Review
Current questions regarding the use of statins in patients with coronary heart disease

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Abstract

The discovery of statins caused a revolution in the field of lipid intervention. Statins are drugs with a good safety profile. Their clinical benefit has been extensively documented in primary and secondary prevention of coronary heart disease. There is substantial evidence that the clinical outcome can be improved with aggressive statin treatment both in patients with unstable as well as with stable coronary heart disease. Also, early administration of statins in acute coronary syndromes is accompanied by rapid clinical benefits, mainly through their “pleiotropic” action (anti-inflammatory, anti-thrombotic, improvement of endothelial function, etc) which is probably a lipid-independent effect. Moreover, emerging data indicate that statins can achieve additional benefit when low density lipoprotein (LDL) cholesterol reduction is coupled with C-reactive protein reduction (< 2 mg/L). The prevailing message from the recent statin trials is that intensive LDL cholesterol lowering treatment with statins achieves further clinical benefit beyond that achieved with standard statin therapy. This should encourage the medical community to consider prescribing statins in every coronary patient, aiming at LDL cholesterol levels < 100 mg/dL, preferably in the range of 70–80 mg/dL in stable coronary patients, while in coronary patients at very high risk, the optional target for LDL cholesterol levels should be in the range of 50–70 mg/dL.

Section snippets

Benefits of aggressive lipid lowering treatment

The first randomized clinical trials with statins during the 90's [5], [6], [7], [8], [9], reported and confirmed the clinical benefits from statin treatment in primary and secondary prevention of CHD. Then, the U.S. National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines in 2001 were released [10], and set the target LDL cholesterol level in CHD patients < 100 mg/dL. During the following 5 years statin trials tested mainly the outcome of early intensive treatment in

How early do the clinical benefits appear after the initiation of intensive lipid lowering therapy?

Early statin trials [5], [6], [7], [8], [9] of primary and secondary prevention of stable CHD showed that the clinical benefit is evident 1–2 years after the initiation of treatment. This delay, however, did not appear in the most recent trials using statins in ACS [11], [13]. Indeed, analysis from the PROVE IT-TIMI 22 trial [19], showed that the clinical benefit from the intensive lipid lowering therapy in patients with ACS, started to emerge as early as 15 days after the initiation of

How safe are the statins?

Skepticism over statin safety was raised after the worldwide withdrawal of cerivastatin in 2001 because of its association with fatal rabdomyolysis. As a result the safety profile of rosuvastatin, the most recently launched statin, had been the subject of increased scrutiny before its approval by the US Food and Drug Administration (FDA).

Accumulating data show that statins are safe drugs [36], [37], [38], [39], [40], [41]. The main concerns related to statin treatment are:

  • a)

    liver toxicity. This

How safe are the very low LDL cholesterol levels achieved by statin treatment?

Such a question is reasonable, since cholesterol is an essential component of cellular membranes and is also necessary for steroid hormones and vitamin D synthesis. However, the answer is not straightforward since only few data exist regarding the safety of very low levels of LDL cholesterol, achieved by intensive statin therapy.

Hunter/gatherer populations (e.g. Pygmies) that continue to live primitively and in whom atherosclerosis is rare or non existent, have cholesterol levels in the range

Is targeting only LDL cholesterol enough?

Several studies have shown that statins reduce CRP levels [57], [58] and that more robust LDL cholesterol reductions are correlated with lower CRP levels [59]. The potential benefit of achieving not only low LDL cholesterol levels, but also low CRP levels has also been investigated. In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, the least reduction in atherosclerosis was noted in those who achieved the greatest reduction in both LDL cholesterol and CRP

Can intensive lipid lowering therapy cause a regression of coronary atherosclerosis?

The question of whether statins can affect the progression of coronary atherosclerosis has been examined since the early 90s [62], [63]. In the first statin studies, where quantitative coronary angiography was used to assess the progression rates, no regression was detected. The absence of angiographic regression, despite the clinical benefits, generated the “stabilization” hypothesis of the plaque and this stabilizing effect was attributed to the pleiotropic properties of statins [63].

Conclusions

There is substantial evidence regarding the clinical benefit of statins both in primary and secondary prevention of CHD. Statins are drugs with a good safety profile. Recent findings suggest that the benefits of statins in CHD patients can be maximised when: a) statins are used in high doses, b) statins are started early in patients with ACS and c) a significant reduction of CRP (< 2 mg/L) besides LDL cholesterol reduction is achieved. This is despite the fact that a substantial proportion of

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