Adverse events associated with individual statin treatments for cardiovascular disease: an indirect comparison meta-analysis.

BACKGROUND: Statins are the most widely prescribed drug available. Due to this reason, it is important to understand the risks involved with the drug class and individual statins. AIM: We conducted a meta-analysis and employed indirect comparisons to identify differing risk effects across statins. DESIGN: We included any randomized clinical trial (RCT) of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin used for cardiovascular disease event prevention. The main outcome was adverse events [all-cause mortality, cancers, rhabdomylosis, diabetes, aspartate and alanine aminotransferase (AST/ALT), and creatinine kinase (CK) increases beyond the upper limit of normal]. In order to evaluate the relative effects of each drug on adverse events, we calculated adjusted indirect comparisons of the adverse-event outcomes. RESULTS: Seventy-two trials involving 159,458 patients met our inclusion criteria. Overall, statin treatments significantly increased the rate of diabetes when compared to controls (OR: 1.09; 95% CI: 1.02-1.16) and elevated AST (OR: 1.31; 95% CI: 1.04-1.66) and ALT (OR: 1.28; 95% CI: 1.11-1.48) levels when compared to controls. Using indirect comparisons, we also found that atorvastatin significantly elevated AST levels compared to pravastatin (OR: 2.21; 95% CI: 1.13-4.29) and simvastatin significantly increased CK levels when compared to rosuvastatin (OR: 4.39; 95% CI: 1.01-19.07). Higher dose studies had increased risk of AST elevations. DISCUSSION: Although statins are generally well tolerated, there are risks associated with almost all drugs. With few exceptions, statins appear to exert a similar risk across individual drugs.

Platelet cationic proteins are present in glomeruli of lupus nephritis patients.

Synthetic polycations have been shown to bind and neutralize glomerular polyanions (GPA), thereby increasing the permeability of the glomerular capillary wall (GCW). In the present study it is demonstrated that human platelet-derived cationic proteins (HuPlt CP), which are able to increase cutaneous vascular permeability, bind in vitro to the GCW following incubation of normal human kidney sections with purified HuPlt CP or with washed human platelets stimulated with thrombin, immune complexes (IC) and platelet-activating factor (PAF), or stimulated with a suspension of washed human platelets and polymorphonuclear leukocytes in the presence of phagocytable substrate. The antiserum used in immunofluorescence test to detect the binding of HuPlt CP was specific for two different molecular types of HuPlt CP, both with an isoelectric point (pI) of 10.5. Glomerular deposits of HuPlt CP were also detectable by immunofluorescence microscopy in renal glomeruli present in tissue obtained by biopsy from patients with systemic lupus erythematosus (SLE), a disease in which platelets have been implicated as mediator of glomerular injury. These data indicate that when activated platelets release HuPlt CP in vivo, these proteins bind to glomerular structures. The binding of HuPlt CP to GCW appears to be ionic in nature since heparin, a polyanion, prevents this binding in vitro. In addition, heparin, as well as a high molarity buffer, removed deposits of HuPlt CP bound in vitro to normal GCW or bound in vivo to glomeruli of patients with SLE. The binding of HuPlt CP to GCW is associated with loss of colloidal iron staining, a qualitative technique that demonstrates primarily epithelial cell surface anionic sialoglycoproteins. In experiments of in vitro binding of purified HuPlt CP to section of normal kidney treatment with heparin completely restores the normal pattern of colloidal iron staining suggesting ionic neutralization of GPA. In contrast, heparin is only partially effective in restoring colloidal iron staining in normal kidney sections treated with platelets directly stimulated with IC or PAF or in kidney sections of patients with SLE. These observations indicate that under these conditions the ionic interaction of HuPlt CP with GCW is only partially responsible for the loss of colloidal iron staining. The results of the present study suggest that biologically active polycationic mediators released from stimulated platelets localize in GCW and participate in the induction of glomerular injury.

The role of platelet-activating factor in experimental immune complex pathology.

Tissue localization of immune complexes (IC) after infusion of synthetic platelet-activating factor (PAF) in rabbits was studied. Bovine serum albumin (BSA) was injected intravenously either before or after the infusion of synthetic PAF, later followed by the administration of anti-BSA antibodies over a 30-min period. Control rabbits received both BSA and anti-BSA antibodies, followed by lyso-PAF or saline-BSA instead of PAF. The infusion of PAF induced structural alterations in the heart, lung and kidney which were consistent with an increased vascular permeability. Deposits of BSA, IgG, and C3 were found in the heart, lung, and kidney of rabbits infused with PAF but not in control rabbits. In the liver of PAF-infused rabbits, immune deposits were only infrequently observed, whereas they were constantly present in the cardiac valves, thoracic aorta and at the bifurcation of the renal artery as they were in the control rabbits. These results suggest that PAF favors the localization of IC in the heart, lung and kidney vessels but does not influence the formation of immune deposits at the sites of turbulence of the blood flow.

Acute lung inflammation induced in the rabbit by local instillation of 1-0-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine or of native platelet-activating factor.

The intratracheal instillation into rabbits of 1-0-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC) or native platelet-activating factor (PAF) was shown to induce a dose-dependent acute pulmonary inflammation characterized by accumulation of macrophages in the alveolar space, degenerative and necrotic changes of alveolar epithelium, and accumulation of polymorphonuclear leukocytes (PMNs) and platelets in the alveolar capillary lumens with degenerative changes of endothelial cells. Infiltration of alveolar septa by inflammatory cells and, in a later stage, pulmonary fibrosis were also observed. Intrabronchial instillation of lysoglyceryl ether phosphorylcholine (lyso-GEPC) produced no inflammatory changes or only mild ones. In comparison with acute inflammation induced by intratracheal instillation of C5a des Arg, which is mainly characterized by the presence of neutrophils, red blood cells, and fibrin in the alveolar space, AGEPC and native PAF seem to induce a more severe accumulation of macrophages in the alveolar space and septa and of platelet and PMNs in the lumens of alveolar capillaries. These results are compatible with the concept that during inflammatory reaction an intraalveolar release of PAF contributes to the development of pulmonary injury.

Effect of prostacyclin (PGI2) on immune-complex-induced neutropenia.

This study reports the results of in vitro and in vivo investigations on the effect of prostacyclin (PGI2) on polymorphonuclear neutrophils (PMN) challenged with immune complexes (IC). In vitro, PGI2 does not affect the interaction of IC with PMN membrane receptors, but prevents the ensuing PMN aggregation and secretion of platelet-activating factor, a lipid mediator responsible for immune-induced PMN aggregation. In vivo, the infusion of PGI2 in New Zealand white rabbits injected with IC prevents IC-induced neutropenia and thrombocytopenia as well as the embolization of PMN into the pulmonary peripheral capillary network. These results suggest a physiological role for PGI2 in modulating the interaction between IC and PMN.