An Evidence-Based Assessment of the NCEP Adult Treatment Panel II Guidelines FREE

The Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II)¹ in 1993 was based on review of observational epidemiology, lipoprotein metabolism, animal studies, and early clinical trials. No clinical trial or meta-analysis had yet demonstrated a reduction in overall mortality. Furthermore, there was concern regarding data suggesting increased noncoronary mortality resulting from drug therapy in some trials. Benefits from pharmacological treatment of lower-risk primary prevention patients could be offset by increased relative risks and costs of therapy. Perhaps most importantly, although studies with the relatively new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) were promising, they were preliminary, and the first large statin trial had not yet been published. For these reasons, the Adult Treatment Panel II (ATP-II) report made relatively cautious recommendations about whom and when to treat, and considered nicotinic acid and bile acid sequestrants preferable to statins in many circumstances.

With the results of several large clinical trials reported after the ATP-II report, it is now possible to assess the recommendations with this additional evidence in mind. In addition, issues addressed in limited fashion or not addressed in the report, such as coronary disease associated with organ transplantation and treatment of lipid abnormalities in elderly patients can be examined.

A group consisting of a general internist, a lipid clinic director/cardiologist, and an atherosclerosis researcher met between February and May 1999 and conducted a review of randomized, controlled clinical trials pertaining to lipid lowering published since 1993. A MEDLINE search of all English-language clinical trials assessing the effects of cholesterol treatment on coronary events, coronary mortality, stroke, and/or total mortality was conducted, yielding 317 studies. Studies were limited to human subjects and studies whose primary outcome measurements were biochemical, physiological, and/or angiographic were excluded unless they were believed to offer unique clinical information. Two trials in press at the time of the review were also included. A total of 37 studies (including several studies of the same clinical trial) were included in the review and were considered the primary evidence by which the ATP-II guidelines should be assessed.

Concern regarding potential adverse effects of lipid-lowering medications prompted the ATP-II to recommend caution in their use in the primary prevention of CHD. Contributing to this cautious approach were (1) the finding of increased risk of accidental and violent death in patients treated for hypercholesterolemia⁷ and (2) reports of increased noncardiovascular death in several lipid-lowering trials. These trials were subsequently reported by Gould et al⁸ to reveal a 30% increase in noncardiovascular mortality and a 17% increase in total mortality with fibrates. Since the ATP-II report's publication, there have been additional trials with fibrates, niacin, resins, and statins showing no increase in noncardiovascular mortality. In a meta-analysis of 29,000 patient-lives in statin monotherapy CHD prevention trials published after the ATP-II report, no increase in noncardiovascular mortality or cancer incidence was seen.⁹

The ATP-II report recommended using CHD risk status as a guide to the intensity of therapy. It divided the population at particular risk for CHD into 3 groups, based on known atherosclerotic disease, multiple CHD risk factors, or isolated hypercholesterolemia without other risk factors. This approach was based in part on (1) clinical trial evidence demonstrating CHD mortality reduction with cholesterol lowering, (2) the desire to reserve what was considered expensive and potentially risky medical therapy for those at greatest CHD risk, and (3) recognition that at the time of the ATP-II report, total mortality benefit with lipid treatment had not been demonstrated. The target low-density lipoprotein cholesterol (LDL-C) levels were less than 4.14 mmol/L (160 mg/dL) for primary prevention patients with fewer than 2 CHD risk factors, less than 3.37 mmol/L (130 mg/dL) for primary prevention patients with 2 or more additional risk factors, and less than 2.59 mmol/L (100 mg/dL) in secondary prevention. The LDL-C recommendations differed somewhat from European standards, which suggest an LDL-C treatment goal of 3.00 mmol/L (116 mg/dL) in patients (with or without CHD) with greater than 2% per year absolute CHD event rates calculated from the Framingham risk model.¹⁰ Both guidelines emphasize the importance of assessing CHD risk in determining candidates for therapy.

Since the ATP-II report, several trials have demonstrated reduction in both CHD and total mortality with statin therapy. First, the Scandinavian Simvastatin Survival Study (4S) of hyperlipidemic subjects with CHD showed a 30% relative and a 3.3% absolute risk reduction in total mortality with simvastatin therapy for just over 5 years.¹¹ Later, the Long-term Intervention With Pravastatin in Ischaemic Disease (LIPID) study showed a 23% relative and a 3.1% absolute risk reduction in total mortality with pravastatin treatment in a diverse group of CHD patients during a 6-year period.¹² Furthermore, other large trials demonstrated benefit from reduction of cholesterol levels considered to be average in the ATP-II report. In the Cholesterol and Recurrent Events (CARE) trial, pravastatin therapy yielded a 24% relative and a 3.0% absolute risk reduction in fatal CHD events and nonfatal myocardial infarctions (MIs) in CHD patients with "average" total cholesterol levels (mean, 5.41 mmol/L [209 mg/dL]).¹³ In these trials, clinical event reductions were noted as early as 3 to 6 months in patients receiving drug therapy. The consistent and early benefit of statin therapy in CHD patients strongly suggests beginning lipid-lowering therapy at the time of CHD diagnosis, rather than after failure of nonpharmacological means as suggested by the ATP-II report. This prompted a recent statement from the American Heart Association Task Force on Risk Reduction that "withholding drug therapy in an effort to reach target LDL with the nonpharmaceutical approach is not necessary" in CHD patients whose LDL-C levels are more than 3.37 mmol/L (130 mg/dL).¹⁴

The ATP-II recommendations for primary prevention are particularly cautious, again based on lack of total mortality benefit seen in this population. Since that time, however, multiple primary prevention studies have demonstrated a relative risk reduction in CHD events in men treated with cholesterol-lowering therapy.¹⁵ In a sample of high-risk men from the West of Scotland Coronary Prevention Study (WOSCOPS) with mean LDL-C levels of 4.97 mmol/L (192 mg/dL), there was a 22% relative and a 0.9% absolute risk reduction in total mortality in association with a 33% relative and a 0.6% absolute reduction in coronary mortality.¹⁶ Most recently, the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonstrated that lovastatin treatment produced a reduction in CHD events in a lower-risk population than that studied in WOSCOPS trial. Only 17% of the study cohort would have qualified for drug therapy according to ATP-II guidelines. Furthermore, treatment with statins did not appear to be associated with adverse noncoronary events.¹⁷ Given that there is significant relative risk reduction in CHD event rates possible with lipid lowering among populations with varying CHD risk, primary prevention guidelines need to consider the absolute event reduction and, as a result, the cost-efficiency of drug therapy.

The target LDL-C levels in the ATP-II report were made with data from angiographic trials and observational studies comparing LDL-C levels and CHD mortality. Since the recommendations were made, several relevant clinical trials and post hoc analyses have been published that indirectly address the issue of optimal LDL-C treatment. The Post Coronary Bypass Graft Trial assessed surrogate end points in approximately 1350 patients who had undergone bypass grafting in the previous 1 to 11 years.¹⁸ Patients were randomized to an aggressive (ie, NCEP standard) target LDL-C level of 2.59 mmol/L (100 mg/dL) or less vs a moderate LDL-C level of approximately 3.50 mmol/L (135 mg/dL) using lovastatin, with cholestyramine added as necessary. Fewer patients showed angiographic progression and required subsequent bypass surgery with the aggressive compared with the moderate lowering approach. In the 4S trial, post hoc review suggested that both lower posttreatment LDL-C levels and greater changes in LDL-C levels from baseline were highly correlated with reduction in major coronary events.¹⁹ In the Atorvastatin Versus Revascularization Trial (AVERT), patients with mild angina were randomized to receive high-dose atorvastatin vs coronary angioplasty and/or usual medical care. The 36% relative and 8% absolute risk reduction in ischemic events in the atorvastatin group trended toward statistical significance and was associated with an LDL-C level of 1.99 mmol/L (77 mg/dL) compared with 2.08 mmol/L (119 mg/dL) in the angioplasty/usual care group. The results were limited by the small trial size (n = 341), the necessity for open-label design, and the heterogeneity of lipid treatment in the angioplasty/usual care group (71% were taking statins at the end of the trial).²⁰

Post hoc analysis of the results from the CARE trial suggest that no additional event-reduction benefit was achieved with pravastatin in LDL-C reduction to less than 3.24 mmol/L (125 mg/dL) compared with patients whose LDL-C levels were greater.²¹ In contrast, a treatment LDL-C threshold was not observed with simvastatin in post hoc analysis of the 4S trial.¹⁹(p1458) However, post hoc analyses can often be misleading; thus, this issue remains unsettled and, to date, no trials have been published comparing mortality using different LDL-C treatment targets.

For patients who have a CHD event and whose LDL-C level is already less than 2.59 mmol/L (100 mg/dL), there were no additional lipid recommendations provided in the ATP-II report. A number of trials examining the effects of aggressive LDL-C reduction beyond this level are under way, which should help provide guidance for such patients. Until these data are available, the possible approaches to such patients include increasing LDL-C reduction with statins; addition of niacin, fibric acid derivative, or bile acid resin; or a combination of these approaches. Given no current data on this subject, the practicing physician is compelled to assess further cholesterol reduction in the context of other concomitant risk factors.

The ATP-II report identified low high-density lipoprotein cholesterol (HDL-C) (<0.91 mmol/L [35 mg/dL]) as a major risk factor for CHD while recognizing high HDL-C (>1.55 mmol/L [60 mg/dL]) as protective. The report recommended that "therapeutic decisions should take into account HDL cholesterol levels." Further, HDL-C levels of less than 0.91 mmol/L (35 mg/dL) have been shown to predict increased coronary mortality in men regardless of total cholesterol level.²² A 2% reduction in CHD events in the LRC-CPPT trial was attributable to the HDL-C–raising effects of cholestyramine in addition to its LDL-C–lowering effects.⁵(p37) Little prospective evidence of the treatment of low HDL-C is available from, either primary or secondary prevention trials. In the 4S²³ and LIPID¹²(p1354) secondary prevention trials, statin treatment reduced risk of coronary death independent of HDL-C concentration. The VA-HDL Intervention Trial (VA-HIT), examining CHD patients with both low HDL-C (<1.03 mmol/L [40 mg/dL]) and relatively low LDL-C (<3.63 mmol/L [140 mg/dL]) levels, showed a 20% relative risk reduction in CHD death and nonfatal MI with gemfibrozil vs placebo.²⁴ The AFCAPS/TexCAPS study showed CHD event reduction using lovastatin in a primary prevention population with low to normal HDL-C (mean, 0.94 mmol/L [36 mg/dL]) and slightly elevated LDL-C (mean, 3.89 mmol/L [150 mg/dL]) levels, although the absolute benefit was small due to low event rates in both groups. Benefit with lovastatin therapy was seen only in patients whose baseline HDL-C levels were in the lowest tertiles (ie, <1.03 mmol/L [40 mg/dL]).¹⁷(p1621)

Because statins have established superior benefit in the CHD population, they should be used as first-line therapy in most secondary prevention patients. Fibrates may be an acceptable alternative if the LDL-C level is less than 3.63 mmol/L (140 mg/dL) and the HDL-C level is less than 1.03 mmol/L (40 mg/dL), as suggested by the VA-HIT trial. Comparative studies of statins and fibrates in the CHD population with low HDL-C levels are not available. There are also insufficient data to specify the most appropriate means to improve risk associated with isolated low HDL-C in a primary prevention population already at LDL-C treatment goals. Given little prospective trial data, the nonpharmacological methods suggested by the ATP-II report—physical activity, smoking cessation, and weight reduction—should remain first-line therapy. Of the medical therapies, niacin achieves the greatest HDL-C improvement in the usual dosage ranges, followed by estrogen replacement therapy for postmenopausal women, fibrates, and statins. No evidence-based conclusion can be made regarding treatment of patients with isolated low HDL-C.

Asymptomatic atherosclerosis was demonstrated in autopsies of persons aged 2 to 39 years who died of various causes in the Bogalusa Heart Study.²⁵ The presence of cardiovascular disease correlated with antemortem ATP-II risk factors, including high LDL-C and triglyceride levels, low HDL-C level, smoking, and hypertension.²⁶ The ATP-II report suggested deferring medical therapy for hyperlipidemia in young adults and lowering cholesterol levels through diet and exercise in most men younger than 35 years and most premenopausal women. The report did suggest drug therapy in patients with extremely high LDL-C (>5.69 mmol/L [220 mg/dL]) or multiple CHD risk factors, usually with resins in very young patients. Since that time, there has been suggestion by some, including the American College of Physicians, that young patients should not be screened at all, based on concern regarding the effects and expense of lifelong therapy in this population.²⁷ Since no randomized prospective trials have assessed long-term lipid-lowering therapy in this age group, no evidence-based recommendation can be made. However, the ATP-II recommendation to begin screening at age 20 years allows for more modest interventions, such as diet and weight loss, to be used in some individuals and also allows for earlier identification of familial hypercholesterolemia (FH).

This disorder, affecting approximately 1 in 500 persons in its heterozygous form (HeFH) and approximately 1 in 1 million persons in its homozygous form, is strongly associated with premature CHD and other vascular events.²⁸ Most authorities recommend treatment of homozygotes at diagnosis. Some have argued for initiating medical therapy for patients with HeFH beginning in childhood as well, given the tendency of these individuals to experience CHD events beginning in the third decade of life.²⁹ Recently, Stein et al³⁰ reported that treatment with lovastatin for 1 year was effective in lowering LDL-C without apparent effect on sexual maturation in boys aged 10 to 17 years old with HeFH, although the study was underpowered to detect significant safety differences.

The ATP-II report suggested to physicians treating hypercholesterolemia in premenopausal women to use a "cautious approach," concentrating on nonpharmacological means to reduce lipid-associated CHD risk. For female patients for whom drug therapy was recommended, those with high LDL-C levels and/or multiple risk factors, estrogen was considered first-line therapy. This was likely in part due to evidence such as the apparent protective effect of estrogen replacement therapy in the Nurses' Health Study and other observational studies. In the Nurses' Health Study, there was a significant reduction in the likelihood of a major CHD event in patients who had ever taken any form of estrogen replacement.³¹ In patients with CHD, the ATP-II report suggested that "the epidemiologic evidence [was] particularly strong for secondary prevention in women with prior CHD," thus providing the basis for the recommendation of estrogen as first-line therapy in this population. Recently published results of the randomized placebo-controlled Heart and Estrogen/Progestin Replacement Study (HERS) argue against this recommendation. This study found no benefit in postmenopausal women who had had an MI and, in fact, found a 58% increase in CHD events in the first year following MI in patients treated with an estrogen/progestin combination. Lower event rates in the latter part of the 4.1-year study led to a net neutral effect of estrogen replacement therapy on rates of total mortality, CHD mortality, MI, and stroke.³² No clinical trial evidence regarding benefit of estrogen replacement in postmenopausal women without CHD is currently available.

In contrast with estrogen replacement therapy, women appear to benefit from statin therapy similar to men, although there were fewer women in the large clinical trials of these agents. Simvastatin treatment in the 4S trial was associated with a decreased coronary event rate in women, who composed less than 15% of the study sample.¹¹(pp1385-1386) In the CARE study, the relative risk reduction for major coronary events appeared even greater for women (43%) than for men (21%) with pravastatin treatment; this was despite similar lipoprotein values in both sexes.³³(p143) In the LIPID trial, women achieved an 11% relative risk reduction in CHD events with pravastatin compared with a 26% reduction in the male study participants.¹²(p1354) Given these data, the ATP-II recommendation to use hormone replacement therapy as first-line therapy in women with CHD is not supported. A statin should be the first-choice lipid-lowering medication in virtually all female patients with CHD. No evidence-based assessment is offered regarding ATP-II recommendations for primary CHD prevention in the premenopausal female population, given the current paucity of relevant data.

Nearly 85% of people who die from CHD are aged 65 years or older.³⁴ The increased CHD mortality in elderly persons makes lipid-lowering therapy aimed at reducing coronary events particularly attractive. Nonetheless, the ATP-II report suggested "caution in proceeding to drug therapy in the elderly" in primary CHD prevention because of increased potential for adverse medication effects. In secondary prevention, without supporting trial data, the report suggested treatment of CHD in the elderly "in the context of patients' overall health status and likelihood of benefit."

Likely because of their significantly higher baseline coronary event risk, patients older than 65 years in both the CARE and 4S trials had greater absolute coronary event risk reductions than younger patients.³⁵(p683),³⁶(p4215) In the LIPID trial, reduction in events appeared to be greatest in patients younger than 55 years, but there was event reduction in all age groups. Because none of these trials enrolled any patients older than 75 years (reaching a maximum age of 81 years by the end of the trials), no definitive conclusion regarding efficacy can be made in very elderly persons. However, currently available studies suggest lipid-lowering therapy in treatment of CHD is likely to benefit elderly patients to a similar if not greater extent than younger patients. In the area of primary CHD prevention, there is insufficient evidence to provide a recommendation beyond the ATP-II guidelines for elderly patients.

Epidemiological studies assessing hypertriglyceridemia as an independent risk factor for CHD events conflict and are confounded by its association with low HDL-C level, hypertension, diabetes, and obesity. In addition, hypertriglyceridemia appears to be synergistic with other well-defined CHD risk factors, such as elevated LDL-C and/or low HDL-C levels, and is associated with other possible markers of atherosclerotic risk, such as small, dense LDL.³⁷ Unfortunately, no trials have specifically assessed the effects or optimal means of triglyceride lowering among patients with severe hypertriglyceridemia. This may also be a difficult population to study given its heterogeneity; however, this is an area in great need of further trial data.³⁸

The ATP-II report recognized the particular risk associated with FH, familial combined hyperlipidemia, and severe polygenic hypercholesterolemia. Even with the availability of high-potency statins, many of these patients require multiple forms of hypolipidemic therapy in combination. In rare circumstances, when this does not achieve an LDL-C goal, patients can undergo LDL-C apheresis, which has been associated with decreased CHD event rate and improved endothelial vasomotion.³⁹ Despite the challenges associated with treating these patients, use of multiple therapeutic modalities is justified, given the marked increase in CHD event risk seen in this population.

A number of treatment options for immunosuppressant-induced hyperlipidemia are available, including statins and fish oils.⁴⁰ Following heart transplantation, beneficial lipid effects, decreased graft vascular disease, and improved overall survival have been achieved by using either simvastatin⁴¹ or pravastatin.⁴² Simvastatin also has been successfully used in combination with apheresis in preventing graft vessel disease in heart transplant recipients.⁴³ Another study also showed improvement in ejection fraction in heart transplant recipients treated with simvastatin; this effect appeared to be independent of lipid effects.⁴⁴ In rats, pravastatin was found to improve survival in orthotopic liver transplant recipients,⁴⁵ and in humans, to reduce acute rejection following cadaveric renal transplantation.⁴⁶ The mechanism(s) of improved patient and graft survival in transplant recipients treated with statins may include an immunosuppressant effect(s), as episodes of severe cardiac rejection were decreased in patients treated with pravastatin compared with placebo.^42,47 The combination of statins with cyclosporine in the transplantation setting justifies caution because cyclosporine increases potential for myopathy from statins, and statins have variable potential to increase serum cyclosporine levels.

The ATP-II report acknowledged the high rate of CHD events in type 2 diabetes, as well as recommendations that the treatment goals in this population should be the same as for patients with established CHD. However, lacking clinical trial data, the panel suggested that type 2 diabetes in patients without known vascular disease be considered only as an additional CHD risk factor. For treatment, the panel suggested bile acid sequestrants or statins, perhaps in combination with fibric acids.

Since the ATP-II report, it has become clear that patients with type 2 diabetes without history of MI have comparable risk of MI as nondiabetic patients with history of MI. Furthermore, the 7-year risk of recurrent MI in the diabetic population was 45%, approximately 2.5 times the rate in the nondiabetic population.⁴⁸ Statin therapy was at least as effective in reducing CHD events in diabetic populations in several recent trials. As a result of these data, the American Diabetes Association (ADA) clinical practice recommendations for 1999 recommend that hypolipidemic therapy be initiated in all patients with type 2 diabetes and LDL-C levels greater than 2.59 mmol/L (130 mg/dL). The ADA-recommended treatment goal is less than 2.59 mmol/L (100 mg/dL).⁴⁹(pS59)

At the time of the ATP-II report, a relationship between cholesterol and total stroke incidence was not evident. Although the Multiple Risk Factor Intervention Trial data suggest a direct relationship between total cholesterol concentration and risk of ischemic stroke, there was an inverse association between total cholesterol levels and risk of hemorrhagic stroke; thus, the effects of lipid-lowering on overall stroke rate were not known.⁵⁰ Furthermore, no reduction in the risk of stroke from cholesterol reduction was seen in meta-analysis of either dietary or drug trials in the treatment or prevention of CHD prior to the advent of statins.⁵¹(p54) Several trials did show regression of carotid intima/media thickness with statin treatment.^52- 56 Furthermore, there appears to be considerable reduction of stroke incidence in CHD patients as well. Relative reduction in stroke risk by 19% to 32% was associated with statin treatment in the CARE, 4S, and LIPID studies, as well as in meta-analyses of statin monotherapy trials by Crouse et al,^57- 58 Blauw et al,⁵⁹ and Hebert et al.⁹ Although there was a trend toward stroke reduction in primary CHD trials, the risk reduction reached statistical significance only in the secondary prevention trials. The reduction in stroke risk by statins in CHD is another rationale for their recommendation for treatment of virtually all CHD patients.

Since the ATP-II report, a variety of nontraditional CHD risk factors have been suggested, including measurements of inflammation, possible infection, abnormalities in vitamin B₁₂ and/or folate metabolism, abnormalities of thrombosis and/or fibrinolysis, and endothelial dysfunction.⁶⁰ In addition, more attention has been placed on the density and distribution of LDL-C particle types and HDL-C subfractions. While many of these risk factors have epidemiological associations with subsequent CHD events, no prospective randomized trials have evaluated targeting these risk factors; thus, it is not yet appropriate to formally recommend their use in a treatment algorithm.

It is consistent with the ATP-II report to treat asymptomatic patients who are identified as having any form of atherosclerosis to a goal LDL-C level of less than 2.59 mmol/L (100 mg/dL), even though these patients have not had a CHD event. Since up to half of patients who have an MI never had angina prior to the event, using symptoms to predict risk is not justified. Patients identified with atherosclerosis are at high risk for CHD events and thus justify an aggressive approach to cholesterol lowering.

From multiple lipid-lowering trials, it is clear that lowering LDL-C levels in CHD or high-risk primary prevention patients leads to clinical benefits. Still, there are not yet prospective trial data on other populations that may also be at risk due to low HDL-C or high triglyceride levels. This makes construction of an entirely trial-based treatment algorithm currently impossible. As noted, several guidelines from other countries use estimated CHD event risk from the Framingham model to stratify necessity for treatment. In addition, variation between treatment thresholds worldwide in part reflects differing views regarding cost-effectiveness of therapy. The algorithm in Figure 1 reflects relevant findings from lipid intervention trials while emphasizing the need for global risk assessment to guide use of lipid-lowering therapy. In this treatment algorithm, lipid-lowering medication is not recommended for women of childbearing age unless known to have CHD, diabetes, or a high-risk profile for CHD as outlined. In general, medical therapy is discouraged in all primary prevention patients who are younger than 40 years who are not at "moderately high risk" (acceptable to use medication beginning at age 35 years) or "high risk" (medication may be considered after puberty).

While the evidence since the publication of the ATP-II report has, to some extent, allowed for modification of some of the recommendations, the substance of the guidelines remains. Sadly, recent data suggest that as many as 25% of the adult population has not had their cholesterol measured, and the majority of patients with CHD are not treated to goal LDL-C levels. Clearly, implementation of these guidelines is as important as refining them with the most current evidence.

Recent studies demonstrate that statins benefit virtually all CHD patients and high-risk primary prevention patients, as well as confer stroke reduction benefit in CHD patients. Fibrates offer potential in reduction of triglyceride levels and small, dense LDL, and improvement of HDL-C levels, especially in CHD patients, although previous evidence of increased noncoronary mortality with this class justifies further study. The role of hormone replacement in secondary CHD prevention needs further study, but cannot be considered first-line therapy at this time. Niacin and/or resin treatment remain second-line therapies in CHD treatment and prevention, although their roles in primary low HDL-C syndromes remain to be elucidated. More studies are needed to address the effects of lipid modification in women, elderly persons, and very young persons. In addition, further studies of alternate markers of lipid metabolism and risk assessment may provide alternate treatment strategies in the future.