Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.

BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was -6.0±1.7 versus 28.0±2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was -6.7±1.8 versus 14.4±2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus -0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7±9.6 versus -119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).

Assessment of eptifibatide dosing in renal impairment before and after in-service education provided by pharmacists.

BACKGROUND: Anticoagulant and antithrombotic agents are frequently cited as sources of medication errors. Several factors increase the risk of receiving excess dosing of glycoprotein IIb/IIIa inhibitors in the management of acute coronary syndrome (ACS), including older age, female gender, elevated serum creatinine, a history of diabetes mellitus, and a history of heart failure. In June 2003, the manufacturer of eptifibatide released a recommendation adjusting infusion rate downward to 1 mcg per kg per minute for eptifibatide in patients with renal impairment, defined as an estimated creatinine clearance (CrCl) < 50 ml per minute. Eptifibatide is known to accumulate in patients with renal impairment, thereby increasing hemorrhagic risk. OBJECTIVE: To assess the impact of education on physician adherence to the renal dosing recommendation for eptifibatide at 2 academic medical centers. The primary outcome measure was the proportion of patients with renal impairment dosed appropriately with eptifibatide before and after in-service education provided by a clinical pharmacist. Secondary outcome measures included the difference in the improvement in dosing adherence between the 2 sites and the influence of patient variables on the incidence of bleeding events. METHODS: This prospective study was conducted in patients with renal impairment who received eptifibatide for the medical management of unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI) or for the interventional management of chronic stable angina, UA, NSTEMI, or ST-elevation myocardial infarction (STEMI, not a Food and Drug Administration-approved use). Patient data were assessed at 2 tertiary care teaching institutions between June 2003 and December 2005. The preeducation phase for the sites ran from June 2003 through April 2005 for Site A and from June 2003 through May 2005 for Site B. The posteducation phase ran from May 2005 through December 2005 for Site A and from June 2005 through December 2005 for Site B. At site A, a 1-hour educational seminar on ACS management strategies was employed, in which 5 minutes focused on adherence of prescribers to the guideline for renal dosing recommendations for eptifibatide. This tutorial was accomplished through (1) an in-service provided by 1 clinical pharmacist to the cardiology department, and (2) handouts containing the renal dosing recommendations for eptifibatide along with dosing for other medications used to manage ACS. The intervention at Site B involved an eptifibatide-focused seminar presented to cardiologists by a clinical pharmacist, 10 minutes of which was devoted to renal dosing recommendations that included (1) a summary of literature supporting the infusion rate reduction in patients with renal impairment and (2) the specific updated dosing recommendation for eptifibatide. The data collected in retrospective chart review included patient demographics, baseline laboratory values, and risk factors for bleeding. An appropriate eptifibatide dose was defined as a physician order for a continuous infusion of 1 mcg per kg per minute in patients with an estimated CrCl < 50 ml per minute. RESULTS: A total of 148 patients with renal impairment who received eptifibatide were evaluated (106 in the preeducation phase and 42 in the posteducation phase). A significant increase in the adherence rate for eptifibatide dosing in patients with renal impairment was observed from 36.8% in the preeducation phase to 69.0% in the posteducation phase (P < 0.001) for the 2 sites combined. The incidence of major and minor bleeding was 16.7% in the preeducation phase and 14.3% in the posteducation phase (P = 0.742). When bleeding incidence was stratified by the appropriateness of infusion, the incidence of major and minor bleeding was also similar for appropriate dosing (1 mcg per kg per minute, 16.4%) versus inappropriate dosing (2 mcg per kg per minute, 15.7%; P = 0.916). CONCLUSION: This educational intervention provided by a clinical pharmacist was associated with improved prescriber adherence to dosing recommendations for eptifibatide in patients with renal impairment. Improved adherence to the dosing guideline and administration of an appropriate infusion rate were not associated with reduction in either minor or major bleeding events.

Statin-related adverse events: a meta-analysis.

BACKGROUND: The absolute frequencies of adverse events (AEs) between statins and placebo are very low in clinical trials, making clinical interpretation and application difficult. OBJECTIVES: This meta-analysis was intended to synthesize the collective AE data observed in prospective randomized clinical trials to facilitate clinical interpretation. METHODS: Using the search terms atorvastatin, simvastatin,pravastatin, rosuvastatin, fluvastatin, lovastatin, prospective trial, and randomized trial, the MEDLINE/EMBASE and the Cochrane Collaboration databases were reviewed for prospective randomized primary and secondary prevention trials of statin monotherapy. Nonrandomized uncontrolled studies and those missing AE data were excluded. The Mantel-Haenszel test for fixed and random effects was used to calculate odds ratios (ORs) and log ORs. RESULTS: Eighteen trials including 71,108 persons, and 301,374 person-years of follow-up were represented in this analysis. There were 36,062 persons receiving a statin and 35,046 receiving a placebo. Statin therapy increased the risk of any AE by 39% (OR = 1.4; 95% CI, 1.09-1.80; P = 0.008; NNH [number needed to harm] = 197) compared with placebo. Statins were associated with a 26% reduction in the risk of a clinical cardiovascular event (OR = 0.74; 95% CI, 0.69-0.80; P < 0.001; number needed to treat = 27). Treating 1000 patients with a statin would prevent 37 cardiovascular events, and 5 AEs would be observed. Serious events (creatine phosphokinase >10 times the upper limit of normal or rhabdomyolysis) are infrequent (NNH = 3400) and rhabdomyolysis, although serious, is rare (NNH = 7428). Atorvastatin was associated with the greatest risk of AEs and fluvastatin with the least risk. Simvastatin, pravastatin, and lovastatin had similar odds of AEs. Nonurgent AEs such as myalgia and liver function elevations were responsible for approximately two thirds of AEs reported in trials. CONCLUSIONS: Statin therapy was associated with greater odds of AEs compared with placebo but with substantial clinical benefit. Similar rates of serious AEs were observed between statin and placebo.

Platelet inhibitors in non-ST-segment elevation acute coronary syndromes and percutaneous coronary intervention: glycoprotein IIb/IIIa inhibitors, clopidogrel, or both?

The role of glycoprotein (Gp) IIb/IIIa receptor antagonists remains controversial and these agents are infrequently utilized during non-ST-segment elevation acute coronary syndromes (NSTE-ACS) despite American Heart Association/American College of Cardiology guidelines. Despite recommendations, the NRMI-4 (National Registry of Myocardial Infarction 4) and CRUSADE (Can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the ACC/AHA guidelines?) registries observed that only 25%-32% of eligible patients received early Gp IIb/IIIa therapy, despite a 6.3% absolute mortality reduction in NRMI-4 and a 2% absolute mortality reduction in CRUSADE. A pooled analysis of Gp IIb/IIIa data from these registries suggest a major reduction in mortality (Odds Ratio = 0.43, 95% Confidence Index 0.25-0.74, p = 0.002) with early Gp IIb/IIIa therapy, yet clinicians fail to utilize this option in NSTE-ACS. The evidence-based approach to NSTE-ACS involves aspirin, clopidogrel, low-molecular weight heparins, or unfractionated heparin in concert with Gp IIb/Ila receptor antagonists, however, newer percutaneous coronary intervention (PCI)-based trials challenge current recommendations. Novel strategies emerging in NSTE-ACS include omitting Gp IIb/Ila inhibitors altogether or using Gp IIb/IIIa inhibitors with higher doses of clopidogrel in selected patients. The ISAR-REACT (Intracoronary stenting and antithrombotic regimen-Rapid early action for coronary treatment) and ISAR-SWEET (ISAR-Is abciximab a superior way to eliminate elevated thrombotic risk in diabetics) trials question the value of abciximab when 600 mg of clopidogrel concurrently administered during PCI. The CLEAR-PLATELETS (Clopidogrel loading with eptifibatide to arrest the reactivity of platelets) and PEACE (Platelet activity extinction in non-Q-wave MI with ASA, clopidogrel, and eptifibatide) trials suggest more durable platelet inhibition when Gp IIb/IIIa inhibitors are used with higher doses clopidogrel. The ISAR-COOL (ISAR: Cooling off strategy) trial found no difference in ischemic outcomes when Gp IIb/IIIa inhibitors were excluded and ARMYDA-2 (Antiplatelet therapy for reduction of myocardial damage during angioplasty) suggested higher doses of clopidogrel are more appropriate during PCI when Gp IIb/IIIa inhibitors are not utilized. This constellation of new trials forces reconsideration of current recommendations in regards to patient risk stratification, choice of antithrombotic therapy, doses, and timing. These new data will impact emerging guidelines and updates are currently in progress.

Rapid progression of familial amyloidotic polyneuropathy: a multinational natural history study.

OBJECTIVES: To assess the association between severity of neuropathy and disease stage, and estimate the rate of neuropathy progression in a retrospective cross-sectional analysis of a multinational population of patients with familial amyloidotic polyneuropathy (FAP). METHODS: We characterize neuropathy severity and rate of progression in available patients with FAP in France, the United States, Portugal, and Italy. Neuropathy Impairment Scores (NIS), time from symptom onset to NIS measurement, polyneuropathy disability (PND) scores, FAP disease stage, and manual grip strength data were collected. We estimated neuropathy progression using Loess Fit and Gompertz Fit models. RESULTS: For the 283 patients studied (mean age, 56.4 years), intercountry genotypic variation in the transthyretin (TTR) mutation was observed, with the majority of patients in Portugal (92%) having early-onset Val30Met-FAP. There was also marked intercountry variation in PND score, FAP stage, and TTR stabilizer use. NIS was associated with PND score (NIS 10 and 99 for scores I and IV, respectively; p < 0.0001) and FAP stage (NIS 14 and 99 for stages 1 and 3, respectively; p < 0.0001). In addition, there was an association between NIS and TTR genotype. The estimated rate of NIS progression for a population with a median NIS of 32 was 14.3 points/year; the corresponding estimated rate for the modified NIS+7 is 17.8 points/year. CONCLUSIONS: In a multinational population of patients with FAP, rapid neuropathic progression is observed and the severity of neuropathy is associated with functional scales of locomotion.

Antifactor Xa levels in four patients with burn injuries who received enoxaparin to prevent venous thromboembolism.

Four patients with severe burn injuries received enoxaparin 40 mg twice/day subcutaneously for the prophylaxis of venous thromboembolism (VTE). Peak antifactor Xa levels were measured 4 hours after administration of a dose, and trough antifactor Xa levels were measured 30 minutes before the next scheduled dose. Ultrasonography was performed once/week to assess the presence of VTE. Any occurrence of major bleeding was documented in the patients' charts. All patients had trough antifactor Xa levels below 0.1 U/ml. Enoxaparin dosages were subsequently adjusted to achieve trough antifactor Xa levels of 0.1-0.2 U/ml. This required dosages higher than those typically recommended for VTE prophylaxis (40 mg every 24 hrs or 30 mg every 12 hrs). One patient needed more than 60 mg every 12 hours. No patient had a venous thromboembolic event or major bleeding. The low antifactor Xa levels that were observed suggest that a reduced dose-response relationship may exist between subcutaneously administered enoxaparin and antifactor Xa activity in patients with severe burn injuries. Prospective studies should be performed to further investigate this relationship.

Sirolimus-eluting coronary stent.

PURPOSE: The mechanism of action and pharmacokinetics of sirolimus when used as part of a drug-eluting stent (DES) and the efficacy and cost of using DESs versus bare-metal stents are discussed. SUMMARY: The use of balloon angioplasty with or without coronary artery stenting is limited by the phenomenon of in-stent restenosis (ISR). Until very recently, most efforts to overcome ISR had been ineffective. The search to prevent or reduce the frequency of ISR has led to the recent development of novel coronary artery stents designed to deliver a drug that acts locally. The first DES was approved by FDA in April 2003. This stent releases sirolimus, an agent that inhibits vascular smooth-muscle-cell proliferation. To date, four major clinical trials have demonstrated the sirolimus-eluting stent to be safe and effective in preventing restenosis in de novo coronary artery lesions. CONCLUSION: The sirolimus-eluting coronary stent is associated with less ISR than non-drug-containing stents, but further investigation is needed to determine its exact place in the treatment of coronary artery occlusion.

HMG-CoA reductase inhibitors for lowering elevated levels of C-reactive protein.

PURPOSE: Clinical trials evaluating the effectiveness of therapy with hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors for reducing elevated C-reactive protein (CRP) levels and associated coronary events are reviewed. SUMMARY: Atherosclerotic plaque growth may be attenuated with therapy aimed at minimizing inflammation. Because increased levels of CRP have been associated with arterial-wall inflammation, statins can prevent ischemia by both inhibiting deposition of lipids and decreasing inflammation. Evaluation of recent clinical trials, including WOSCOPS, PRINCE, AFCAPS/ TexCAPS, MIRACL, CURVES, REVERSAL, and JUPITER, demonstrated the correlation of statin therapy with decreased levels of CRP. WOSCOPS found that patients with CRP values of > 4.59 mg/L at baseline were at the highest risk of coronary events. The PRINCE trial evaluated the antiinflammatory effects of pravastatin and found a mean 16.9% reduction in CRP levels after 24 weeks of therapy. AFCAPS/TexCAPS researchers found that lovastatin provded a 14.8% reduction in the median levels of CRP (p < 0.001). The MIRACL study showed that atorvastatin reduced CRP levels by 83% (p < 0.001). Researchers in the CURVES study found a significant reduction in CRP levels with pravastatin, simvastatin, and atorvastatin compared with baseline (p < 0.025). Results of the REVERSAL study linked atorvastatin with a 36.4% decrease in CRP levels, while pravastatin was associated with a 5.2% decrease (p < 0.0001). JUPITER is ongoing and will determine whether long-term use of rosuvastatin can reduce the rate of coronary events. CONCLUSION: The lowering of elevated CRP levels by statins may reduce the risk of coronary events independently of the effect of statins on lipid levels.

Fluconazole- and levofloxacin-induced torsades de pointes in an intensive care unit patient.

Patients initiated on fluconazole and levofloxacin should be closely monitored for QTc-interval prolongation. While there have been published reports of fluconazole and levofloxacin causing QTc-interval prolongation when given alone, coadministration of these two agents may further increase this risk. This case describes an episode of TdP in which levofloxacin and fluconazole were likely significant factors. QT prolongation was present at baseline prior to drug initiation (QTc = 454-505 ms) and levofloxacin resulted in further prolongation (QTc = 480-536 ms). After two days of therapy with fluconazole, overlapping with levofloxacin, the patient had an episode of PMVT with syncope, and progressive QT prolongation was evident (QTc = 554 ms). Only mild hypokalemia (potassium concentration = 3.6 meq/L) was present, and not additional etiologies for TdP were identified. Levofloxacin and fluconazole were discontinued and no further PMVT was observed, but the QT interval did not return to normal until after an additional 11 days (QTc = 436 ms). As in many cases of TdP, multiple factors were involved. Renal failure, drug dosing, mild hypokalemia, and a baseline abnormal QT interval potentiated the role of levofloxacin and fluconazole in the development of TdP. We recommend that neither drug be used alone or in combination when there is baseline QT prolongation. We also recommend that concomitant use of these agents be avoided when possible. If combination therapy is required, caution is warranted, particularly in patients with risk factors for QT prolongation. Specific attention should be given to drug dosing, interactions, electrolytes, and ECG monitoring.

Outpatient consolidation treatment with clofarabine in a phase 2 study of older adult patients with previously untreated acute myelogenous leukemia.

This report describes outpatient (OP) administration of clofarabine in older patients (≥60 years) with untreated acute myelogenous leukemia (AML). Overall, 112 patients underwent clofarabine induction. Clofarabine was administered to 35 OPs for a total of 72 OP cycles, with 81% of these cycles representing consolidation treatment. Median length of hospital stay was 0-6 days and 5-25 days across OP and inpatient (IP) cycles, respectively. The most common adverse events (AEs) were nausea, vomiting, diarrhea, febrile neutropenia, edema, hypokalemia and pneumonia. The overall frequency of treatment-emergent grade ≥3 AEs and serious AEs was generally not different with IP or OP administration of clofarabine. No deaths were reported within 30 days following OP or IP consolidation cycles. In the appropriately selected older patient, OP administration of clofarabine consolidation appears feasible, is as well tolerated as IP administration and has potential to contribute to the quality of life in elderly patients with AML.

Randomized Trial of a Pharmacist-Delivered Intervention for Improving Lipid-Lowering Medication Adherence among Patients with Coronary Heart Disease.

A randomized trial of a pharmacist-delivered intervention (PI) versus usual care (UC) was conducted; 689 subjects with known coronary heart disease were recruited from cardiac catheterization laboratories. Participants in the PI condition received 5 pharmacist-delivered telephone counseling calls post-hospital discharge. At one year, 65% in the PI condition and 60% in the UC condition achieved an LDL-C level <100 mg/dL (P = .29); mean statin adherence was 0.88 in the PI, and 0.90 in the UC (P = .51). The highest percentage of those who reached the LDL-C goal were participants who used statins as opposed to those who did not use statins (67% versus 58%, P = .05). However, only 53% and 56% of the patients in the UC and PI conditions, respectively, were using statins. We conclude that a pharmacist-delivered intervention aimed only at improving patient adherence is unlikely to positively affect outcomes. Efforts must be oriented towards influencing physicians to increase statin prescription rates.

Lepirudin-induced thrombocytopenia following subcutaneous administration.

PURPOSE: A case of lepirudin-induced thrombocytopenia is reported. SUMMARY: A 61-year-old white man arrived at the emergency department with complaints of pain in his left thigh that worsened with walking. His medical history was significant for extensive thromboses over a period of six months. He had recently been discharged from the hospital for suspected heparin-induced thrombocytopenia (HIT) while on enoxaparin. A venous duplex scan revealed two new deep venous thromboses in the left common, superficial, and popliteal veins. The patient was admitted and initiated on aspirin 325 mg and warfarin sodium 2 mg daily. Intravenous lepirudin with an activated partial thromboplastin time (aPTT) goal of 60-80 seconds was also started. Because of his recurrent thrombotic event, a new International Normalized Ratio (INR) goal of 3.0-3.5 was established for warfarin therapy. Eighteen days after admission, the patient's INR and aPTT were high; therefore, his warfarin dose was reduced and i.v. lepirudin was changed to subcutaneous administration. The patient was transferred to the intensive care unit (ICU) and, 5 days later, he developed melena. During the 7 days of treatment with subcutaneous lepirudin, a drop in platelet counts was observed. Subcutaneous lepirudin was discontinued after resolution of melena, and i.v. lepirudin was restarted. After 15 days, his platelet counts increased and he was switched back to subcutaneous lepirudin, which again led to a drop in platelets. After 27 days in the ICU, the patient's INR and aPTT remained high. Lepirudin was discontinued and i.v. bivalirudin was initiated. His platelet count increased and he was discharged. Eleven days later, the patient was found unresponsive with left-sided fasciculations. The patient died secondary to respiratory arrest as a consequence of intracranial hemorrhage. CONCLUSION: A 61-year-old white man with a history of thromboses and suspected HIT developed thrombocytopenia possibly associated with receiving two courses of subcutaneous lepirudin. Careful monitoring of platelet counts are warranted in patients who have a history of HIT and are receiving subcutaneous lepirudin.

Possible mechanisms of drug-induced aspirin and clopidogrel resistance.

Aspirin (ASA) and clopidogrel have been identified as standard of care in the prevention of major cardiovascular events. Aspirin irreversibly inhibits the cyclooxygenase-1 (COX-1) enzyme, whereas non-steroidal anti-inflammatory drugs (NSAIDs) reversibly inhibit the COX-1 enzyme. An analysis of the literature revealed a statistically significant decrease in clinical benefit of ASA with concomitant administration of ibuprofen. Another NSAID, diclofenac, showed minimal effect on the inhibition of platelet aggregation when administered with ASA. Furthermore, the selective COX-2 inhibitor, rofecoxib, was not shown to influence the effect of ASA. Clopidogrel is metabolized to an active thiol metabolite by the CYP 3A4 enzyme. Some HMG CoA reductase inhibitors have the ability to inhibit the CYP 3A4 enzyme, which can result in a possible interaction if administered concomitantly with clopidogrel. Studies have demonstrated clopidogrel's platelet inhibition being significantly attenuated by atorvastatin. However in a post-hoc analysis, it was demonstrated that there was no difference in clinical outcomes between patients taking clopidogrel and HMG-CoA reductase inhibitors metabolized by and not metabolized by CYP 3A4. Data suggest that the interaction observed involving clopidogrel and HMG-CoA reductase inhibitors appears to be significant in-vitro. Therefore, practitioners should advise patients receiving chronic aspirin therapy to limit the use of ibuprofen and may consider concomitant administration of clopidogrel with HMG-CoA reductase inhibitors without regard for the drug interaction. The intent of this paper is to review the literature discussing possible mechanisms of drug-induced aspirin and clopidogrel resistance and discuss whether the interactions translate into clinical effects.

Emergency management of hemorrhagic complications in the era of glycoprotein IIb/IIIa receptor antagonists, clopidogrel, low molecular weight heparin, and third-generation fibrinolytic agents.

Antithrombotic, antiplatelet, and fibrinolytic agents are the mainstay for the management of patients with acute coronary syndromes (ACS). In addition to their well-documented efficacy, these pharmacologic agents have the potential for the untoward effect of bleeding. Recent data suggest medication errors related to the dose, duration, and concomitant use of these agents contribute to increasing the risk of hemorrhage in patients treated for ACS. In the event of a major hemorrhage, clinicians should be aware of strategies used to reverse the pharmacologic effects of the offending agent. This paper critically assesses literature directed toward reversal of agents based on drug-specific pharmacodynamic and pharmacokinetic parameters.

A review of the clinical uses of ximelagatran in thrombosis syndromes.

Ximelagatran, an oral direct thrombin inhibitor, has been investigated for the prevention and treatment of venous thromboembolism as well as for anticoagulation in atrial fibrillation. Unique properties of ximelagatran are that it is a prodrug, it does not require routine laboratory monitoring and it has minimal drug interactions. The dose of ximelagatran needs to be modified in patients with renal failure; however, dosing guidelines in this specific patient population have not been established. Preliminary and emerging data suggest that ximelagatran is superior or at least as effective as low molecular weight heparins and warfarin in the setting of venous thromboembolism prevention and treatment. Ximelagatran has comparable bleeding rates to low molecular weight heparins and warfarin; however, it is associated with transient elevations in hepatic transaminases.

Possible mechanisms of aspirin resistance.

Data regarding possible mechanisms of aspirin (ASA) resistance in patients with recurrent myocardial infarction (MI) or vascular ischemia are limited. Five major possible mechanisms of ASA resistance are documented in the primary literature and are discussed in this paper. These mechanisms include: (1) inadequate blockade of erythrocyte-induced platelet activation; (2) biosynthesis of F2-isoprostane 8-iso-prostaglandin (PGF2alpha), a bioactive product of arachidonic acid peroxidation; (3) stimulation of platelet aggregation by cigarette smoking; (4) ASA resistant platelet aggregability by increased levels of norepinephrine, as seen during excessive exercise or periods of mental stress; and (5) increased platelet sensitivity to collagen. Recognizing mechanisms of platelet activation and identifying reversible risk factors such as smoking and mental stress may help decrease the occurrence of ASA resistance and possibly improve patient outcomes. Until more definitive data become available, when prescribing and dosing ASA for the prevention of MI or vascular ischemia, clinicians should identify possible risk factors for ASA resistance. Whether or not patients at risk for ASA resistance are candidates for additive antiplatelet therapy remains to be determined.

CD40 ligand: a novel target in the fight against cardiovascular disease.

OBJECTIVE: To discuss the role of CD40 ligand (CD40L) in atherosclerosis and acute coronary syndromes (ACS), as well as describe relevant clinical literature evaluating the effects of pharmacotherapeutic agents on CD40L expression and soluble CD40L levels. DATA SOURCES: A MEDLINE and EMBASE search (1966-September 2003) was conducted using the key terms CD40, CD40 ligand, platelets, inflammation, and drug therapy. Additional primary literature was identified by reviewing the reference lists of relevant original and review papers. STUDY SELECTION AND DATA EXTRACTION: All articles identified in the search were evaluated, and those deemed relevant were incorporated into the review. DATA SYNTHESIS: CD40L is a transmembrane protein expressed on T cells, B cells, mast cells, basophils, eosinophils, natural killer cells, macrophages, endothelial cells, vascular smooth muscle cells, and activated platelets. It is also found in plasma as a soluble protein, sCD40L. As a consequence of CD40L binding to its receptor (CD40), several inflammatory processes are initiated. Studies have demonstrated elevated CD40L levels in patients with hypercholesterolemia and ACS, and elevated sCD40L levels have been associated with increased risk of cardiovascular events. Statins, glitazones, glycoprotein IIb/IIIa inhibitors, and clopidogrel have been demonstrated to effectively reduce CD40L levels both in vitro and in vivo. Abciximab has been shown to reduce the occurrence of death or myocardial infarction during 6 months of follow-up in patients with ACS who had the highest levels of sCD40L. CONCLUSIONS: The proinflammatory and procoagulant protein CD40L represents a novel target in the treatment of atherosclerosis and ACS. A number of therapeutic agents have been shown to modulate the expression of CD40L, findings that could have important clinical applications.

Aspirin resistance and genetic polymorphisms.

Differences in genetic makeup or polymorphisms can affect individual drug response. Detecting genetic variation may help predict how a patient will respond to a drug and could be used as a tool to select optimal therapy, tailor dosage regimens, and improve clinical outcomes. The data are replete relative to the therapeutic efficacy of aspirin (ASA) for the prevention of ischemic events. However, there is a paucity of published data on the relationship between polymorphisms and the clinical effects on ASA. Prothrombotic genetic variations that may contribute to ASA resistance, and increased risk of cardiovascular events may involve: (1) a polymorphism on the cyclooxygenase-1 (COX-1) gene affecting Ser529; (2) overexpression of COX-2 mRNA on platelets and endothelial cells; (3) polymorphism PLA1/A2 of the gene encoding glycoprotein IIIa (GPIIIa); and (4) the homozygous 807T (873A) polymorphism allied with increased density of platelet GP Ia/IIa collagen-receptor gene. Because of the possible increased risk of ischemic vascular events, carriers of these genetic polymorphisms may be resistant to the antithrombotic effects of ASA and should be considered for additional or alternative treatment.