CYP2C19*2/ABCB1-C3435T polymorphism and risk of cardiovascular events in coronary artery disease patients on clopidogrel: Is clinical testing helpful?

BackgroundStudies evaluating CYP2C19*2 and ABCB1-C3435T polymorphisms have shown conflicting results. We performed this meta-analysis to evaluate role of clinical testing for these polymorphisms in CAD patients on clopidogrel.Methods19,601 patients from 14 trials were analyzed. The endpoints were major adverse cardiovascular events (MACE), cardiovascular (CV) death, stent thrombosis (ST), myocardial infarction (MI), stroke and major bleeding. Combined relative risks (RR) with 95% confidence intervals (CI) were computed for each outcome by using standard methods of meta-analysis and test parameters were computed.ResultsCYP2C19*2 polymorphism was associated with higher risk of MACE [RR: 1.28, CI: 1.06–1.54; p = 0.009], CV death [RR: 3.21, CI: 1.65–6.23; p = 0.001], MI [RR: 1.36, CI: 1.12–1.65; p = 0.002], ST [RR: 2.41, CI: 1.69–3.41; p < 0.001]. No difference was seen in major bleeding events [RR: 1.02, CI: 0.86–1.20; p = 0.83]. Subgroup analysis showed similar results for elective PCI [RR: 1.34, CI: 1.01–1.76; p = 0.03], and PCI with DES [RR: 1.53, CI: 1.029–1.269; p = 0.03]. CYP2C19*2 polymorphism has very low sensitivity (28–58%), specificity (71–73%), positive predictive value (3–10%) but good negative predictive value (92–99%). ABCB1-C3435T polymorphism analysis revealed similar MACE [RR: 1.13, CI: 0.99–1.29; p = 0.06], ST [RR: 0.88, CI: 0.52–1.47; p = 0.63] and major bleeding [RR: 1.04, CI: 0.87–1.25; p = 0.62] in both groups.ConclusionIn CAD patients on clopidogrel therapy, CYP2C19*2 polymorphism is associated with significantly increased adverse cardiovascular events. However, due to the low positive predictive value, routine genetic testing cannot be recommended at present.     

Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery

One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3' kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug-delivery challenges.     

Evaporation-induced cavitation in nanofluidic channels

Cavitation, known as the formation of vapor bubbles when liquids are under tension, is of great interest both in condensed matter science as well as in diverse applications such as botany, hydraulic engineering, and medicine. Although widely studied in bulk and microscale-confined liquids, cavitation in the nanoscale is generally believed to be energetically unfavorable and has never been experimentally demonstrated. Here we report evaporation-induced cavitation in water-filled hydrophilic nanochannels under enormous negative pressures up to -7 MPa. As opposed to receding menisci observed in microchannel evaporation, the menisci in nanochannels are pinned at the entrance while vapor bubbles form and expand inside. Evaporation in the channels is found to be aided by advective liquid transport, which leads to an evaporation rate that is an order of magnitude higher than that governed by Fickian vapor diffusion in macro- and microscale evaporation. The vapor bubbles also exhibit unusual motion as well as translational stability and symmetry, which occur because of a balance between two competing mass fluxes driven by thermocapillarity and evaporation. Our studies expand our understanding of cavitation and provide new insights for phase-change phenomena at the nanoscale.     

Lipoprotein(a), interleukin-10, C-reactive protein, and 8-year outcome after percutaneous coronary intervention

Background:

This prospective study investigated the association between preprocedural biomarker levels and incident major adverse cardiac events (MACE) in complex patients undergoing percutaneous coronary intervention (PCI) with sirolimus‐eluting stenting.

Hypothesis:

Lipoprotein(a) (Lp[a]), interleukin‐10 (IL‐10), and high‐sensitivity C‐reactive protein (CRP) have long‐term prognostic value in patients undergoing PCI.

Methods:

Between April 2002 and February 2003, 161 patients were included in the study. Blood was drawn before the procedure, and biomarkers were measured. Patients were followed‐up for MACE (death, nonfatal myocardial infarction, and repeat revascularization). Cox proportional hazard models were used to determine risk of MACE for tertiles of biomarkers. Both 1‐year and long‐term follow‐up (median, 6 years; maximum, 8 years) were evaluated.

Results:

Mean age was 59 years, and 68% were men. During long‐term follow‐up, 72 MACE occurred (overall crude cumulative incidence: 45% [95% confidence interval (CI): 37%‐52%]). Lp(a) was associated with a higher 1‐year risk of MACE, with an adjusted hazard ratio (HR) of 3.1 (95% CI: 1.1‐8.6) for the highest vs the lowest tertile. This association weakened and lost significance with long‐term follow‐up. IL‐10 showed a tendency toward an association with MACE. The 1‐year HR was 2.1 (95% CI: 0.92‐5.0). Long‐term follow‐up rendered a similar result. The association of CRP with MACE did not reach statistical significance at 1‐year follow‐up. However, CRP was associated with long‐term risk of MACE, with an HR of 1.9 (95% CI: 1.0‐3.5).

Conclusions:

In this prospective study, preprocedural Lp(a) level was associated with short‐term prognosis after PCI. The preprocedural CRP level was associated with long‐term prognosis after PCI. Clin. Cardiol. 2012 DOI: 10.1002/clc.21988 The authors have no funding, financial relationships, or conflicts of interest to disclose.     

Thigh-length versus knee-length compression stockings for deep vein thrombosis prophylaxis in the inpatient setting

Deep vein thrombosis may be a complication of extended length hospital stays. Immobilized patients, such as patients in the postoperative period, are at particularly high risk of developing a deep vein thrombosis, which can be associated with high levels of morbidity and mortality. Due to this, prevention of deep vein thrombosis is of great importance in the inpatient setting. Compression stockings have proven to play an important role in prophylaxis and may be used in their knee-length or thigh-length variety. Although randomized trials have studied the efficacy of both varieties in prevention of deep vein thrombosis, selection is often made without regard to evidence. This meta-analysis pools the findings of current studies comparing knee-length and thigh-length compression stockings for deep vein thrombosis prophylaxis. A fixed effects model was used for this study with a two-sided α-error less than 0.05 considered to be statistically significant. When both varieties of compression stockings are compared, thigh-length stockings offer a risk reduction in deep vein thrombosis development when compared with knee-length (odds ratio 1.197, confidence interval 0.983-1.458). This, however, is an insignificant finding. This analysis concludes that current data does not favor either thigh-length or knee-length compression stockings when it comes to prophylaxis of deep vein thrombosis.