Statin Withdrawal: Clinical Implications and Molecular Mechanisms

Abstract

Retrospective analyses of data from the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM), the National Registry of Myocardial Infarction 4, and the Global Registry of Acute Coronary Events (GRACE) trials revealed that the benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) on acute coronary outcomes are rapidly lost and outcomes worsened if statins are discontinued during a patient's hospitalization for an acute coronary syndrome. Withdrawal of statin therapy in the first 24 hours of hospitalization for non-ST-elevation myocardial infarction increased the hospital morbidity and mortality rate versus continued therapy (11.9% vs 5.7%, p<0.01). Data from the Treating New Targets (TNT) study, however, suggested that short-term discontinuation of statin therapy in patients with stable cardiac conditions may not substantially increase the risk of acute coronary syndromes. In patients with acute coronary syndromes who discontinue statins, the rapid increase in risk of an event may result not only from the lost benefits from the therapy, but also from rebound inhibition of vascular protective substances and activation of vascular deleterious substances. Statins inhibit cholesterol synthesis in vascular cells. By reducing levels of isoprenoid intermediates, statins increase the production of nitric oxide and downregulate angiotensin II AT(1) receptors, endothelin-1, vascular inflammatory adhesion molecules, and inflammatory cytokines. These benefits are rapidly lost and often transiently reversed when statins are acutely discontinued. Acute removal of pleiotropic effects and rebound vascular dysfunction may be more important in an acute coronary event, where inflammation promotes rupture of atherosclerotic plaques and inflammatory and prothrombosis markers are present in high concentration, than in stable chronic vascular disease. In the absence of data from randomized controlled trials, current information suggests that statin therapy should be continued, and possibly boosted, during hospitalization for an acute coronary syndrome. Because statins are discontinued during the early hospitalization of many patients, practitioners must ensure that statins are not omitted, unless contraindicated, from the treatment of patients with acute coronary syndromes.

Delirium after elective surgery among elderly patients taking statins

“…29,30 Our findings are not easily explained as drug withdrawal, because statin cessation generally led to a decreased effect (not rebound harm) and because the observed risk was no lower for the statin with the longest half-life (atorvastatin). 31 The endothelial nitric oxide synthase mechanism emphasized the role of microvascular blood flow autoregulation for preserving neuronal function. 32 Our results are not readily attributable to unmeasured underlying severity of vascular disease for several reasons.…”

Drug Discontinuation Effects Are Part of the Pharmacology of a Drug

“…They are not limited to drugs with abuse or addiction potential but also occur after discontinuation of therapeutic drugs. Recent examples include aspirin (Sung et al, 2010), statins (Cubeddu and Seamon, 2006), and heparin (Bijsterveld et al, 2003). Usually we pay no attention to the possibility that a drug without addiction liability can cause a discontinuation syndrome until a clinical catastrophe occurs and is identified as caused by discontinuation of the drug.…”

El tratamiento con atorvastatina reduce la actividad de xantina-oxidasa unida al endotelio en pacientes con insuficiencia cardíaca crónica: ¿Un posible nuevo efecto pleiotrópico?

“…Sin embargo, los pacientes con IC han sido sistemáticamente excluidos de estos estudios haciendo alusión a problemas de seguridad en la terapia. Pese a lo anterior, existe evidencia contradictoria con respecto a la suspensión de la terapia con estatinas en pacientes con IC podría ser perjudicial 35,36 . Por una parte, estudios como el Controlled Rosuvastatin Multinational Trial In Heart Failure 37 (CORONA) y Gruppo Italiano Per Lo Studio Della Sopravvivenza Nell´infarto MiocardicoHeart Failure 38 (GISSI-HF) han mostrado que la terapia con rosuvastatina en pacientes con insuficiencia cardíaca isquémica y no isquémica, no confieren beneficios en cuanto a mortalidad.…”

“…Estos trabajos podrían inducir a la suspensión de la terapia con estatinas. Sin embargo, evidencia reciente en estudios poblacionales y animales han mostrado que la suspensión de la terapia con estatinas en pacientes de alto riesgo cardiovascular, particularmente en pacientes con cardiopatía coronaria, se asocian a disfunción vascular y a eventos cardiovasculares 35,36,39 .…”