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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

The gap between theory and practice: what do the trials tell us?

Terje R. Pedersen

Centre for Preventive Medicine, Ullevål University Hospital, Building 19, Kirkeveien 166, N-0407 Oslo, Norway

Corresponding author. Tel: +47 22 11 79 32; fax: +47 22 60 19 00. E-mail address: t.r.pedersen{at}medisin.uio.no


   Abstract
Top
 Abstract
Introduction
 Lipoproteins and coronary risk
 Management of cardiovascular...
 Conclusions
 References
 
Numerous intervention trials with statins conducted over the last two decades have demonstrated marked and significant reductions in cardiovascular event rates. Indeed, a meta-analysis of 14 such trials has demonstrated a reduction in the risk of major cardiovascular events of 21% for every decrease in LDL-cholesterol of 1 mmol/L (39 mg/dL). Recent evaluations of intensive vs. moderate lipid-lowering strategies support a ‘lower is better’ approach to controlling LDL-cholesterol, with some additional outcome benefits observed when LDL-cholesterol is reduced to well below the 2.6 mmol/L (100 mg/dL) guideline goal value for patients with coronary heart disease or equivalent. Accordingly, statins now provide the mainstay of pharmacological intervention for dyslipidaemia. However, a substantial burden of cardiovascular disease remains in statin-treated patients. Practical strategies are available for improving the prognosis of patients with dyslipidaemia. First, many patients with dyslipidaemia are under-treated, and it is important to adhere to evidence-based guideline targets as closely as possible to maximize the benefits of treatment. In addition, statins do relatively little to correct low HDL-cholesterol, which is common among patients receiving lipid-modifying treatment. Correction of this independent cardiovascular risk factor, for example, with a combination of a statin plus nicotinic acid, provides an alternative evidence-based strategy for reducing the risk of an adverse cardiovascular outcome in these patients.

Key Words: Dyslipidaemia • LDL-cholesterol • HDL-cholesterol • Cardiovascular risk • Statins • Intervention trials • Nicotinic acid


   Introduction
Top
 Abstract
 Introduction
Lipoproteins and coronary risk
 Management of cardiovascular...
 Conclusions
 References
 
The Scandinavian Simvastatin Survival Study (4S), published in 1994,1 and the West of Scotland Coronary Prevention Study (WOSCOPS), published during the following year,2 first defined the potential of intervention with an HMG-CoA-reductase inhibitor (statin) to significantly reduce the incidence of coronary events in high-risk patient populations with hypercholesterolaemia with or without coronary disease. Many randomized, controlled trials have been conducted since these first studies, and all confirm the efficacy of the statins in controlling excess cardiovascular risk in any patient population. These results are recognized in guidelines for the management of cardiovascular disease worldwide, which focus strongly on the use of these agents to improve cardiovascular prognosis in patients with dyslipidaemia.3,4

Cardiovascular disease remains the leading cause of premature mortality in the West, despite the widespread use of statins in patients with dyslipidaemia and/or diabetes, however. For example, in 4S, the risk of coronary death was almost halved by statin treatment [relative risk vs. placebo 0.58 (95% CI 0.46–0.73)], but more than 60% of all deaths in the statin group were still due to coronary disease.1 Clearly, it is important to optimize the delivery of therapy to correct the lipid profile in order to derive the maximum therapeutic benefit from such interventions. This is often difficult in routine, daily clinical practice outside the controlled environment of a randomized clinical trial, particularly as dyslipidaemia itself is heterogeneous in nature and may receive important contributions from low HDL-cholesterol and hypertriglyceridaemia in some patients. The purpose of this review is to consider the principal sources of coronary risk within the overall lipid profile, the barriers to the effective implementation of therapeutic strategies to optimize coronary risk through the management of the lipid profile, and to make recommendations as to how we can achieve for our patients the benefits from lipid modification, which we have all seen in the major randomized trials.


   Lipoproteins and coronary risk
Top
 Abstract
 Introduction
 Lipoproteins and coronary risk
Management of cardiovascular...
 Conclusions
 References
 
Cholesterol and coronary events
Many studies have analysed the relationships between levels of individual lipoproteins and cardiovascular or all-cause mortality. Figure 1A shows the 9-year mortality rate from coronary heart disease at different levels of total cholesterol from the analysis of data that was conducted three decades ago in 361 662 middle-aged men (aged 35–57) screened for enrolment into the Multiple Risk Factor Intervention Trial (MRFIT).5 The relationship between the cholesterol level and risk of coronary mortality was continuous and progressive. The relationship between these variables appeared to become less steep at levels of total cholesterol below about 5 mmol/L (equivalent to about 200 mg/dL), although there was no obvious threshold point at which the risk of coronary death declined abruptly.


Figure 0351
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  		Figure 1 Relationships between lipid parameters and risk of cardiovascular events in epidemiological analyses. (A) Relationship between levels of total cholesterol and cardiovascular event rates in MRFIT. Reprinted from Martin MJ, Hulley SB, Browner WS, Kuller LH, Wentworth D. Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361 662 men. Lancet 1987;2:531, with permission from Elsevier. (B) Relationship between on-treatment levels of LDL-cholesterol and cardiovascular event rates in patients randomized to a statin (S) or placebo (P) in major intervention trials evaluating statins. Open symbols show results of recent evaluations of intensive vs. moderate lipid lowering (see text). Adapted from Kastelein13 with permission from Elsevier.

 
The MRFIT data clearly support lipid-lowering intervention in patients with high cholesterol, as subjects with total cholesterol above the 85th percentile for the population [6.5 mmol/L (253 mg/dL)] were at a four-fold higher risk of coronary death than subjects with serum cholesterol below the 20th percentile. Importantly, however, half of all the excess coronary deaths in the remainder of the population occurred in subjects with moderately increased levels of serum cholesterol, i.e. those between the 20th and 85th percentiles. Thus, although intervention in patients at the highest risk is clearly justified, a substantial burden of morbidity and mortality is associated with lower severity of hypercholesterolaemia. Accordingly, more recent studies have focused on the potential benefits that may arise from intensive lipid lowering.

Intensive LDL-cholesterol lowering
Two recent double-blind, randomized, controlled studies in patients with stable coronary artery disease (CAD) have provided head-to-head comparisons of conventional and intensive interventions with statins to investigate whether there is reduction of LDL-cholesterol to levels well below the 2.6 mmol/L (100 mg/dL) goal value currently recommended in cardiovascular management guidelines.3,4 The Treat to New Targets (TNT) study randomized 10 001 patients with stable coronary disease and LDL-cholesterol <3.4 mmol/L (130 mg/dL) to receive a daily dose of atorvastatin of either 10 or 80 mg for an average of 4.9 years.6 The Incremental Decrease in Endpoints through Aggressive Lipid lowering (IDEAL) study compared effects on outcomes of intensive intervention on LDL-cholesterol with atorvastatin 80 mg with moderate intervention with simvastatin 20 mg in a prospective, open-label, blinded endpoint (PROBE) design. Patients eligible for this study had a history of myocardial infarction and an indication for statin therapy according to local guidelines at the time.7 Both studies employed a composite cardiovascular endpoint as the primary outcome (Table 1). The intensive interventions resulted in markedly lower levels of LDL-cholesterol and a lower risk of primary events in either study (Table 1). The 22% risk reduction in TNT was statistically significant, whereas the 11% risk reduction in IDEAL marginally failed to achieve statistical significance.


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  		Table 1 Effects of intensive intervention with a statin on lipids and event rates in the TNT and IDEAL studies6,7

 
However, important secondary cardiovascular endpoints were reduced significantly in IDEAL.8 Positive effects on secondary endpoints must be interpreted with caution unless they are strongly supported by results of other similar trials, otherwise they are only useful in generating hypotheses.9 For example, the inclusion of stroke within the definition of major cardiovascular events, producing a similar endpoint to the TNT trial, yielded a significant risk reduction of 13% (P=0.02). Similarly, a 16% reduction (P<0.001) in the risk of any cardiovascular endpoint including revascularization reproduced the main finding of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial (TIMI-22), also shown in Table 1.10 This trial evaluated the effectiveness of statins in improving outcomes within 10 days of admission for an acute coronary syndrome over an average follow-up period of 24 months.

Table 1 also illustrates two further evaluations in intensive statin therapy in patients with acute coronary syndromes. The A to Z trial randomized patients to a conservative regimen (placebo for 4 months followed by simvastatin 20 mg/day) or an intensive regimen (simvastatin 40 mg/day for 30 days followed by a dose of 80 mg/day) for a median follow-up of 721 days.11 The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study was a 16-week, placebo-controlled evaluation of the effect of atorvastatin 80 mg/day on early recurrent ischaemic events in patients with unstable angina or non-Q-wave myocardial infarction.12 In each case, levels of LDL-cholesterol below 2.6 mmol/L (100 mg/dL) were achieved. There was a trend towards a superior outcome with the more intensive regimen in A to Z and a significant benefit from the intensive statin treatment in MIRACL, although the benefit was mainly seen in ‘soft’ endpoints.

The general concordance between the results of TNT, IDEAL, and other trials such as PROVE-IT, A to Z, and MIRACL, when considered together, suggests that lowering LDL-cholesterol beyond the current goal value of 2.6 mmol/L (100 mg/dL) for patients with coronary heart disease or equivalent offers further benefit when compared with a conservative approach to lipid management. Indeed, the relationship between on-treatment levels of LDL-cholesterol and the risk of cardiovascular events appears to extend in a roughly linear fashion to the levels of LDL-cholesterol achieved in TNT and IDEAL (Figure 1B),13 and future management guidelines in this area are likely to take account of these findings.8 It is not known how much further this relationship extends and how much additional benefit can be realized from the achievement of lower levels of LDL-cholesterol. As ever, appropriately designed, randomized clinical studies will be required to resolve this question.

Broad utility of statin therapy
Overall, the studies described earlier show that control of LDL-cholesterol is undoubtedly important in the overall management of cardiovascular risk, with lower LDL-cholesterol providing incrementally lower cardiovascular event rates. Nevertheless, an important lesson learned from the statin era relates to the efficacy of these agents in improving outcomes irrespective of the nature of the underlying coronary risk. Figure 2A shows the principal results of several intervention trials with statins.1,2,14–16 Significant and proportionally comparable reductions in major coronary event rates in hyperlipidaemic patients occurred irrespective of the severity of underlying cardiovascular risk, as indicated by the event rate in the placebo group, in 4S,1 the Cholesterol and Recurrent Events (CARE) study,14 the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study,15 and WOSCOPS.2


Figure 0352
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  		Figure 2 Statins reduce coronary risk irrespective of the level of cardiovascular risk before treatment: evidence from intervention studies. (A) Event rates in selected major trials evaluating statins. (B) Event rates according to LDL-cholesterol at baseline in the Heart Protection Study.

 
Statins were also effective in a population specifically recruited for having low HDL-cholesterol in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) (Figure 2A).16 Other studies have demonstrated significant coronary protection with statins in elderly patients [the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)]17 and in patients without hypercholesterolaemia at baseline [Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA)].18 An analysis from the Heart Protection Study (Figure 2B) shows that the benefit from statin treatment did not depend on LDL-cholesterol at baseline,19,20 consistent with the findings from the intensive evaluations of statins described earlier.


   Management of cardiovascular risk in practice
Top
 Abstract
 Introduction
 Lipoproteins and coronary risk
 Management of cardiovascular...
Conclusions
 References
 
Undertreatment of dyslipidaemia
US NCEP/ATPIII guideline goals for LDL-cholesterol are flexible and vary with the extent of cardiovascular comorbidity.3 A target of <4.1 mmol/L (160 mg/dL) is set for patients with no more than one additional cardiovascular risk factor, <3.4 mmol/L (130 mg/dL) for patients with at least two cardiovascular risk factors and 10-year Framingham risk ≤20%, and <2.6 mmol/L (100 mg/dL) for patients with established coronary heart disease or an equivalent condition, such as diabetes. Nevertheless, most high-risk patients may not reach their treatment goal in the USA. The Lipid Treatment Assessment project (L-TAP) surveyed 4888 patients from five regions of the USA, who had received stable lipid-lowering therapy for at least 3 months.21 The majority (68%) of low-risk patients (≤1 cardiovascular risk factor and no coronary heart disease) achieved their NCEP/ATPIII lipid goal. However, the success rates were considerably lower in patients with at least two risk factors but no coronary heart disease (37%) and lowest of all in patients with established coronary heart disease (18%).

The EUROASPIRE II Euro Heart Survey Programme surveyed lipid management in a population of 8181 patients with a history of coronary heart disease in 15 European countries in 1999–2000.22 All of these patients would now be considered candidates for statin therapy, but the proportions of patients receiving a statin varied between ~40 and 75% in individual countries (Figure 3). Moreover, only about half of these patients achieved the relatively conservative lipid management goal of total cholesterol <5.0 mmol/L (193 mg/dL).


Figure 0353
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  		Figure 3 Proportions of patients receiving lipid-lowering medications and proportions of those patients (percentage reaching goal) achieving total cholesterol <5.0 mmol/L (193 mg/dL) in the EUROASPIRE Study.

 
These surveys suggest that dyslipidaemia is undertreated in the USA and Europe. The potential consequences of undertreatment of dyslipidaemia were highlighted in a recent meta-analysis of 14 randomized evaluations of statins that enrolled more than 90 000 patients.23 The risk of a major vascular event decreased by 21% for every 1 mmol/L (39 mg/dL) decrease in LDL-cholesterol [relative risk (RR) 0.79 (95% CI 0.77–0.81), P<0.0001]. Similarly, there were large and significant (P<0.0001) corresponding decreases in the risk of major coronary events [RR 0.77 (95% CI 0.74–0.80)], stroke [RR 0.83 (95% CI 0.78–0.88)], or coronary revascularization [RR 0.76 (95% CI 0.73–0.80)].

Why don't physicians follow guidelines?
The barriers identified by physicians,which prevent them from following guidelines successfully, have been identified in a systematic review.24 Although these are relevant to guidelines in general, the general principles are likely to apply to cardiovascular management guidelines and are thus relevant to the management of the lipid profile. The barriers are related in general to knowledge, attitudes, and behaviour on the part of physicians. In terms of knowledge, unfamiliarity with guidelines (both of their content and existence) arose through the large volume of material involved, lack of time to review it, and issues relating to access to material. Common attitudes contributing to non-compliance included personal disagreement with elements of specific guidelines or with the concept of guidelines in general. In addition, physicians may not believe that achieving the treatment goal will achieve the desired outcome or that achieving the treatment goal is possible. Habits and routines from pre-guideline practice may be difficult to break. External barriers to compliance include conflicts between different guidelines in the same area, conflicts between treatment goals and patient preferences, and operational or environmental constraints relating to time, resources, or local reimbursement practices.

Lipid modification beyond LDL-cholesterol
Prognostic importance of low HDL-cholesterol
Many studies have shown that low HDL-cholesterol is associated with an increased risk of coronary events, including the landmark Framingham Study in the USA in the 1970s25,26 and the more recent PROCAM Study in a European cohort in the 1980s,27,28 together with more recent analyses.29,30 Indeed, epidemiological data from studies in the USA31 and Europe32,33 suggest that an increase in HDL-cholesterol of 1 mg/dL (0.03 mmol/L) corresponds to a reduction in the risk of coronary events of 2–3%.

The InterHeart study, a large case–control study involving almost 30 000 participants from 52 countries, considered the contribution of a range of cardiometabolic risk factors to the overall population-attributable risk of a first myocardial infarction.34 Dyslipidaemia was defined as an elevated ApoB:ApoAI ratio, which is commonly found in individuals with low HDL-cholesterol. The population-attributable risk of myocardial infarction associated with this lipid abnormality was 49%, i.e. almost half of the overall risk of a first myocardial infarction was due to this specific lipid abnormality in the analysis. The relative risk of myocardial infarction for the highest vs. lowest quintile of ApoB:ApoAI was 3.25 (95% CI 2.81–3.76). The elevated cardiovascular risk associated with an elevated ApoB:ApoAI ratio was graded and continuous when the InterHeart population was divided into deciles of ApoB:ApoAI ratio (Figure 4). These findings strongly supported the results of the AMORIS study from Sweden that also found the ratio of ApoB/ApoAI to be the strongest lipid/lipoprotein predictor of coronary heart disease.35


Figure 0354
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  		Figure 4 Relationship between ApoB:ApoAI ratio and the risk of a first myocardial infarction in the InterHeart study. The lowest decile of this parameter served as the reference group. Reprinted from Yusuf et al.34 with permission from Elsevier.

 
Low HDL-cholesterol: practical aspects
Low HDL-cholesterol is a common manifestation of dyslipidaemia, especially among patients with type 2 diabetes or the metabolic syndrome. Statins exert relatively little effect on HDL-cholesterol, as shown by the lack of effect of intensive statin therapy on this parameter in the trials illustrated in Table 1. In addition, a meta-analysis of five major outcome studies with statins (4S, CARE, LIPID, WOSCOPS, and AFCAPS/TexCAPS) demonstrated net changes in HDL-cholesterol of only 5–7% when compared with net changes in LDL-cholesterol of between –25 and –36%.36 Not surprisingly, surveys of patients receiving treatment for dyslipidaemia in Europe have shown that roughly one patient in three has low HDL-cholesterol despite lipid-modifying treatment.37,38

The meta-analysis of statin trials,23 described earlier, evaluated the effects of statins on outcomes after stratification of patients for levels of HDL-cholesterol at baseline (Figure 5). The statin was effective in patients with or without low HDL-cholesterol, consistent with the results of AFCAPS/TexCAPS, also described earlier.16 However, it should be noted that the event rates were markedly higher in the low HDL-cholesterol group, so that the event rate with statin treatment in patients with low HDL-cholesterol [≤0.9 mmol/L (35 mg/dL)] was higher than the event rate without statin treatment in patients with normal levels of HDL-cholesterol [>1.1 mmol/L (43 mg/dL)].


Figure 0355
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  		Figure 5 Higher event rates in patients with low HDL-cholesterol despite treatment with a statin: data from a meta-analysis of more than 90 000 patients.

 
A growing body of clinical opinion suggests that greater emphasis should be placed on low HDL-cholesterol as an independent coronary risk factor within cardiovascular management guidelines. A group of 21 physicians experienced in the management of cardiovascular risk from nine European countries recently came together under the banner of ‘The European Consensus Panel on HDL-C’ to consider the status of low HDL-cholesterol as a cardiovascular risk factor and to make recommendations relating to future updating of guidelines.39 The group considered that guidelines should indeed contain treatment goals for HDL-cholesterol, supported by improved assay methodology and consistent definitions of low HDL-cholesterol in important patient subgroups. It was concluded that simultaneous intervention to correct low HDL-cholesterol and elevated LDL-cholesterol is rational and evidence-based. A combination of a statin with nicotinic acid, currently the most effective agent for increasing HDL-cholesterol,3 is an effective and proven strategy for correcting low HDL-cholesterol for most patients.


   Conclusions
Top
 Abstract
 Introduction
 Lipoproteins and coronary risk
 Management of cardiovascular...
 Conclusions
References
 
Numerous intervention trials with statins have demonstrated marked and significant reductions in coronary event rates, with recent trials suggesting that ‘lower is better’ with regard to LDL-cholesterol. Nevertheless, a substantial burden of coronary risk remains after statin treatment, which must be addressed by other means. Low HDL-cholesterol is common among patients receiving lipid-lowering treatment, and simultaneous correction of elevated LDL-cholesterol and low HDL-cholesterol may improve prognosis further in these patients.

Conflict of interest: The author has received research grants from Pfizer and MSD and consulting and speakers honoraria from Pfizer, MSD, AstraZeneca and Merck KGaA.


   References
Top
 Abstract
 Introduction
 Lipoproteins and coronary risk
 Management of cardiovascular...
 Conclusions
 References
 

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