Low-density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome

INTRODUCTION — All patients with coronary heart disease, including those with an acute coronary syndrome (ACS), should receive long-term, intensive lipid-lowering therapy starting with a statin irrespective of baseline low-density lipoprotein cholesterol (LDL-C) level. In addition, all such patients should receive dietary instruction, which has the potential to lower elevated levels of LDL-C. (See "Lipid management with diet or dietary supplements", section on 'Summary and recommendations' and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Diet'.)

This topic will discuss issues related to the use of lipid-lowering agents in patients with an ACS. Cholesterol treatment recommendations for other patients with coronary heart disease are discussed separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

OUR APPROACH TO IN-HOSPITAL THERAPY

●For all ACS patients, we attempt to lower the LDL-C to approximately 50 mg/dL (1.29 mmol/L) (algorithm 1). We start LDL-C lowering therapy as early as possible after the diagnosis has been made.

For patients whose baseline LDL-C is ≥55 mg/dL (1.29 mmol/L) before treatment with a statin, we initiate high-intensity statin therapy (80 mg of atorvastatin or 20 to 40 mg of rosuvastatin daily) and continue it indefinitely (table 1).

For patients taking moderate-dose statin, we intensify statin therapy. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Intensity of statin therapy'.)

For patients already receiving high-intensity statin, we start ezetimibe 10 mg daily. In patients who are not likely to achieve the LDL-C goal of 50 mg/dL (1.29 mmol/L) with the addition of ezetimibe, it is reasonable to consider adding a PCSK9 during the hospitalization.

If the baseline LDL-C is very high (ie, >160 mg/dL [4.14 mmol/L]), such that the achieved LDL-C after treatment with high-intensity statin would not be anticipated to be <70 mg/dL (1.81 mmol/L), ezetimibe can be started with high-intensity statin therapy.

●For the uncommon patient whose baseline (before statin therapy) LDL-C is <50 mg/dL (1.29 mmol/L), there are no data to support a specific recommendation regarding statin therapy. We re-screen these patients to ensure that the low LDL-C was not a spurious result and then consider other risk factors that may have contributed to the coronary event such as lipoprotein(a) excess. (See "Lipoprotein(a)".)

We treat patients whose baseline LDL-C is <50 mg/dL (1.29 mmol/L) with moderate intensity statin therapy (table 1). (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Intensity of statin therapy'.)

●If the above approach could not be started in hospital, it should be applied as soon as possible in the outpatient setting.

MECHANISM OF ACTION — The mechanisms of benefit from LDL lowering are discussed in detail elsewhere. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)

GOAL OF THERAPY — In patients with ACS, the goal of treatment of elevated LDL-C is to lower the incidence of cardiovascular death, myocardial infarction (MI), stroke, and recurrent ischemic events. LDL-C lowering in all patients with atherosclerotic cardiovascular disease (ASCVD), including those with ACS, prevents these events. The magnitude in the reduction in risk is related to the baseline risk as well as the degree (percentage change and absolute level) of LDL-C lowering.

Among all patients with ASCVD, the risk of an ischemic event is higher in ACS patients than most of those with stable disease. Other very high-risk patients include those with familial hypercholesterolemia, diabetes, advanced chronic kidney disease, or multisystem ASCVD (eg, coronary and peripheral artery disease).

While patients with ACS are at very high risk, it is possible, even likely, that the risk varies based on baseline LDL-C. All other risk factors being equal, an ACS patient with a baseline (before LDL-C-lowering therapy) LDL-C of 120 mg/dL has a higher risk than one with a baseline LDL-C of 80 mg/dL.

In these very high-risk patients, data from randomized trials and observational studies have shown that the 10-year risk may be in excess of 40 percent. By comparison, ASCVD patients without these high-risk features may have a 10-year risk in the range of 20 to 25 percent. LDL-C lowering, across all subgroups of patients with ASCVD, reduces the risk by approximately 21 percent for each 38.7 mg/dL (1 mmol/L) reduction in LDL-C [1].

Due to this very high baseline risk in ACS patients, we believe that most of them will accept a recommendation to receive at least two LDL-C-lowering medications. The use of high-dose statin plus ezetimibe has the potential to lower the 10-year risk by more than 50 percent (from 40 to less than 20 percent). While the use of three drugs has the potential to lower risk further, each patient needs to decide when the risks/costs of therapy outweigh the benefits.

However, our ability to precisely define baseline risk in the individual patient leads to imprecision in our ability to explain to the patient (to predict) the magnitude of benefit from a specific LDL-C-lowering intervention.

INPATIENT MANAGEMENT — We treat most patients with an acute coronary syndrome (ACS) with high-intensity statin therapy as early as possible after the diagnosis has been made. Our approach is summarized above. (See 'Our approach to in-hospital therapy' above.)

Statin intensity — At their highest doses, atorvastatin and rosuvastatin lower the LDL-C to a greater extent than other statins. We typically use atorvastatin 80 mg daily, as it is the best studied statin in this setting. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Intensity of statin therapy'.)

However, it is uncertain whether the benefits seen in early therapy with atorvastatin 80 mg in patients with ACS represent a class effect of high-intensity statin therapy or are specific to atorvastatin. Rosuvastatin 40 or 20 mg lowers LDL-C to a comparable or greater degree than atorvastatin 80 mg and we consider it a reasonable alternative, particularly in those with prior intolerance to atorvastatin, those who are taking medications that might interact with atorvastatin but not rosuvastatin, or those for whom greater lowering of LDL-C is needed [2].

The randomized trials presented below suggest that the intensity of statin therapy (the degree of LDL-C lowering), rather than the agent used, is the principal determinant of clinical outcomes.

●PROVE IT-TIMI 22 trial − The PROVE IT-TIMI 22 trial randomly assigned 4162 patients with an ACS (35 percent ST-elevation myocardial infarction [STEMI], 36 percent non-ST elevation [NSTEMI], and 29 percent unstable angina) to pravastatin 40 mg/day or atorvastatin 80 mg/day [3]. The median LDL-C at initiation of therapy was 106 mg/dL (2.74 mmol/L). At a mean follow-up of two years, the following was noted:

•The median LDL-C achieved was significantly lower with atorvastatin (62 versus 95 mg/dL [1.60 versus 2.46 mmol/L]). Among the 2985 patients who had not previously received statin therapy, median LDL-C levels fell more with atorvastatin (51 versus 22 percent), and among the 990 patients previously on statin therapy, LDL-C levels fell by an additional 32 percent with atorvastatin but were unchanged from baseline with pravastatin.

•The primary end point (all-cause mortality, MI, unstable angina requiring rehospitalization, revascularization more than 30 days after randomization, or stroke) was significantly reduced with atorvastatin (22.4 versus 26.3 percent; hazard ratio [HR] 0.84, 95% CI 0.74-0.95).

•The Kaplan Meier curves and analysis of the HRs showed that the benefit started after only 15 days and persisted through the trial.

●MIRACL trial − In the MIRACL trial, 3086 adults with non-ST elevation ACS with a planned noninvasive approach were randomly assigned to atorvastatin 80 mg/day or placebo between 24 and 96 hours after hospital admission [4]. Atorvastatin led to a reduction in mean LDL-C concentration from 124 to 72 mg/dL (3.2 to 1.9 mmol/L). At 16-week follow-up, the primary end point (nonfatal MI, cardiac arrest with resuscitation, or recurrent symptomatic ischemia requiring hospitalization) was less frequent with atorvastatin (14.8 versus 17.4 percent for placebo); the benefit was primarily due to a reduction in recurrent symptomatic ischemia requiring emergency hospitalization (6.2 versus 8.4 percent).

●IMPROVE-IT – IMPROVE-IT was not a comparison of particular statins or their doses but rather of the addition of a non-statin agent, ezetimibe, on top of statin therapy. We believe IMPROVE-IT supports the concept that, in ACS patients, lower LDL-C is better.

●IDEAL trial – In a post-hoc analysis of 999 patients in the IDEAL trial who had a first acute MI less than two months before randomization, rates of the composite end point were 37.9 percent in the atorvastatin group and 44.7 percent in the simvastatin group (HR 0.82, 95% CI 0.67-0.99, p = 0.04) at five years [5].

Timing of initiation — We recommend starting intensive LDL-C lowering therapy as soon as possible after the diagnosis of ACS. While the evidence below (mostly from statin trials) supports its use as early as 12 hours post-diagnosis, there is no harm (and possible benefit) from very early initiation [3,4,6-10].

Initial high-intensity statin therapy, rather than gradual dose titration upward, is recommended because of the suggestion of benefit in PROVE IT-TIMI 22 (discussed below) when started within 10 days, an interval before the first fasting, steady state serum cholesterol measurement on therapy would usually be obtained.

The following evidence supports early initiation of statin therapy in patients with ACS:

●A clinical benefit for early statin therapy in ACS patients undergoing percutaneous coronary intervention (PCI), (eg, ARMYDA-ACS trial). (See "Percutaneous coronary intervention with intracoronary stents: Overview".)

●Chronic statin therapy may reduce the risk of no-reflow in patients undergoing primary PCI.

●In the PROVE-IT TIMI 22 trial (see 'Inpatient management' above), treatment was initiated within 10 days of presentation, but as early as 24 hours after diagnosis. Subset analysis revealed a trend toward benefit from atorvastatin as early as 30 days after the initiation of therapy; the risk reduction was similar to that seen at later time periods. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

●In the MIRACL trial, 3086 adults with a non-ST elevation ACS were randomly assigned to atorvastatin 80 mg/day or placebo between 24 and 96 hours after hospital admission [4]. At 16-week follow-up, the primary end point (nonfatal MI, cardiac arrest with resuscitation, or recurrent symptomatic ischemia requiring hospitalization) was less frequent with atorvastatin (14.8 versus 17.4 percent for placebo); the benefit was primarily due to a reduction in recurrent symptomatic ischemia requiring emergency hospitalization (6.2 versus 8.4 percent). (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

●The benefit of early statin therapy seen at one to four months in PROVE IT-TIMI 22 and MIRACL was not reproduced in phase Z of the A to Z trial. In this trial, patients with an ACS were randomly assigned to aggressive statin therapy (simvastatin 40 mg/day for one month, then 80 mg/day) or to delayed conservative statin therapy (placebo for four months, then simvastatin 20 mg/day) [6]. The median follow-up was 721 days. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

A combined end point of cardiovascular death, MI, readmission for ACS, and stroke occurred less frequently in the aggressive strategy arm but did not achieve statistical significance (14.4 versus 16.7 percent, HR 0.89, 95% CI 0.76-1.04). Similarly, death from any cause occurred less frequently in the aggressive strategy arm but did not achieve statistical significance (5.5 versus 6.7 percent, HR 0.79, 95% CI 0.61-1.02).

The primary combined end point was not decreased in the aggressive strategy arm during the first four months of therapy, during which time the conservative strategy arm was receiving placebo (HR 1.01, 95% CI 0.83-1.25), but it was decreased from four months to the end of the study (HR 0.75, 95% CI 0.60-0.95).

●The SECURE-PCI trial attempted to ascertain whether very early use of statin improves outcomes compared with somewhat later use [11]. ACS patients (n = 4191) were randomly assigned to receive two loading does of 80 mg of atorvastatin or placebo before and 24 hours after planned PCI. All patients were then treated with 40 mg for 30 days, starting 24 hours after the second dose of study medication. At 30 days, the rate of the primary outcome, a composite of all-cause mortality, MI, stroke, and unplanned coronary revascularization, was not different between the two groups (6.2 versus 7.1 percent; absolute difference 0.85 percent, 95% CI -0.70 to 2.41 percent). In a secondary analysis, patients who underwent PCI (n = 2710) compared with those who did not, appeared to derive benefit (HR 0.72, 95% CI 0.54-0.96). Despite no overall benefit, but a benefit in the PCI group, in SECURE-PCI, we continue to recommend that high-dose statin be given as early as possible after the diagnosis of ACS is made when feasible [12-14].

The EVOPACS study discussed directly below also provides support for the early initiation of LDL-C therapy after ACS.

PCSK9 inhibitors — We do not use PCSK9 inhibitors as initial LDL-C lowering therapy, as clinical outcomes with their early use have not been studied. Their role in subsequent outpatient management of individuals treated with maximally tolerated doses of statin is discussed below. (See 'PCSK9 inhibitors' below.)

The inpatient addition of PCSK9 inhibitors to high-intensity statin therapy was evaluated in the EVOPACS trial [15]. In EVOPACS, 308 patients hospitalized for ACS with elevated LDL-C levels (≥70 mg/dL [1.8 mmol/L] on high-intensity statin for at least four weeks; ≥90 mg/dL [2.3 mmol/L] on low- or moderate-intensity statin; or ≥125 mg/dL [3.2 mmol/L] on no statin) were randomly assigned to receive evolocumab 420 mg or placebo on top of atorvastatin 40 mg. The primary endpoint of a decrease in mean percentage change from baseline was significantly lower with PCSK9 treatment at eight weeks (-77.1 versus -35.4 percent). Serious adverse events occurred with similar frequency in both groups. Clinical cardiovascular endpoints were not evaluated.

OUTPATIENT MANAGEMENT — After initiation of high-intensity statin therapy, we check the LDL-C in four to eight weeks (algorithm 1). For patients who are tolerating high-intensity statin therapy and who have not lowered their LDL-C below 50 mg/dL (1.29 mmol/L), we add ezetimibe 10 mg daily in most cases, as was done in IMPROVE-IT (see 'Inpatient management' above). For patients whose LDL-C remains above 50 mg/dL (1.29 mmol/L) after an additional four to eight weeks despite high-dose statin and ezetimibe, we consider adding a PCSK9 inhibitor.

Some experts prefer a PCSK9 inhibitor (to ezetimibe) as the second agent in patients whose LDL-C is unlikely to be lowered to a level close to 50 mg/dL (1.29 mmol/L). (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Our practice to attempt to lower the LDL-C to approximately 50 mg/dL (1.29 mmol/L) is based on the results in IMPROVE-IT. (See 'Our approach to in-hospital therapy' above.)

Ezetimibe — Our recommendation to add ezetimibe to intensive statin therapy for any ACS patient with an LDL-C ≥50 mg/dL (1.29 mmol/L) is based on the IMPROVE-IT trial, in which combination therapy lowered the average LDL-C to 53 mg/dL from 69 mg/dL (in the statin only group).

IMPROVE-IT was not a comparison of particular statins or their doses but rather of the addition of a non-statin agent, ezetimibe, on top of statin therapy. IMPROVE-IT included 18,144 patients with an ACS in the preceding 10 days and an LDL-C of 50 to 100 mg/dL (1.3 to 2.6 mmol/L) if on lipid-lowering therapy, or an LDL-C of 50 to 125 mg/dL (1.3 to 3.2 mmol/L) if not on lipid-lowering therapy [16]. Patients were randomly assigned to simvastatin 40 mg daily plus ezetimibe 10 mg daily, or to simvastatin 40 mg daily plus placebo. If the LDL-C was above 79 mg/dL (2.0 mmol/L) on two consecutive measurements, the dose of simvastatin was increased to 80 mg daily prior to June 2011; after that time, the dose of simvastatin was not increased, and patients who had been on the higher dose for less than one year had the dose reduced to 40 mg daily. The median time-weighted, average achieved LDL-C was lower in the ezetimibe-simvastatin arm (53.7 versus 69.5 mg/dL [1.4 versus 1.8 mmol/L]).

After a median follow-up of six years, there was a reduction in the primary composite end point (cardiovascular death, nonfatal MI, unstable angina requiring hospitalization, coronary revascularization more than 29 days after randomization, or nonfatal stroke) in the ezetimibe-simvastatin arm (hazard ratio [HR] 0.936, 95% CI 0.89-0.99). This resulted in an absolute reduction in the rate of the primary end point at seven years (32.7 versus 34.7 percent). There was no reduction in all-cause mortality (HR 0.99, 95% CI 0.91-1.07) or cardiovascular mortality (HR 1.00, 95% CI 0.89-1.13); however, MI (HR 0.87, 95% CI 0.80-0.95) and stroke (HR 0.86, 95% CI 0.73-1.00) were reduced. Adverse events were similar in the two arms.

PCSK9 inhibitors — PCSK9 inhibitors (antibodies) have been shown to significantly lower LDL-C in numerous clinical trials and improve outcomes in high-risk subjects such as those with an ACS. In these studies of short and medium length, serious adverse effects have not been identified [17-19]. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

It is reasonable for selected ACS patients to be started on PCSK9 inhibitors in view of their lipid-lowering and additional mechanisms in ACS [20]; the following are examples:

●ACS patients with an LDL-C of ≥50 mg/dL (1.29 mmol/L) on high-dose statin plus ezetimibe.

●ACS patients who cannot tolerate high-dose statin therapy and do not lower their LDL-C below 70 mg/dL (1.81 mmol/L) on low dose (or no) statin plus ezetimibe.

Some lipid experts add a PCSK9 inhibitor directly to a statin rather than using ezetimibe in patients with ACS events whose LDL-C is >70 mg/dL (1.81 mmol/L).This is based on the greater LDL-C lowering potency of the inhibitors. (See 'Outpatient management' above.)

Factors that may influence a patient's decision to start PCSK9 therapy include cost, the need for periodic injection, and the absence of long-term safety data. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)

The ODYSSEY OUTCOMES trial randomly assigned 18,924 patients with an ACS 1 to 12 months earlier and an LDL-C level of at least 70 mg/dL (1.81 mmol/L), a non-high density lipoprotein cholesterol (HDL-C) level of at least 100 mg/dL (2.6 mmol/L), or an apolipoprotein B level of at least 80 mg/dL to alirocumab subcutaneously at a dose of 75 mg or placebo every two weeks [19]. The dose of alirocumab was adjusted for an LDL-C >50 mg/dL to target an LDL-C of 25 to 50 mg/dL (0.6 to 1.3 mmol/L). All patients were receiving high-intensity statin or the maximally-tolerated dose. The following findings were noted at a median duration of follow-up of 2.8 years:

●The baseline LDL-C was 92 mg/dL (2.4 mmol/L). At 48 months, the LDL-C in the treatment and placebo groups was 66 and 103 mg/dL, respectively, in the intention-to-treat analysis. In the on-treatment analysis, the LDL-C was 53 mg/dL in the alirocumab group.

●The primary composite end point (death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) occurred less often with alirocumab (9.5 versus 11.1 percent, respectively; HR 0.85, 95% CI 0.78-0.93). The risk of death from any cause was lower with alirocumab (3.5 versus 4.1 percent; HR 0.85, 95% CI 0.73-0.98).

●The incidence of adverse events was similar in the two groups, with the exception of local injection site reactions, which was higher with alirocumab (3.8 versus 2.1 percent).

●A prespecified analysis evaluated the extent to which alirocumab could reduce total (first and subsequent) nonfatal cardiovascular disease events and all-cause deaths [21]. There were 3064 first and 5425 total events with 190 fewer first and 385 fewer total nonfatal events or deaths with alirocumab. Alirocumab reduced total nonfatal cardiovascular events (HR 0.87, 95% CI 0.82-0.93) and deaths (HR 0.83, 95% CI 0.71-0.97).

●A prespecified analysis evaluated stroke outcomes stratified by baseline LDL-C [22]. Over a median follow-up of 2.8 years, alirocumab reduced the risk of any stroke (HR 0.72, 95% CI 0.57-0.91) and ischemic stroke (HR 0.73, 95% CI 0.57-0.93). These findings were present at all levels of baseline LDL-C. In addition, there was no increase in the risk of hemorrhagic stroke, including patients who achieved very low levels of LDL-C. This latter finding is important given a long-standing concern for an association between low LDL-C and hemorrhagic stroke [23].

●A prespecified analysis found that alirocumab-induced reduction in lipoprotein(a), independent of LDL-C lowering, led to a lowering of major adverse clinical events [24]. This issue is discussed separately. (See "Lipoprotein(a)", section on 'Next steps' and "Lipoprotein(a)", section on 'PCSK9 inhibitors'.)

Long-term management — We continue all therapies to lower LDL-C indefinitely.

SPECIAL POPULATIONS

Low baseline LDL-C — For uncommon patients whose baseline, off-statin, LDL-C is below 50 mg/dL (1.29 mmol/L), we have a slightly different approach. We start all such patients on moderate-dose statin as soon as possible after the diagnosis. After two to four weeks, we repeat the LDL-C. If the value is <50 mg/dL (1.29 mmol/L), we continue moderate-intensity statin. If the value is ≥50 mg/dL (1.29 mmol/L), we initiate high-intensity statin. Subsequent management is similar to that in other patients. (See 'Outpatient management' above.)

Our rationale for this approach in these patients is as follows. While randomized trials have enrolled few patients with LDL-C <50 mg/dL (1.29 mmol/L), the linear relationship between LDL-C and CVD events extends below this level. The potential benefit seems to outweigh any significant harm of statin therapy.

There are two broad causes of low LDL-C: genetic/familial determinants and acute phase illness such as infections, trauma, and surgery (see "Low LDL-cholesterol: Etiologies and approach to evaluation", section on 'Etiology').

In patients whose low LDL-C is likely genetic/familial, other potential non-LDL-C risk factors, aside from diabetes, hypertension, and smoking, should be considered. We often evaluation the patient's non-HDL-C, apolipoprotein B, and lipoprotein(a).

Statin intolerance — Statin intolerance is not uncommon and may lead to a reduction in dose or discontinuation. (See "Statin muscle-related adverse events".)

For patients who cannot receive statin therapy, despite multiple attempts, other lipid-lowering therapy should be used. For these patients, most experts would start with ezetimibe based on the results of IMPROVE-IT. Others would add a PCSK9 inhibitor before considering ezetimibe. (See 'Outpatient management' above.)

Older individuals — The use of statins in older patients is discussed separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Older patients'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders in adults" and "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)" and "Society guideline links: ST-elevation myocardial infarction (STEMI)" and "Society guideline links: Primary prevention of cardiovascular disease" and "Society guideline links: Secondary prevention of cardiovascular disease".)

SUMMARY AND RECOMMENDATIONS

●Approach to in-hospital therapy – For all patients with an acute coronary syndrome (ACS) whose baseline low-density lipoprotein-cholesterol (LDL-C) is ≥50 mg/dL (1.29 mmol/L), we recommend high-intensity statin therapy (atorvastatin 80 mg daily or rosuvastatin 20 or 40 mg daily) (Grade 1A). (See 'Our approach to in-hospital therapy' above and 'Inpatient management' above.)

We start this therapy as soon as possible after the diagnosis is made (algorithm 1). In patients previously taking low- or moderate-intensity statin, we intensify statin therapy. (See 'Timing of initiation' above.)

In addition, all patients should receive dietary instruction. (See "Lipid management with diet or dietary supplements", section on 'Summary and recommendations' and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

●Inpatient management – In patients for whom LDL-C remains >55 mg/dL (1.29 mmol/L) on high-intensity statin therapy, we recommend adding ezetimibe 10 mg daily (Grade 1A). (See 'Inpatient management' above.)

●Outpatient management – For patients with LDL-C >70 mg/dL or >25 percent above their recommended goal, we recommend adding a PCSK9 inhibitor [25].

For ACS patients treated with maximally tolerated statin plus ezetimibe and whose LDL-C remains >55 mg/dL (1.29 mmol/L), we suggest adding a PCSK9 inhibitor (Grade 2A). (See 'PCSK9 inhibitors' above.)

Some patients and their healthcare providers may reasonably prefer a higher LDL-C threshold, such as 70 mg/dL (1.81 mmol/L), for reasons of cost or inconvenience.