Achieving LDL cholesterol goals in elderly patients with ACS

Standard doses of statin drugs have been shown to be beneficial for elderly patients with a history of vascular disease or major risk factors for atherosclerosis. ¹ However, despite the high risk of death and nonfatal coronary events among elderly patients with acute coronary syndrome (ACS), they are treated with fewer proven therapies, such as cardioprotective drug treatments, including lipid-lowering agents (statins), and revascularization procedures.²

The National Cholesterol Expert Panel (NCEP) recently recommended a target low-density lipoprotein (LDL) cholesterol level of < 70 mg/dL for patients at very high risk for cardiovascular events.³ This article summarizes the key findings of a subanalysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction (PROVE IT-TIMI) 22 trial, which was conducted to determine the safety and efficacy of achievement of the new NCEP-recommended LDL cholesterol target level among ACS patients aged 70 years and older.⁴

Subjects and methods

The PROVE IT-TIMI 22 trial included ACS patients hospitalized on average 10 days after ACS.⁵ Subjects were randomly assigned to receive intensive statin therapy with 80 mg of atorvastatin (Lipitor) or moderate therapy with 40 mg of pravastatin (Pravachol). The relationship between 30-day LDL cholesterol levels and subsequent risk of death, myocardial infarction (MI), or unstable angina over 2 years was assessed in subjects ≥ 70 years of age. Total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels were measured in fasting samples, and LDL cholesterol was obtained by calculation.

Results

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A total of 730 patients aged 70 years or older and 3432 patients younger than 70 years of age were enrolled in the PROVE IT-TIMI 22 trial. Comorbid conditions, such as hypertension and diabetes, occurred more often in elderly subjects. Elderly subjects also had lower LDL cholesterol and triglyceride levels, but higher HDL cholesterol levels ( < .001 for each).

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Levels of LDL cholesterol in the elderly subjects were markedly lower than in the younger subjects at all points of measurement throughout the study (at 30 days, 4 months, and the end of the study). In the elderly group, 74.6% of subjects receiving 80 mg of atorvastatin achieved the NCEP goals at 30 days, compared with only 27.7% of elderly subjects receiving 40 mg of pravastatin ( < .001), which was expected. In younger subjects, 72.1% of those taking atorvastatin reached NCEP goals, compared with 20.5% of those taking pravastatin ( < .001).

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Elderly subjects had a markedly higher risk of individual acute events or a combination of events throughout the trial. With each increasing decade of age, the composite triple end point of death, MI, or unstable angina occurred more often in elderly subjects (20.1% ) compared with younger subjects (11.0%; hazard ratio [HR] = 1.93; 95% confidence interval [CI], 1.59-2.33; < .001).

Figure 1. Risk of death, myocardial infarction, or unstable angina requiring

rehospitalization after 30 days stratified by day 30 low-density lipoprotein

(LDL) cholesterol level and decades of age. (Reprinted with permission from

Ray KK, Bach RG, Cannon CP, et al. Benefits of achieving the NCEP optional

LDL-C goal among elderly patients with ACS. Eur Heart J. 2006;

27[19]:2310-2316.)

Figure 2. Relationship between achievement of or failure to reach National

Cholesterol Expert Panel low-density lipoprotein (LDL) cholesterol goal

(< 70 mg/dL) at 30 days and subsequent risk of clinical events (death,

myocardial infarction [MI], or unstable angina [UA] requiring

rehospitalization) in elderly and younger subjects. HR indicates hazard ratio;

CI, confidence interval. (Reprinted with permission from Ray KK, Bach RG,

Cannon CP, et al. Benefits of achieving the NCEP optional LDL-C goal among

elderly patients with ACS. Eur Heart J. 2006;27[19]:2310-2316.)

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Over 2 years, the absolute benefit of achieving the new NCEP goal and subsequent reduction in death, MI, or unstable angina was greatest for those older than 70 years of age and lowest in those younger than 50 years of age, with increasing benefit across decades of age (Figure 1). At day 30, 634 elderly subjects and 3150 younger subjects were free of events. Elderly subjects who reached the LDL-cholesterol target of < 70 mg/dL had a 40% lower risk of clinical events compared with older subjects who did not reach this target (13.5% vs 21.5% absolute rates, respectively; HR = 0.60; 95% CI, 0.41-0.87; = .008; Figure 2). Although younger subjects also showed improved outcomes by attaining the NCEP goals, the absolute benefit was less marked (8.1% vs 10.4% absolute rates, respectively; HR = 0.74; 95% CI, 0.59-0.94; = .013). Attaining the NCEP goals among older subjects was associated with an absolute benefit of 8% (number needed to treat [NNT], 12) compared with 2.3% in younger subjects (NNT, 43). After statistical adjustment for comorbidity and statin regimen, the benefits of achieving the NCEP goals remained unchanged.

The treatment of 1000 elderly ACS subjects to a target of NCEP goals for 2 years would be expected to prevent 43 deaths, 58 MIs, 14 rehospitalizations for unstable angina, 43 revascularizations after 30 days; and 1 stroke. Overall, 4 times as many deaths or acute coronary events (MI or unstable angina) would be reduced among the elderly (80 events) compared with 23 events in younger patients attaining the same LDL cholesterol target (Table).

Table. Expected number of cardiovascular events preventable* at 2 years by achieving a low-density lipoprotein cholesterol level < 70 mg/dL† at 30 days for every 1000 subjects treated with statins in different age groups.

Age group, n

Event

Young

Elderly

Death

5

43

MI

12

58

UA requiring rehospitalization

9

14

Revascularization after 30 days

15

43

Stroke

5

1

Death, MI, or UA requiring hospitalization

23

80

Primary end point (death, MI, UA, revascularization after 30 days or stroke)*

29

75

MI indicates myocardial infarction; UA, unstable angina.

*Counting only the first event per subject.

†Low-density lipoprotein (LDL) cholesterol level of 1.8 mmol/L corresponds to a value 70 mg/dL.

Eur Heart J.

This analysis considers only patients alive at day 30 who reach the LDL cholesterol goal and assesses subsequent events after day 30. (Reprinted with permission from Ray KK, Bach RG, Cannon CP, et al. Benefits of achieving the NCEP optional LDL-C goal among elderly patients with ACS. 2006;27[19]:2310-2316.)

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Elderly and younger subjects had comparable rates of increased liver enzymes (alanine transaminase level > 3 times the upper limit of normal [ULN]): 2.3% for elderly subjects vs 2.2% for younger subjects ( = .8). The rates of increased creatine kinase (CK) levels (> 3 times ULN) were also comparable between the 2 groups: 1.1% for elderly subjects vs 1.3% for younger subjects ( = .6). Rates of discontinuation of either drug because of myalgia or an increase in CK levels were also similar in both groups of subjects. Atorvastatin 80 mg caused transient elevations in liver enzymes in older subjects compared with pravastatin 40 mg (4.8% vs 0, respectively; < .001), which was similar to rates in younger subjects. The increase in CK levels was identical for the atorvastatin and pravastatin elderly groups (both 1.1%; = .9). No cases of rhabdomyolysis occurred during the follow-up period.

Discussion

The subgroup analysis of PROVE IT-TIMI 22 suggested that the new NCEP target of achieving an LDL cholesterol levels of < 70 mg/dL is safe and effective for elderly patients.⁴ Attaining this goal after an ACS event was associated with a significant 8% absolute lower rate of clinical events compared with patients not reaching this therapeutic goal. Among patients aged 70 years or older who survive an acute coronary event, an estimated 80 recurrent events (death, MI, or unstable angina) over 2 years could be prevented by achieving this lower LDL cholesterol level for every 1000 elderly ACS patients treated.

Younger counterparts appeared to benefit similarly in relative terms by achieving the new NCEP target. Because the risk of death, MI, or unstable angina after ACS is much higher in elderly subjects, the absolute difference is numerically greater among the elderly compared with younger subjects (8.0% vs 2.3% achievers vs nonachievers). This is an important observation from a public health perspective because it implies that achieving LDL cholesterol levels < 70 mg/dL has the potential to prevent nearly 4 times as many acute events among the elderly as among younger counterparts.

There is disparity, however, between current prescribing practices and the benefits to subjects observed in this study. The Global Registry of Acute Coronary Events (GRACE)⁵ and the National Registry of Myocardial Infarction 3⁶ provide data showing that lipid-lowering medication is less likely to be given to older patients than to their younger counterparts when being released from the hospital after ACS. This disparity was further underscored in a recent study of 400,000 subjects older than 66 years of age in which only 19% of subjects who were eligible for lipid-lowering therapy received statins.⁷

The benefits of statin therapy for those older than 65 years of age have been consistently corroborated in several secondary prevention statin trials.^8-10 However, subjects with stable coronary heart disease (CHD) only achieved LDL cholesterol levels of from 103 mg/dL⁸ to 115 mg/dL⁹ in these studies. The Heart Protection Study (HPS) showed a 5.1% absolute reduction in the risk of a major CHD event with statin therapy in subjects older than 70 years of age.¹¹ In light of these data, the American Heart Association issued a statement recommending that statin therapy should not be withheld from older patients as secondary prevention for CHD.¹² The Prospective Study of Pravastatin in Elderly at Risk (PROSPER) study subsequently confirmed the benefit of statin therapy prospectively in stable 70- to 82-year-old subjects with preexisting vascular disease or cardiovascular risk factors by demonstrating that achieving an LDL cholesterol level of 97.5 mg/dL was associated with a relative reduction in the risk of CHD death or MI by 19%.¹ Results from the PROVE IT-TIMI 22 trial concur with the findings from these studies and add to the existing data by showing that elderly ACS patients may receive greater absolute benefit from aggressive lipid-lowering treatment compared with younger patients because of their inherent higher risk after ACS.

Conclusions

Findings from this study showed that achieving the more intensive NCEP LDL cholesterol therapeutic goal of < 70 mg/dL appears to be safe and effective for elderly patients. The public health importance of achieving the new NCEP optional goal in elderly patients is significant because of the potential to prevent 4 times as many events among elderly patients as among younger patients. In a CHD population that is increasingly older, it is therefore important for health care professionals to address the underuse of statin therapy in the elderly at hospital discharge and attempt to achieve the NCEP LDL cholesterol targets during follow-up.