European Heart Journal Advance Access originally published online on August 1, 2008
European Heart Journal 2008 29(17):2061-2063; doi:10.1093/eurheartj/ehn348
More good reasons for adherence to statin therapy during acute coronary syndromes
1 Department of Experimental Medicine, Ludwig Maximilian University, Marchioninistr. 15, 81377 Munich, Germany
2 Department for Internal Medicine III, University of the Saarland, Homburg, Germany
* Corresponding author. Tel: +49 89 7095 3438, Fax: +49 89 7095 6433, Email: christopher.heeschen{at}med.uni-muenchen.de
This editorial refers to ‘Discontinuation of statin therapy following an acute myocardial infarction: a population-based study’
by S.D. Daskalopoulo et al., on page 2083
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
During the last decade, the evidence that statins have potent effects in reducing death and myocardial infarction in patients following acute coronary syndromes has become overwhelming, both in patients with elevated cholesterol levels and in those with normal cholesterol levels.1,2 Beyond their intended impact on blood cholesterol levels, statins are also known to have multiple non-lipid effects that contribute to the reduction of cardiovascular morbidity and mortality.3,4 Statins may prevent acute thrombus formation at the site of plaque rupture by inhibiting platelet function and inhibiting platelet deposition on damaged vessels. They have also been shown to contribute to plaque stabilization, not only through a reduction in lipids but also as a result of reduced macrophage accumulation in atherosclerotic lesions and inhibition of expression of matrix metalloproteinases. Statins have anti-inflammatory properties; they reduce levels of high sensitivity C-reactive protein and, through attenuation of P-selectin expression, protect the ischaemic myocardium. Statins restore endothelial function before any significant reduction in cholesterol levels may have occurred. In the context of acute coronary syndromes, the statin-mediated improvement of vascular function by inhibiting the production of harmful intermediates of the cholesterol biosynthetic pathway appears to play a major role. Therefore, the effects of statins include an increase in nitric oxide bioavailability, reduced expression of endothelin-1, and increased expression of tissue plasminogen activator. Ongoing clinical trials with highly potent statins are now expected to provide valuable information about the most appropriate agents and doses to improve the treatment of patients with acute coronary syndromes.5
Despite these demonstrated beneficial effects of statins and the low incidence of undesired effects, the use of statins is still highly variable in daily clinical routine. Up to 30% of prescriptions are discontinued during the first year.6 Discontinuation of statin therapy may bear a substantial cardiovascular risk, particularly in the context of acute coronary syndromes. Several years ago, animal studies by Laufs and colleagues had already suggested that the acute withdrawal of statin therapy leads to a profound rebound phenomenon with impaired nitric oxide bioavailability.7 Termination of statin therapy in mice resulted in a marked reduction of endothelial nitric oxide production below baseline levels mediated by the regulation of Rho, whereas lipid levels remained unchanged during this early period. Consistently, a study in patients with stable coronary heart disease showed a three-fold increase in thrombotic vascular events after simvastatin treatment was stopped and treatment was continued with lower doses of fluvastatin.8 Stimulated by these data, a subsequent subgroup analysis in the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) trial provided the first evidence that this detrimental effect of statin withdrawal may be particularly evident in patients with acute coronary syndromes.9 This study suggests that the risk of cardiovascular events is elevated shortly after statin discontinuation within the first 72 h following the onset of acute coronary syndromes and, as predicted from the animal studies, is independent of cholesterol levels. In contrast, when statin therapy was initiated after onset of the acute coronary syndrome, significant beneficial effects were not observed before day 14. Therefore, the discontinuation of statin therapy in patients with acute coronary syndromes may not only reverse the up-regulation of endothelial nitric oxide synthase by statins, but may also suppress nitric oxide production and potentially other Rho-dependent pathways. A number of subsequent studies have supported this notion in different study populations. While discontinuation of statins in patients with stable chronic vascular disease does not seem to have profound adverse clinical effects,10 several clinical studies in patients with acute coronary syndromes have now confirmed that the beneficial effects of statins are often transiently reversed when statins are acutely discontinued. Specifically, analysis of the National Registry of Myocardial Infarction 4 revealed that continued statin treatment or newly started statin treatment within 24 h after acute myocardial infarction led to a decreased risk of in-hospital mortality, whereas the discontinuation of statins was associated with a higher risk of in-hospital mortality.11 Consistently, in patients with non-ST elevation myocardial infarction, discontinuation in the first 24 h was associated with a two-fold risk when compared with continuation of statin treatment.12
Neither of these studies can apparently answer the question of whether this effect of statin discontinuation is sustained during long-term follow-up. Even more importantly, there is a strong requirement for convincing data based on actual clinical practice that go considerably beyond the special circumstances of these controlled clinical trials, which apparently were not designed to investigate the effects of statin discontinuation, in order to support the argument for a reassessment of the guidelines for the use of statins. In this context, a new study by Daskalopoulou and colleagues is to be welcomed because it demonstrates the prognostic effects of changes in patterns of statin medication in patients with acute coronary syndromes.13 Using population-based data from the UK General Practice Research Database, the authors investigated the impact of different patterns of statin use in patients with acute myocardial infarction. This sets the present study apart from previous studies, which were primarily based on subgroup analyses of multicentre trials and their rather selected populations. Consistently with these previous studies, the authors now confirm a detrimental effect of statin withdrawal in unselected patients with acute myocardial infarction. This effect was associated with a higher mortality rate compared with any other statin medication pattern. Importantly, the initiation of statin medication during hospitalization was found to result in a markedly lower mortality rate compared with all other patterns of statin use. With gradually increasing mortality rates over time, these early significant differences were maintained during 1 year of follow-up, and the lowest mortality rates were still seen in statin starters at 1 year of follow-up. It is important to note, however, that the study of Daskalopoulou and colleagues was observational and non-randomized. Most notably, the group of statin stoppers constituted only 1.4% of the total sample, rendering the results susceptible to confounding factors. Despite these apparent limitations, the present results are of particular scientific value because of the relatively long follow-up period and the much more general approach, using the UK General Practice Research Database. Therefore, although the results of the present study are still inherently more hypothesis-generating than hypothesis-proving, they provide strong, additional evidence for the detrimental effect of statin withdrawal in patients with acute coronary syndromes. Indeed, given these results, one may actually conclude that a prospective study investigating the outcome of unstable patients after discontinuation of statin therapy would be highly unethical. These concerns are corroborated by the recently published results of a randomized, controlled study investigating the effects of statin withdrawal in patients with ischaemic stroke. Discontinuation of statin therapy for the first 3 days after admission was associated with a five-fold increase in the risk of death or dependency at 90 days.14
Of course, the present study as well as previous studies leave the most pressing question unanswered: whether the higher event rates following statin discontinuation are indeed attributable to a true biological rebound phenomenon, as observed in animal models, and/or are related to a risk–treatment mismatch. Therefore, reliable prognostic risk parameters might be helpful in identifying patients at increased risk of secondary cardiovascular events and providing the opportunity to adjust medication patterns individually, including the use of statins during the early phase following the onset of acute coronary syndromes. Along the same lines, previous studies on placental growth factor (PlGF), a member of the vascular endothelial growth factor family, reported that high PlGF levels are independently associated with an increased risk of death and non-fatal myocardial infarction during the first 30 days of follow-up.15 Most intriguingly, further analysis of the data revealed that the negative effect of statin withdrawal was mostly confined to patients with elevated PlGF levels (C.H., unpublished data). Patients presenting with low baseline PlGF levels were at considerably lower risk of cardiovascular events, independently of their subsequent statin medication pattern. These data are consistent with the hypothesis that patients with a strong inflammatory reaction in the vascular system, as evidenced by elevated PlGF levels, are highly vulnerable and therefore suffer more than other patients from statin withdrawal during an acute coronary event.
The present investigation by Daskalopoulou and colleagues substantiates and consolidates the notion that statins significantly reduce cardiovascular event rates in patients with acute coronary syndromes. Therefore, the continuation of statin therapy following onset of acute coronary syndromes is crucial and is probably most important in patients at high cardiovascular risk.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehn346 
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[Abstract/Free Full Text] - Daskalopoulou SS, Delaney JAC, Filion KB, Brophy JM, Mayo NE, Suissa S. Discontinuation of statin therapy following an acute myocardial infarction: a population-based study. Eur Heart J. 2008;29:2083–2091. First published on July 29, 2008. doi:10.1093/eurheartj/ehn346.
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The above article uses a new reference style being piloted by the EHJ that shall soon be used for all articles.
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