Volume 17, Issue 7 , Pages 495-499, November 2006
Primary prevention in high-risk dyslipidemic patients without an established cardiovascular disease: Undertreatment and rationale for lipid-lowering therapy
Article Outline
Abstract
Background
Recent updated guidelines expand the usage of lipid-lowering therapy for primary prevention in high-risk individuals without an established cardiovascular disease (CVD). In contrast to secondary prevention, the extent of the target population and the utilization of lipid-lowering drugs are insufficiently clear. We examine the implementation of statin therapy as primary prevention in high-risk patients without a known CVD and discuss the rationale for the management of dyslipidemia in this population.
Methods
Records of 371 consecutive patients without an established CVD who were hospitalized in an internal medicine department between January and June 2005 were evaluated for CVD-equivalent high-risk factors (diabetes mellitus, stroke of carotid origin, peripheral vascular disease, abdominal aortic aneurysm, or Framingham 10-year risk score ≥
20%). Demographic and clinical data, in addition to lipid profile and usage of statin drugs prior to and during hospitalization, were analyzed.
Results
Of the 371 non-cardiovascular patients, 88 (24%) were defined as high-risk individuals eligible for statin therapy as primary prevention of CVD. Their mean age was 71±11 years and their mean LDL-C level was 132±30 mg/dL. Seventeen patients (19%) were treated with statin drugs prior to admission and only two more patients (19/88, 22%) received statins in addition during hospitalization. Patients treated with statins had non-significantly higher LDL-C levels.
Conclusions
There is considerable undertreatment of high-risk patients without an established CVD with lipid-lowering drugs. There is also sub-optimal implementation of guidelines in clinical practice, despite well-established evidence of the benefits of statins in the primary prevention of CVD for high-risk individuals with average cholesterol levels, diabetes mellitus, and in elderly patients, as represented by our study population.
Keywords: Primary prevention, Cardiovascular disease, Statins, Dyslipidemia
1. Introduction
Dyslipidemia is a major modifiable risk factor for coronary heart disease. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are one of the most often prescribed and cost-effective drugs for the reduction of cardiovascular events [1]. Secondary prevention with statin therapy in even mildly dyslipidemic patients who suffer from cardiovascular disease (CVD) or who present with an acute coronary syndrome is a common practice nowadays, and low-density lipoprotein cholesterol (LDL-C) target goals continue to decline. Emerging clinical trials still demonstrate a log-linear relationship between the reduction of LDL-C levels and the relative risk of coronary heart disease, even at low LDL-C levels (<70 mg/dL) in very high-risk patients [2], [3].
However, in contrast to secondary prevention of established CVD, primary prevention with statin drugs in high-risk dyslipidemic patients without a known CVD is naturally less often implemented in clinical practice, even though large randomized, controlled trials have demonstrated a substantial reduction in the overall morbidity and mortality in high-risk patients [4], [5], [6], [7], [8], [9], [10], [11]. It appears that many physicians are not familiar with the practice guidelines in this field, resulting in undertreatment of this population, which does not receive an effective therapy as part of primary prevention of coronary heart disease.
The updated guidelines of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), published in 2004 according to recent clinical statin trials, expanded the intensity of LDL-lowering therapy in higher risk individuals with CVD risk-equivalent disorders that include diabetes, clinical manifestations of non-coronary forms of atherosclerotic disease such as peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease (transient ischemic attack or stroke of carotid origin, or >50% obstruction of a carotid artery) [12]. In addition, high-risk patients with multiple (2+) coronary heart disease risk factors and a 10-year risk of hard CVD endpoints ≥20%, calculated by the Framingham risk score charts, are entitled to have LDL-C lowering statin therapy. LDL-C target levels should be reduced to less than 100 mg/dL in these high-risk populations [12].
The objective of this study was to examine the implementation of statin lipid-lowering therapy as primary prevention in high-risk patients without an established CVD who were hospitalized in a typical academic internal medicine department. There is insufficient data in the literature concerning lipid-lowering therapy in this high-risk population. We wanted to test the hypothesis that there is undertreatment of statin therapy in this population and non-compliance with recently updated practice guidelines. The rationale for primary prevention of CVD by statin therapy is discussed.
2. Methods
Records of all 1130 consecutive patients admitted to an internal medicine department between January and June 2005 were reviewed. Excluded were all patients with a known coronary heart disease, patients admitted due to chest symptoms or acute coronary syndromes, and patients who died during hospitalization. All of the remaining 371 patients (33%) were evaluated for having at least one CVD-equivalent high-risk factor, defined according to practice guidelines as peripheral vascular disease, diabetes mellitus, stroke of carotid origin or known carotid artery stenosis >50%, and abdominal aortic aneurysm [12]. For patients without one of these risk factors, the 10-year risk score was calculated according to the Framingham risk score charts for men and women [13], [14]. Patients with a 10-year risk ≥20% of developing hard coronary heart disease events (myocardial infarction or coronary related death) were also regarded as high risk according to Framingham risk score charts and were included in the study (electronic 10-year risk calculators are available at www.nhlbi.nih.gov/guidelines/cholesterol).
Data collection included, in addition to the abovementioned risk factors, age, gender, blood pressure, smoking, full cholesterol profile, lack or existence of statin therapy on admission and during hospitalization, liver function tests, creatinine kinase levels, and antiplatelet or anticoagulation therapy.
2.1. Statistical analysis
Statistical analysis was performed using SPSS version 10 statistical software. The results are presented as means±standard deviation for continuous variables. Absolute and relative frequencies were measured for discrete variables. Differences between groups were analyzed with the independent, two-tailed Student's t-test for continuous variables. In cases of small numbers of patients per category, Fisher's exact test was used. A P-value of 0.05 or less was considered statistically significant.
3. Results
Of the 371 patients evaluated, 88 (24%) were defined as CVD-equivalent high-risk patients according to the above criteria. They had, in addition, LDL-C levels above 100 mg/dL and were, therefore, eligible for primary prevention with statin therapy according to NCEP ATP III guidelines. An additional 24 high-risk patients had borderline LDL-C levels between 70 and 100 mg/dL and were evaluated separately.
The high-risk population was distributed as follows: 9 patients (10%) were included in the study due to peripheral vascular disease, 45 (51%) had a diagnosis of diabetes mellitus, 16 (18%) had stroke or a severe carotid occlusion, and 1 patient was included in the study due to an abdominal aortic aneurysm. Thirty patients (34%) had none of those high-risk factors for CVD but were entitled to lipid-lowering therapy due to an elevated 10-year risk score ≥20% for hard CVD endpoints according to the Framingham risk score charts.
The mean age of the study population was 71±11 years. Basic characteristics of the patients are presented in Table 1. The mean LDL-C level of the study population was 132±30 mg/dL (range 100–237 mg/dL), triglycerides were 149±71 mg/dL, HDL-C 42±15 mg/dL, and the mean total cholesterol level was 201±43 mg/dL.
Table 1. Baseline characteristics of patients
| Parameter | No. (%) |
|---|---|
| Total no. of patients | 88 (100%) |
| Male | 49 (56%) |
| Female | 39 (44%) |
| Age (mean±S.D.) | 71±11 |
| Hypertension | 64 (72%) |
| Smoking | 27 (31%) |
| Low-density lipoprotein (mg/dL±S.D.) | 132±30 |
| High-density lipoprotein (mg/dL±S.D.) | 42±15 |
| Triglycerides (mg/dL±S.D.) | 149±71 |
| Total cholesterol (mg/dL±S.D.) | 201±43 |
| Creatinine kinase (U/L±S.D.) | 80±74 |
| SGPT (U/L±S.D.) | 24±20 |
| SGOT (U/L±S.D.) | 22±11 |
| Antiplatelet/anticoagulant treatment | 35 (40%) |
Of all the patients in the high-risk study population having LDL-C levels above 100 mg/dL and entitled to cholesterol-lowering therapy as primary prevention of CVD, only 17 (19%) were already being treated with a statin drug on admission (Table 2), and just two more patients (22%) received a statin drug in addition during hospitalization. In other words, 69 eligible patients (78%) did not receive statin therapy at all. Patients who received a statin drug had non-significantly higher LDL-C levels than non-treated patients (137±30 vs 132±30, respectively; p=0.49), a trend that was observed in all of the various risk groups (Table 2).
Table 2. Rate of statin therapy and LDL-C levels according to risk groups
| Risk group | No. of patients | Patients treated with statins on admission | LDL-C | ||
|---|---|---|---|---|---|
| Statin-treated | Not treated with statins | P-value | |||
| PVD | 9/88 (10%) | 3/9 (33%) | 130±24 | 117±20 | 0.39 |
| Stroke or carotid stenosis | 16/88 (18%) | 5/16 (31%) | 140±32 | 115±14 | 0.04 |
| Diabetes mellitus | 45/88 (51%) | 11/45 (24%) | 140±28 | 132±28 | 0.42 |
| Risk score ≥20%a | 30/88 (34%) | 4/30 (13%) | 137±48 | 135±36 | 0.93 |
| AAA | 1/88 (1%) | 0/1 (0%) | – | 109 | – |
| Total study population | 88 (100%) | 17/88 (19%) | 137±30 | 132±30 | 0.49 |
aAccording to Framingham risk score charts. |
None of the patients had an absolute contraindication for statin therapy due to symptomatic elevated liver enzymes or creatinine kinase levels. Only 35 patients (40%) received concomitant antiplatelet drugs or anticoagulation therapy.
4. Discussion
Recent prospective, randomized trials show that intensive statin therapy significantly reduces the incidence of coronary events in high-risk individuals without a known CVD, even in patients with average or low cholesterol levels. These benefits have been demonstrated in elderly patients and in various co-morbid atherosclerotic conditions such as diabetes, peripheral arterial disease, carotid stenosis, and in high-risk patients with cumulative risk factors [4], [5], [6], [7], [8], [9], [10], [11], [15], [16], [17], [18], [19]. Though practice guidelines recommend statin therapy for primary prevention of CVD in those high-risk individuals, our study shows that, in daily clinical practice, those guidelines are not well implemented and that there is sub-optimal usage of lipid-lowering drugs for the primary prevention of CVD. Twenty-four percent (88/371) of the patients without a known CVD who were hospitalized in our internal medicine department were entitled to statin therapy as primary prevention of CVD. More than three-quarters of this study group (69/88 patients, 78%), who were eligible for lipid-lowering therapy as primary prevention of CVD based on NCEP ATP III guidelines, did not receive statin therapy either at primary care clinics or during hospitalization in an internal medicine department. This is emphasized especially in the group of patients at risk due to a Framingham risk score ≥20%, in which only 4/30 patients (13%) were treated with statins prior to hospitalization (Table 2). This is most probably due to the fact that primary prevention in patients without an established CVD naturally attracts less attention than secondary prevention after acute coronary syndromes, as well as the tendency of physicians to treat acute diseases more thoroughly than they apply preventive medicine. Moreover, it would appear that physicians are not sufficiently aware of updated practice guidelines and LDL-C target goals in the primary prevention of CVD.
4.1. LDL-C target goals in high-risk patients without a known CVD
Clinical trials emphasize the efficacy of primary risk reduction in patients with average or relatively low LDL-C levels [6], [9]. Although different recommendations have varying cholesterol target goals, the trend is towards increasingly lower LDL-C levels. NCEP ATP III updated guidelines indicate an LDL-C target goal of less than 100 mg/dL in high-risk patients with CVD-equivalent disorders [12]. Other similar guidelines have even lower LDL-C target goals. For example, the European Society of Hypertension recommends an LDL-C target level below 77 mg/dL for primary prevention in patients with a 10-year CVD risk ≥20% [20]. These recommendations are based on clinical trials in recent years, such as the Human Project Study (HPS) trial, showing the benefit of statin therapy in patients with LDL-C levels below 116 mg/dL at baseline, and high-risk patients in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA) study, which had LDL-C levels below 130 mg/dL at baseline and experienced a significant lowering of cardiovascular risk when treated with a standard dose of a statin [6], [9].
As shown in this study (Table 2), patients already being treated with statins on admission had a non-significant trend towards higher LDL-C levels than non-treated patients, and this may have contributed to the prior decision to treat them with lipid-lowering drugs. Nevertheless, our study group, which had a mean LDL-C level of 132 mg/dL, similar to that of the abovementioned primary prevention clinical trials, is expected to benefit from statin lipid-lowering therapy. In accordance with the literature, standard statin doses will lower LDL-C levels by 30–40%, achieving target goals and translating into coronary heart disease risk reduction. The emphasis for therapy should be on targeting the relative risk level of the patient and not solely the degree of dyslipidemia.
4.2. Primary prevention of CVD in diabetic patients with dyslipidemia
Half of our high-risk study population consisted of diabetic patients who were eligible for statin therapy as primary prevention of CVD. The majority of them (34/45 diabetic patients, 76%) did not receive lipid-lowering therapy. Patients with diabetes are at a high risk for morbidity and mortality, even in the absence of CVD, and when they develop coronary disease they have a poor prognosis. Therefore, an important goal of therapy in diabetic patients should be to prevent cardiovascular events through optimal management of modifiable risk factors. The HPS sub-study in diabetic patients found that, in 2912 patients with diabetes and without a diagnosed coronary artery disease, simvastatin therapy significantly reduced major vascular events by 33% (p=0.0003) compared to placebo [17]. A meta-analysis of six studies evaluating primary prevention in type 2 diabetes showed that treatment with lipid-lowering agents reduces cardiovascular risk, even in patients with LDL-C levels below 115 mg/dL [pooled relative risk for cardiovascular events with lipid lowering therapy 0.78 (CI 0.67–0.89) and the pooled absolute risk reduction in CHD events 0.03 (CI 0.01–0.04), estimate of the number needed to treat to prevent an event 34.5)] [15], [16]. Recently, the Collaborative Atorvastatin Diabetes Study (CARDS) demonstrated that giving 10 mg atorvastatin/day to 2838 diabetic patients without a previous history of CVD resulted in a 36% rate reduction in acute coronary events, a 48% reduction in stroke, and a 27% reduced death rate compared to placebo [18]. These overall data emphasize the importance of treating diabetic patients without an established CVD with cholesterol-lowering drugs. Yet, in the current study, the majority of the diabetic population was not adequately treated.
4.3. Statin therapy as primary prevention of CVD in the elderly
Our study group represents a typical population hospitalized in internal medicine departments today, namely, elderly patients with several co-morbidities. The mean age of our study population was 71±11 years. Older patients are at a higher absolute risk because of a progressive accumulation of coronary atherosclerosis. However, in clinical practice, elderly patients are less likely to receive statins than younger patients because of concerns about adverse effects, poor compliance, drug interactions, and reduced life expectancy. Results of several clinical trials have demonstrated the efficacy of statin therapy in older, high-risk patients without an established CVD. The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial examined the efficacy of pravastatin treatment in a population aged 70–82 years, with or at high risk of developing CVD and stroke [7]. The composite endpoint (coronary death, myocardial infarction, or stroke) was reduced on pravastatin therapy by 15% (p=0.014). The HPS trial demonstrated a similar significant cardiovascular event rate reduction on simavastatin therapy for patients either under or over 70 years of age at entry to the study, while the ASCOT-LLA study randomized patients up to the age of 79 years with multiple CVD risk factors for receiving atorvastatin 10 mg or placebo and showed a reduction in total cardiovascular events by 21% (p=0.0005) [6], [9]. Thus, elderly patients over 70 or even 75 years of age, which comprise a major part of our study population and of hospitalized patients in internal medicine departments, benefit from a reduction in LDL-C levels at least as much as younger patients. These results support the efficacy and extension of statin therapy to older, higher risk individuals without an established CVD.
In conclusion, our data suggest that the use of statin lipid-lowering drugs as primary prevention of CVD in an academic internal medicine department is inadequate due to undertreatment of high-risk patients, despite considerable evidence that these high-risk patients can benefit from appropriate lipid-lowering therapy, even for relatively low LDL-C levels. Recent clinical trials emphasize in particular the benefit of using statins in older patients and in diabetic patients without an established CVD.
Caution is advised when interpreting these results, which cannot be automatically generalized to other countries in Europe, though the situation may not be much better in many other internal medicine departments and primary care clinics. The current situation deprives many high-risk patients from receiving effective protection against coronary heart disease. Local health policies should reinforce and emphasize the importance of preventive medicine in primary care and daily internal medicine practice. Physicians need to adhere to current guidelines and to identify and treat high-risk dyslipidemic individuals in order to reduce cardiovascular morbidity and mortality.
5. Learning points
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PII: S0953-6205(06)00185-3
doi:10.1016/j.ejim.2006.03.005
© 2006 European Federation of Internal Medicine. Published by Elsevier Inc. All rights reserved.
Volume 17, Issue 7 , Pages 495-499, November 2006
