reduction in LDL cholesterol in our trial is consistent with previous trials . Myopathy was increased with 80 mg simvastatin daily , but intensive lowering of LDL cholesterol can be achieved safely with other regimens . Funding Merck ; The Clinical Trial Service Unit also receives funding from the UK Medical Research Council and the British Heart Foundation
Population Characteristics and Study Quality of Included Trials , by Combination Therapy Agent and Potency Comparison Long-Term Clinical Outcomes We found insufficient evidence to compare long-term clinical outcomes ( mortality , acute coronary events , cerebrovascular events , and revascularization procedures ) for all combination therapy and statin intensity comparisons .
Figure 1 presents an evidence map of studies that evaluated these
Atherosclerotic cardiovascular disease ( ASCVD ) affects more than 15 million Americans ( 1 ) and is the leading cause of death for both men and women in the United States ( 2 ) .
Trials have demonstrated reductions in low-density lipoprotein ( LDL ) cholesterol levels ( 3 ) and decreased ASCVD risk with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ( statin ) monotherapy ( 4 ) .
Over the past decade , statins have often been used in combination with other lipid-modifying agents .
Recently , several high-profile r and omized , controlled trials ( RCTs ) have evaluated add-on therapy ( 57 ) , wherein statin monotherapy is compared with the combination of the same statin dose and another lipid-modifying agent .
Add-on combination therapy can lead to superior lipid outcomes , but studies have not shown decreased rates of cardiovascular death , myocardial infa rct ion , revascularization , or stroke ( 57 ) .
Therefore , the 2013 American College of Cardiology ( ACC ) and American Heart Association ( AHA ) guidelines recommend moderate- or high-intensity statin monotherapy as the first-line strategy for ASCVD risk reduction among patients with LDL cholesterol levels of 4.91 mmol/L or greater ( 190 mg/dL ) , preexisting ASCVD , diabetes mellitus ( DM ) , or estimated 10-year ASCVD risk of 7.5 % or greater ( 8) .
Adverse effects are more common with higher-intensity statin regimens ( 9 ) , and musculoskeletal adverse events occur frequently among patients with the C variant in the SLCO1B1 gene ( 10 ) .
The 2013 ACC/AHA guidelines suggest that clinicians consider moderated combination therapy with a lower-intensity statin and another lipid-modifying medication among high-risk patients ( LDL cholesterol level 4.91 mmol/L [ 190 mg/dL ] , preexisting ASCVD , or DM ) who are intolerant of or unresponsive to statins ( evidence grade E : expert opinion ) ( 8) .
Yet , it is unclear whether this strategy results in similar ASCVD risk reductions and fewer adverse effects compared with higher-intensity statin monotherapy .
A 2009 systematic review that examined these questions found insufficient evidence to weigh benefits and risks of moderated combination therapy ( 12 ) .
We aim ed to compare the effectiveness , safety , and tolerability of moderated combination therapy of statin with another lipid-modifying medication ( bile acid sequestrant , ezetimibe , fibrate , niacin , or -3 fatty acid ) with those of higher-intensity statin monotherapy among high-risk patients .
We sought to compare the long-term clinical benefits and short-term lipid effects of moderated combination therapy with those of higher-intensity statin monotherapy , as well as to determine whether these regimens differ in rates of adherence and harms .
Given the recent release of the 2013 ACC/AHA guidelines ( 8) , we narrowed the scope of this manuscript to focus on evidence most relevant to high-risk population s for whom combination therapy might be considered .
Prior studies have suggested schemes to group statins on the basis of their reported LDL cholesterol reduction ( 17 , 18 ) , which are similar to the strategy used by the ACC/AHA committee ( 8) .