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J Am Coll Cardiol, 2005; 46:1411-1416, doi:10.1016/j.jacc.2005.04.064
© 2005 by the American College of Cardiology Foundation
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FOCUS ISSUE: PROVE IT-TIMI 22

Can Low-Density Lipoprotein Be Too Low? The Safety and Efficacy of Achieving Very Low Low-Density Lipoprotein With Intensive Statin Therapy

A PROVE IT-TIMI 22 Substudy

Stephen D. Wiviott, MD*,{dagger},*, Christopher P. Cannon, MD, FACC*,{dagger}, David A. Morrow, MD, MPH, FACC*,{dagger}, Kausik K. Ray, MD{dagger}, Marc A. Pfeffer, MD, PhD, FACC*, Eugene Braunwald, MD, MACC*,{dagger} for the PROVE IT-TIMI 22 Investigators

* Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
{dagger} The TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts

Manuscript received January 27, 2005; revised manuscript received March 28, 2005, accepted April 4, 2005.

* Reprint requests and correspondence: Dr. Stephen D. Wiviott, TIMI Study Group, 350 Longwood Avenue, 1st Floor, Boston, Massachusetts 02115 (Email: swiviott{at}partners.org).


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 Safety
 Efficacy
 Conclusions
 References
 
OBJECTIVES: This study sought to evaluate the safety and efficacy of achieving very low calculated low-density lipoprotein (LDL) levels with intensive statin therapy.

BACKGROUND: Intensive statin therapy reduces clinical events occurring after acute coronary syndrome (ACS) and may result in LDL levels markedly lower than guideline levels. Prior epidemiologic and preclinical studies raise concerns about the safety of very low cholesterol levels.

METHODS: The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) study compared intensive therapy (atorvastatin, 80 mg) and moderate therapy (pravastatin, 40 mg) in patients after ACS. Patients treated with atorvastatin were divided by four-month LDL values into groups: >100, >80 to 100 (reference-range-meeting guidelines), >60 to 80, >40 to 60, and <40 mg/dl. Baseline, clinical, and safety data were compared among groups achieving guideline recommendation levels or lower.

RESULTS: Among 1,825 patients with four-month LDL, 91% were at goal (<100 mg/dl). The distribution was >80 to 100 mg/dl (14%), >60 to 80 mg/dl (31%), >40 to 60 mg/dl (34%), and <40 mg/dl (11%). Those with lower LDL levels were more often male, older, and diabetic, and had lower baseline LDL levels. They had prior statin therapy and fewer prior myocardial infarctions (MI). There were no significant differences in safety parameters, including muscle, liver, or retinal abnormalities, intracranial hemorrhage, or death, in the very low LDL groups. The <40 mg/dl and 40 to 60 mg/dl groups had fewer major cardiac events (death, MI, stroke, recurrent ischemia, revascularization).

CONCLUSIONS: Compared with patients treated with an accepted LDL goal (80 to 100 mg/dl), there was no adverse effect on safety with lower achieved LDL levels, and apparent improved clinical efficacy. These data identify no intrinsic safety concern of achieving low LDL and, therefore, a strategy of intensive treatment need not be altered in patients achieving very low LDL levels.

Abbreviations and Acronyms
  ACS = acute coronary syndrome
  LDL = low-density lipoprotein
  MI = myocardial infarction
  PROVE IT-TIMI 22 = Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22
  ULN = upper limit of normal

The 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors (statins) have been shown consistently to reduce cardiovascular events in patients with elevated cholesterol levels. These benefits have been observed in major primary prevention (1–3) and secondary prevention trials (2–5) in stable patients with progressively lower baseline cholesterol levels. Indications for the use of statins have been extended to patients with cholesterol levels previously considered to be normal (3,6–8). The Heart Protection Study showed a benefit of treatment with simvastatin compared with placebo regardless of baseline cholesterol level in high-risk patients (3). Treatment benefit was observed in patients who had baseline calculated low-density lipoprotein (LDL) <100 mg/dl, the target of therapy in a similar population at the time of the study (6). Recent data have extended these observations to the early time period after acute coronary syndromes (ACS) (9–11). The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial showed that intensive therapy (atorvastatin, 80 mg) that achieved a median LDL level of 62 mg/dl was superior to standard therapy (pravastatin, 40 mg) that achieved a median LDL level of 95 mg/dl after ACS in reducing clinical events (11).

However, intensive cholesterol lowering may not be without risk. Cholesterol serves important physiologic roles as a component of cell membranes and in vitamin synthesis. Treating patients with average or below average cholesterol levels with high doses of potent statins can be expected to result in many patients achieving LDL cholesterol levels significantly below target levels (6–8) (<60 mg/dl). Preclinical and epidemiologic data have raised some concerns about very low lipid levels. Early animal data with statins showed increased rates of retinal and optic neuronal degeneration (12,13), and some epidemiologic studies have suggested a relationship between low cholesterol levels, total mortality, and intracranial hemorrhage (14–16). These studies have not defined causality, and reflect that low cholesterol levels may be the result of systemic illness, not the cause of it. Nonetheless, concern remains that pharmacologically lowering cholesterol well beyond current targets may be harmful. The most common severe side effects of statins, muscle and liver toxicity, seem to be agent- and dose-related (17). Although increasing doses of statins result in lower LDL levels, no definitive relationship between achieved LDL level and side effects has been noted. Further, clinicians responding to recent trials have voiced concerns about the safety of very low LDL levels after intensive statin therapy.

To assess the safety and efficacy of achieving very low LDL levels after ACS, we analyzed the outcomes of patients in the PROVE IT-TIMI 22 trial treated with intensive statin therapy.


   Methods
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 Methods
Results
 Discussion
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 Efficacy
 Conclusions
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The PROVE IT-TIMI 22 study was a randomized controlled trial of intensive versus moderate cholesterol lowering with statins and infection therapy with gatifloxacin versus placebo in patients stabilized from an ACS (18). Patients were enrolled within 10 days of presentation for acute myocardial infarction (MI) or non–ST-segment elevation ACS after stabilization (including revascularization if planned). Patients with ACS were eligible if total cholesterol was <240 mg/dl (or <200 mg/dl if already treated with cholesterol-lowering therapy including statins). Patients were randomized to intensive therapy (atorvastatin, 80 mg) or standard therapy (pravastatin, 40 mg). A second randomization of therapy with gatifloxacin versus placebo was performed concurrently. Patients were followed up for a mean of two years. The primary composite end point of death, MI, stroke, revascularization and unstable angina requiring hospital admission was reduced by 16% (p = 0.005) in the intensive therapy arm. No difference was seen in the gatifloxacin versus placebo comparison (19). End points were adjudicated by an independent clinical events committee. Definitions of trial end points were described previously (11).

The purpose of the present analysis was to examine the safety and clinical outcomes of patients achieving very low levels of cholesterol. Therefore the primary analyses were restricted to the intensive treatment arm, because these patients were far more likely to achieve such LDL levels (<60 mg/dl). In addition, limiting the analysis to the intensive treatment arm removed any effect of the interaction between lipid level achieved and the specific statin to which the patient was randomized. Further, patients who did not achieve guideline-based recommendations (<100 mg/dl) were excluded from this analysis, because there is a consensus that LDL lowering beyond this point is warranted. Subjects were divided into subgroups by achieved lipid levels at four months (>80 to 100, >60 to 80, >40 to 60, and ≥40 mg/dl), a time at which it would be expected that lipid levels would have become stable from treatment and recovery from ACS and its sequelae.

Kaplan-Meier event rates (rates estimated from Kaplan-Meier curves at two years) for efficacy end points, including the primary end point of the trial and its components, death, MI, and total stroke, were determined by four-month LDL level. Hazard ratios were calculated using the 80- to 100-mg/dl LDL group as the referent because these patients achieved cholesterol goals and did not achieve very low cholesterol levels. Comparisons were made using the chi-square test for trend, and p values for trend are reported unless otherwise stated. Kaplan-Meier estimates are compared using the log-rank test. For the primary efficacy composite end point, multivariable analysis was performed accounting for differences in baseline characteristics among achieved lipid groups (age, gender, diabetes, prior history of MI, baseline LDL levels, and smoking status). Crude (unadjusted) rates of safety measures were reported by subgroup, including hemorrhagic stroke, liver-related events (alanine aminotransferase >3x the upper limit of normal (ULN) and/or discontinuation of study drug for liver function abnormalities), muscle-related events (myopathy, myositis creatine kinase >3x ULN, creatine kinase >10x ULN without concurrent MI, and rhabdomyolysis) (17), retinal adverse events (any event from the adverse event database that mapped to a preferred term abnormality, retina, and trauma/suicide.


   Results
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 Methods
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Discussion
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Study population and baseline characteristics.   In the PROVE IT-TIMI 22 trial, a total of 4,162 patients were enrolled, and 2,099 were randomized to the intensive treatment arm. Of these patients, 1,949 (92.9%) had four-month LDL levels checked. The distribution of four-month LDL levels in the intensive treatment group is shown in Figure 1. Of the patients who had four-month LDL levels checked, 193 (9.9%) had LDL >100 mg/dl; 1,756 patients (90.1%) met guideline treatment goals of LDL <100 mg/dl. When the latter group was divided by achieved LDL into four groups for analysis, LDL levels were >80 to 100 mg/dl in 256 (13.9%), >60 to 80 mg/dl in 576 (31.4%), >40 to 60 mg/dl in 631 (34.4%), and ≤40 mg/dl in 193 (10.5%).



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  		Figure 1 Distribution of four-month calculated low-density lipoprotein (LDL) (mg/dl) levels among subjects treated with intensive statin therapy (atorvastatin, 80 mg).

 
Baseline characteristics by treatment group are shown in Table 1. Patients who reached lower LDL levels were more likely to be older, male, and diabetic. Those who reached lower LDL levels were less likely to have had a prior MI or a prior coronary artery bypass graft, to be a cigarette smoker, or to have been on a statin before study initiation. Those achieving lower LDL levels had lower baseline total cholesterol and LDL levels (with the four groups having a median LDL of 118, 112, 103, and 91 mg/dl in order of descending achieved LDL level). Despite lower baseline LDL and total cholesterol levels, baseline high-density lipoprotein and triglyceride levels did not differ between groups. The percent reduction in LDL was progressively greater in the groups that achieved lower LDL levels ranging from 23.9% to 62.5% (Table 1).


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  		Table 1. Baseline Characteristics
 
Safety results.   Muscle side effects were infrequent (Table 2), with no episodes of rhabdomyolysis observed. There did not seem to be any relationship between achieved LDL level and the development of muscle side effects. Similar results were observed for liver-related side effects, with no relationship between achieved LDL and the frequency of either liver enzyme elevations or discontinuation for abnormal liver enzyme levels (Table 2). Similarly, there was no significant association between the frequency of adverse ophthalmologic events (Table 2) and achieved LDL level. There was one suicide in the intensive therapy arm (achieved LDL >100 mg/dl) and no traumatic deaths.


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  		Table 2. Major Safety and Efficacy Outcomes (Percent of Subjects)
 
There was no difference in total strokes (Table 2). A small number of cerebral hemorrhages was seen in this cohort, one in the >80 to 100 mg/dl group (0.4%), and none observed in patients with achieved LDL <60 mg/dl (p = 0.12). Aspirin was taken by 95% of subjects at the four-month visit, including the subjects with intracranial hemorrhage. Aspirin use did not differ among achieved LDL groups. Subjects who did not have an LDL <100 mg/dl at four months were more likely to have discontinued the study drug, including for adverse events. Not surprisingly, more patients who had adverse events and were off of the study drug did not achieve the LDL goals. Beyond four months, however, the group of patients who at four months had LDL >100 mg/dl had similar safety features compared with those who achieved lower LDL levels.

Efficacy results.   When the primary end point of the trial was examined, there was a trend toward lower rates in the descending achieved LDL groups (26.1%, 22.2%, 20.4%, and 20.4%, respectively, ptrend = 0.1.) with the lowest rates in the 40 to 60 mg/dl group and the ≤40 mg/dl group. A multivariable analysis was performed accounting for baseline differences and showed that both of the lowest LDL groups, >40 to 60 (hazard ratio = 0.67 [95% confidence interval 0.50 to 0.92]) and ≤40 (hazard ratio 0.61 [95% confidence interval 0.40 to 0.91]) showed significantly lower end point rates than the referent group (Fig. 2).



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  		Figure 2 Hazard ratio of the primary end point compared with achieved calculated low-density lipoprotein (LDL) 80 to 100 mg/dl (adjusted for age, gender, baseline calculated low-density lipoprotein, diabetes mellitus, and prior myocardial infarction).

 
When the individual components of the primary end point were examined (Table 2), there was no apparent effect of achieved LDL on total mortality (p = 0.8), however, MI tended to be lower with lower LDL levels (p < 0.01).


   Discussion
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Safety
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In this analysis performed among the intensively treated patients in the PROVE IT-TIMI 22 trial, there seemed to be a lower rate of clinical events and no increase in adverse events in patients who achieved very low cholesterol levels. The results of recent lipid-lowering trials in ACS suggest a paradigm shift in the management of lipids in high-risk patients (8,20); an appropriate strategy in high-risk patients may be to commence therapy with a high dose of a potent statin, monitor for side effects, and reduce the dose when side effects are seen. This is in contrast to previous strategies of starting with a low dose and titrating upward to achieve a specific goal. This strategy resulted in a majority of patients achieving LDL levels well below current guidelines. Clinical features that predicted lower achieved LDL levels included lower baseline LDL, older age, male gender, diabetes, and the absence of prior statin therapy.


   Safety
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 Methods
 Results
 Discussion
 Safety
Efficacy
 Conclusions
 References
 
In patients treated with intensive lipid-lowering therapy, there did not seem to be a relationship between achieved LDL levels and the likelihood of adverse safety events. There were no trends toward increases in the rates of expected side effects such as myopathy or elevations in liver enzyme levels based on achieved LDL levels. Rates of anticipated adverse events such as elevations in liver and muscle enzymes seen in the PROVE IT-TIMI 22 trial are consistent with previous data (21). In addition to the examination of rates of anticipated side effects, there was no increase in all-cause mortality, intracranial hemorrhage, ophthalmologic side effects, or trauma/suicide with lower achieved LDL levels, as had been suggested by previous epidemiological data in non–statin-treated patients (14–16).

Statins have been extensively studied, and the side effect profile is well characterized. However, specific statins and the class of drugs have not been without important side effects, including rhabdomyolysis and renal failure (22,23). Previous data suggest that the incidence of expected side effects such as myopathy and elevation of liver enzyme levels with statins is related to the specific statin and its dose, as well as to concomitant medications and illnesses (17,24). A previously published report of more than 100,000 person-years of treatment with pravastatin from the prospective Pravastatin Pooling Project (PPP), however, showed a remarkable safety profile in the controlled and monitored setting of clinical trials; the incidence of adverse effects was similar in pravastatin-treated and placebo-treated patients (25). The largest previously published experience, with 80 mg of atorvastatin in 2,345 patients in multiple combined trials with shorter-term follow-up (21), showed an excellent safety profile. In the PROVE IT-TIMI 22 trial, both treatment arms had favorable side effect profiles similar to those observed previously, but overall there were similar rates of muscle side effects and a higher rate of elevations in liver enzyme levels among patients treated with intensive lipid lowering with atorvastatin 80 mg compared with standard lipid-lowering therapy with pravastatin 40 mg (11).

The present analysis extends the observations regarding the safety of intensive statin therapy in several important ways. This is the largest long-term specific study of the safety of high-dose atorvastatin published to date. The study was performed in a post-ACS population with multiple concomitant medications and comorbidities; these patients would be expected to be at high risk for adverse events. However, despite this risk profile, low rates of severe adverse events were noted. The observation that patients who achieved very low LDL levels (<60 mg/dl) did not have an excess of complications provides evidence that when using high-dose statins, an achieved LDL level below goal levels is not associated with increased risks and therefore need not be a reason for dose reduction. These findings are consistent with previous pooled data from multiple trials showing no excess risk of adverse events for patients achieving cholesterol levels below 80 mg/dl with a range of doses of atorvastatin (26), but extends the range down to below even 40 mg/dl.


   Efficacy
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 Methods
 Results
 Discussion
 Safety
 Efficacy
Conclusions
 References
 
In this analysis, patients treated with intensive statin therapy who achieved very low LDL levels had fewer cardiovascular events than patients who achieved levels nearer to previous guideline recommendations (80 to 100 mg/dl). This supports a "lower is better" hypothesis, but goes beyond even what was seen in the PROVE IT-TIMI 22 trial, which showed a benefit of intensive therapy (with a median LDL of 62 mg/dl) compared with standard therapy (with a median LDL of 95) (11). It suggests the possibility that further LDL lowering beyond the new guideline optimal goal of <70 mg/dl (8) may translate into an additional clinical benefit.

This benefit is consistent with the results of several other trials. The Treating to New Targets (TNT) trial showed fewer major adverse cardiac events in stable patients treated with 80 mg of atorvastatin compared with 10 mg of atorvastatin daily, the first to show such a benefit with a single agent (27). The Heart Protection Study showed a benefit with statin therapy for the lowering of cholesterol from any baseline, including in those patients with baseline levels <100 mg/dl (3). The Z phase of the Aggrastat to Zocor (A to Z) trial showed no significant benefit for early intensive simvastatin therapy (40 followed by 80 mg) versus delayed standard simvastatin therapy (placebo followed by 20 mg). However, a significant reduction in events after six months was seen with resultant LDL levels of 66 mg/dl compared with 81 mg/dl (10). Extrapolation from previous trials and epidemiologic data suggests that there may be a linear or log-linear relationship of achieved LDL levels with protection from cardiovascular events and that benefit may extend to lowering LDL beyond the resultant levels in recent trials (8,28). Furthermore, cholesterol levels are in the range of 30 to 70 mg/dl in healthy neonates and 50 to 75 mg/dl in hunter/gatherer populations without evidence of atherosclerosis (28).

Study limitations.   This is a post-hoc analysis, and all hypotheses based on the results should be considered exploratory. Perhaps most importantly, the analyses are being performed using subgroups based on an achieved parameter (LDL). This raises the concern that there may be important differences in patients who achieve one LDL level compared with those who achieve another. We have attempted to exclude such confounding by performance of multivariable analysis; however, we cannot exclude the effects of either unmeasured or unidentified covariates. In addition, no inference can be made regarding safety end points not examined in this analysis.

It is also important to note that the absence of a relationship of side effects with achieved LDL was in patients treated with a single dose of a single statin. It cannot be excluded that the rate of side effects would increase if physicians increase dosing of one agent, change agents, or add additional cholesterol-lowering agents in an attempt to achieve a lower LDL goal. Finally, the numbers of patients with major safety end points in the PROVE IT-TIMI 22 trial was low; therefore, a clinically meaningful difference could have been missed as a result of a lack of statistical power. However, this is the largest group of patients after ACS achieving such low LDL levels in the published literature of which we are aware.


   Conclusions
Top
 Abstract
 Methods
 Results
 Discussion
 Safety
 Efficacy
 Conclusions
References
 
When treating patients with intensive lipid-lowering therapy (with atorvastatin, 80 mg daily) after ACS, there did not seem to be a relationship between the achieved LDL level and the risk of complications from statin therapy over a two-year period. However, there were lower rates of cardiovascular events in those achieving these very low LDL levels. Therefore, it is not necessary to reduce the dose of a statin based on resultant LDL levels well below guideline recommendations. Additional data are needed to determine whether tailoring drug therapy to specifically target very low LDL levels would be safe and beneficial in high-risk patients.


   Footnotes
 
The PROVE IT–TIMI 22 study was funded by Bristol-Myers Squibb. The A to Z trial was funded by Merck.


   References
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 Results
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 Safety
 Efficacy
 Conclusions
 References
 

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