Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction

Background:

Patients prescribed antiplatelet treatment to prevent recurrent acute myocardial infarction are often also given a selective serotonin reuptake inhibitor (SSRI) to treat coexisting depression. Use of either treatment may increase the risk of bleeding. We assessed the risk of bleeding among patients taking both medications following acute myocardial infarction.

Methods:

We conducted a retrospective cohort study using hospital discharge abstracts, physician billing information, medication reimbursement claims and demographic data from provincial health services administrative databases. We included patients 50 years of age or older who were discharged from hospital with antiplatelet therapy following acute myocardial infarction between January 1998 and March 2007. Patients were followed until admission to hospital due to a bleeding episode, admission to hospital due to recurrent acute myocardial infarction, death or the end of the study period.

Results:

The 27 058 patients in the cohort received the following medications at discharge: acetylsalicylic acid (ASA) (n = 14 426); clopidogrel (n = 2467), ASA and clopidogrel (n = 9475); ASA and an SSRI (n = 406); ASA, clopidogrel and an SSRI (n = 239); or clopidogrel and an SSRI (n = 45). Compared with ASA use alone, the combined use of an SSRI with antiplatelet therapy was associated with an increased risk of bleeding (ASA and SSRI: hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.08–1.87; ASA, clopidogrel and SSRI: HR 2.35, 95% CI 1.61–3.42). Compared with dual antiplatelet therapy alone (ASA and clopidogrel), combined use of an SSRI and dual antiplatelet therapy was associated with an increased risk of bleeding (HR 1.57, 95% CI 1.07–2.32).

Interpretation:

Patients taking an SSRI together with ASA or dual antiplatelet therapy following acute myocardial infarction were at increased risk of bleeding.Antiplatelet agents such as acetylsalicylic acid (ASA) and clopidogrel are a mainstay of therapy following acute myocardial infarction. These agents are effective in reducing the risk of recurrent acute myocardial infarction and other cardiovascular events, with the potential for additive benefit when used in combination.^1–3 The risk of bleeding associated with their use, however, is of concern.^4–6 This risk may be increased further by the frequent concomitant use of other medications associated with an increased risk of bleeding, such as anticoagulant therapy⁷ and selective serotonin reuptake inhibitors (SSRIs).Up to 20% of patients with cardiovascular disease experience depression and are most often prescribed an SSRI.^8–13 The vast majority of these patients also use antiplatelet therapy. The risk of bleeding associated with combining SSRI therapy with single or dual antiplatelet therapy is uncertain. Two large clinical trials that examined SSRI use following acute myocardial infarction did not specifically report on the risk of bleeding,^14,15 and earlier studies suggested no increase in risk associated with SSRI therapy combined with single-agent antiplatelet therapy.^16,17SSRI use itself has been associated with an increased risk of bleeding, particularly during the first month of use.¹⁸ The inhibition of serotonin transporters by SSRIs is thought to be responsible for the risk of bleeding.¹⁹ Platelets release serotonin at sites of bleeding and vascular damage; however, they do not synthesize serotonin and instead acquire it from the blood and store it.^19,20 By this mechanism, SSRIs may also worsen the bleeding caused by ASA and clopidogrel.^19,20 Inhibition of cytochrome P450 by certain SSRIs has also been associated with increased risk of drug interaction causing bleeding;²¹ however, data on this issue are scarce.We examined the risk of bleeding associated with the use of SSRIs when combined with single and dual antiplatelet therapy among patients following acute myocardial infarction.     

Viral expression directs the fate of B cells in bovine leukemia virus-infected sheep

The host immune response is believed to tightly control viral replication of deltaretroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV). However, this assumption has not been definitely proven in vivo. In order to further evaluate the importance of the immune response in the BLV model, we studied the fate of cells in which viral expression was transiently induced. Using a dual fluorochrome labeling approach, we showed that ex vivo induction of viral expression induces higher death rates of B cells in vivo. Furthermore, cyclosporine treatment of these animals indicated that an efficient immune response is required to control virus-expressing cells.     

Clathrin triskelia show evidence of molecular flexibility

The clathrin triskelion, which is a three-legged pinwheel-shaped heteropolymer, is a major component in the protein coats of certain post-Golgi and endocytic vesicles. At low pH, or at physiological pH in the presence of assembly proteins, triskelia will self-assemble to form a closed clathrin cage, or “basket”. Recent static light scattering and dynamic light scattering studies of triskelia in solution showed that an individual triskelion has an intrinsic pucker similar to, but differing from, that inferred from a high resolution cryoEM structure of a triskelion in a clathrin basket. We extend the earlier solution studies by performing small-angle neutron scattering (SANS) experiments on isolated triskelia, allowing us to examine a higher q range than that probed by static light scattering. Results of the SANS measurements are consistent with the light scattering measurements, but show a shoulder in the scattering function at intermediate q values (0.016 Å⁻¹), just beyond the Guinier regime. This feature can be accounted for by Brownian dynamics simulations based on flexible bead-spring models of a triskelion, which generate time-averaged scattering functions. Calculated scattering profiles are in good agreement with the experimental SANS profiles when the persistence length of the assumed semiflexible triskelion is close to that previously estimated from the analysis of electron micrographs.     

Earlier Onset of δ-Retrovirus-Induced Leukemia after Splenectomy

Infection by δ-retroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) is mostly asymptomatic. Indeed, only a minority (<5%) of δ-retrovirus infected hosts will develop either lymphoproliferative or neurodegenerative diseases after long latency periods. In fact, the host immune response is believed to tightly control viral replication but this assumption has not been definitely proven in vivo. Here, we provide direct experimental evidence demonstrating that integrity of the spleen is required to control pathogenesis. In the BLV model, we show that asplenia decreases efficiency of the immune response and induces an imbalance in cell dynamics resulting in accelerated onset of leukemia. These observations enlighten a potential threat in splenectomized HTLV-1 carriers and justify a regular preventive evaluation.     

Detection of viral genomes of caprine arthritis-encephalitis virus (CAEV) in semen and in genital tract tissues of male goat

The aim of this study was to determine the infectious status of semen and genital tract tissues from male goat naturally infected with the caprine lentivirus. Firstly, polymerase chain reaction (PCR) was used to detect the presence of CAEV proviral-DNA in the circulating mononuclear cells, semen (spermatozoa and non-spermatic cells), and genital tract tissues (testis, epididymis, vas deferens, and vesicular gland) of nine bucks. RT-PCR was used to detect the presence of CAEV viral RNA in seminal plasma. Secondly, in situ hybridization was performed on PCR-positive samples from the head, body, and tail of the epididymis. CAEV proviral-DNA was identified by PCR in the blood cells of 7/9 bucks and in non-spermatic cells of the seminal plasma of 3/9 bucks. No CAEV proviral-DNA was identified in the spermatozoa fraction. The presence of CAEV proviral-DNA in non-spermatic cells and the presence of CAEV in the seminal plasma was significantly higher (p<0.01) in bucks with PCR-positive blood. Two of the three bucks with positive seminal plasma cells presented with at least one PCR-positive genital tract tissue. Proviral-DNA was found in the head (3/9), body (3/9), and tail (2/9) of the epididymis. In situ hybridization confirmed the presence of viral mRNA in at least one of each of these tissues, in the periphery of the epididymal epithelium. This study clearly demonstrates the presence of viral mRNA and proviral-DNA in naturally infected male goat semen and in various tissues of the male genital tract.     

Identification of a novel protease from the thermophilic Anoxybacillus kamchatkensis M1V and its application as laundry detergent additive

Extremophiles - A thermostable extracellular alkaline protease (called SAPA) was produced (4600&nbsp;U/mL) by Anoxybacillus kamchatkensis M1V, purified to homogeneity, and biochemically...     

Magneto‐optical characteristics of human sperms: normal and deformed

In this study we report on magnetic orientation of human sperms. Samples were taken from 17 donors. Normal human sperms became oriented with their long axis perpendicular to the magnetic field (1 T maximum). Total orientation was achieved with magnetic field of about 1 T, while for abnormal sperms the magnetic behavior was different. The dependence of the measured degree of orientation on the intensity of the magnetic field was in good agreement with the theoretical equation for the magnetic orientation of diamagnetic substances. As a result of a numerical analysis based on the equation, the anisotropic diamagnetic susceptibility of normal sperm was found to be Δ_χ = 8 × 10^–20 J/T². The degree of orientation was influenced by the alterations in the shape of the head, body or the tail. It has been suggested that the DNA in the sperm head retain the strong magnetic anisotropy to counterbalance the magnetic anisotropy retained by flagellum microtubules. Recent studies demonstrated a well‐defined nuclear architecture in human sperm nucleus, where the head morphology has significant correlation with sperm chromatin structure assay SCSA. Then, as the methods to evaluate SCSA can be difficult and expensive our simple magnetic orientation technique can be an alternative to diagnose alteration in DNA. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Postdischarge thromboprophylaxis and mortality risk after hip-or knee-replacement surgery

Background

Patients undergoing hip or knee replacement are at high risk of developing a postoperative venous thromboembolism even after discharge from hospital. We sought to identify hospital and patient characteristics associated with receiving thromboprophylaxis after discharge and to compare the risk of short-term mortality among those who did or did not receive thromboprophylaxis.

Methods

We conducted a retrospective cohort study using system-wide hospital discharge summary records, physician billing information, medication reimbursement claims and demographic records. We included patients aged 65 years and older who received a hip or knee replace ment and who were discharged home after surgery.

Results

In total we included 10 744 patients. Of these, 7058 patients who received a hip replacement and 3686 who received a knee replacement. The mean age was 75.4 (standard deviation [SD] 6.8) years and 38% of patients were men. In total, 2059 (19%) patients received thomboprophylaxis at discharge. Patients discharged from university teaching hospitals were less likely than those discharged from community hospitals to received thromboprophylaxis after discharge (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.80–1.00). Patients were less likely to receive thromboprophylaxis after discharge if they had a longer hospital stay (15–30 days v. 1–7 days, OR 0.69, 95% CI 0.59–0.81). Patients were more likely to receive thromboprophylaxis if they had hip (v. knee) replacement, osteoarthritis, heart failure, atrial fibrillation or hypertension, higher (v. lower) income or if they were treated at medium-volume hospitals (69–116 hip and knee replacements per year). In total, 223 patients (2%) died in the 3-month period after discharge. The risk of short-term mortality was lower among those who received thromboprophylaxis after discharge (hazard ratio [HR] 0.34, 95% CI 0.20–0.57).

Interpretation

Fewer than 1 in 5 elderly patients discharged home after a hip-or knee-replacement surgery received postdischarge thromboprophylaxis. Those prescribed these medications had a lower risk of short-term mortality. The benefits of and barriers to thromboprophylaxis therapy after discharge in this population requires further study.Venous thromboembolism is a leading cause of mortality among patients in hospital.^1,2 Major orthopedic surgery (e.g., hip or knee replacement) is associated with a high risk for postoperative venous thromboembolism.^1,3,4 Because the clinical diagnosis of venous thromboembolism is unreliable and its first manifestation may be a life-threatening pulmonary embolism,⁵ it is recommended that patients undergoing hip or knee replacement receive routine thromboprophylaxis with anticoagulant therapy after surgery unless they have contraindications to anticoagulant therapy.^1,3,5,6Thromboprophylaxis is commonly administered for the entire hospital stay, which is usually between 4 and 14 days.⁷ Expert consensus guidelines recommend that patients undergoing hip or knee replacement receive thromboprophylaxis medications for at least 10 days after surgery.⁶ These guidelines also recommend extended thromboprophylaxis for up to 28–35 days after surgery for patients undergoing hip replacement.⁶ Although there is evidence that extended thromboprophylaxis after hospital discharge is effective for reducing the risk of venous thromboembolism among patients who undergo hip replacement,⁸ the benefit among patients who undergo knee replacement has not been established.⁶ Thromboprophylaxis after discharge is likely to most benefit patients at high risk for venous thromboembolism, such as those with cancer, heart failure or major respiratory disease.^6–9 However, given that patients who undergo joint replacement are often elderly and have multiple comorbidities, the risks associated with extended thromboprophylaxis, particularly gastrointestinal bleeding and hemorrhagic strokes, may be substantial and may be relative contraindications for this therapy.¹⁰Among patients discharged home after hip-or knee-replacement surgery, we sought characterize the use of thromboprophylaxis after discharge and its consequences on risk of short-term mortality.