24- and 6-month dual antiplatelet therapy after coronary stenting did not differ for clinical outcomes

QUESTION What is the relative efficacy of dual antiplatelet therapy (DAPT) given for 24 months compared with 6 months after coronary stent implantation? METHODS DESIGN Randomized controlled trial (RCT) (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study [PRODIGY]). ClinicalTrials.gov NCT00611286. ALLOCATION Unclear allocation concealment.* BLINDING Blinded* (event adjudication committee). FOLLOW-UP PERIOD 2 years. SETTING 3 referral centers in Italy. PATIENTS 1970 patients ≥?18 years of age (mean age 68 y, 77% men) who had chronic, stable coronary artery disease or an acute coronary syndrome; ≥?1 lesion with ≥?50% diameter stenosis in a vessel ≥?2.25 mm in diameter that was suitable for coronary stent implantation; and elective, urgent, or emergent coronary angioplasty with 1 of 4 randomly assigned types of stent (bare metal or everolimus-, paclitaxel-, or zotarolimus-eluting) 30 days before DAPT randomization. Exclusion criteria included planned surgery within 24 months unless DAPT could be continued, major surgery within 15 days, history of bleeding diathesis, active bleeding or stroke in the past 6 months, expected need for oral anticoagulation therapy, pregnancy, or life expectancy <?24 months. INTERVENTION DAPT using oral clopidogrel, loading dose of 300 or 600 mg and then 75 mg/d, plus aspirin, loading dose of 160 to 325 mg orally or IV 500 mg and then 80 to 160 mg/d orally for 24 months (n =?987); or for 6 months followed by aspirin alone (n =?983). OUTCOMES Primary composite endpoint (all-cause mortality, nonfatal myocardial infarction, or cerebrovascular accident). Other outcomes included components of the composite endpoint, stent thrombosis, and bleeding. 1700 patients were needed to detect a 40% relative reduction in the primary endpoint at 2 years from 8% in the 6-month group (80% power, 2-sided α =?0.05). PATIENT FOLLOW-UP 99.6% (intention-to-treat analysis). MAIN RESULTS The main results are in the Table. CONCLUSION 24-month dual antiplatelet therapy after stent implantation increased bleeding and did not improve a composite of mortality, myocardial infarction, and cerebrovascular accident more than 6-month therapy.24 mo vs 6 mo of dual antiplatelet therapy after coronary stent implantation?Outcomes24-mo treatment6-mo treatmentAt 2 yRRI (95% CI)NNH (CI)Primary composite?10.1%10.0%2% (-27 to 25)Not significantBleeding§7.4%3.5%53% (30 to 68)26 (20 to 45)RRR (CI)NNT (CI)Definite or probable stent thrombosis1.3%1.5%15% (-45 to 139)Not significant?Abbreviations defined in Glossary. RRI, RRR, NNH, and CI calculated from hazard ratios and event rates in article.?All-cause mortality (6.6% vs 6.6%, P =?0.98), myocardial infarction (4.0% vs 4.2%, P =?0.80), and cerebrovascular accident (2.1% vs 1.4%, P =?0.17).§Bleeding Academic Research Consortium classification type 5, 3, or 2.     

Blocking of ERK1 and ERK2 sensitizes human mesothelioma cells to doxorubicin

Background  

Malignant mesotheliomas (MM) have a poor prognosis, largely because of their chemoresistance to anti-cancer drugs such as doxorubicin (Dox). Here we show using human MM lines that Dox activates extracellular signal-regulated kinases (ERK1 and 2), causally linked to increased expression of ABC transporter genes, decreased accumulation of Dox, and enhanced MM growth. Using the MEK1/2 inhibitor, U0126 and stably transfected shERK1 and shERK2 MM cell lines, we show that inhibition of both ERK1 and 2 sensitizes MM cells to Dox.     

Inhibition of inflammatory cell infiltration by bicyclic imidazoles,SK&F 86002 and SK&F 104493

The mode of action of the dual inhibitors of eicosanoid metabolism, SK&F 86002 and SK&F 104493 was evaluated on inflammatory cell infiltration induced in mice by carrageenan, monosodium urate crystals, and arachidonic acid. The results were compared to those seen with standard antiinflammatory compounds. Inflammatory cell infiltration was inhibited by SK&F 86002, SK&F 104493, colchicine, and phenidone but not naproxen. In vivo, PMN infiltration induced by LTB₄ was inhibited by colchicine but not by SK&F 86002, SK&F 104493, or phenidone treatment. Similarly, in vitro chemotaxis to LTB₄ was not inhibited by SK&F 86002. The 5-lipoxygenase inhibitors, SK&F 86002, SK&F 104493, and phenidone inhibited LTB₄ production in vivo as well as inflammatory cell infiltration induced by arachidonic acid. The data are consistent with the suggestion that the bicyclic imidazoles inhibit PMN infiltration by virtue of inhibition of LTB₄ production.