Age, risk-benefit trade-offs, and the projected effects of evidence-based therapies

BACKGROUND: Physicians underutilize evidence-based therapies in the elderly, perhaps because of concerns about the generalizability of clinical trial results in elderly patients given that the relative efficacy of therapies may vary with age. We compared the estimated effects of age and efficacy of treatment on survival among patients with acute coronary syndromes. METHODS: Baseline risk, defined as mortality in the year after hospitalization for acute coronary syndromes, was determined for different age strata among 81,584 patients who had been discharged between April 1, 1997, and March 31, 2000, in Ontario, Canada. We calculated the relative efficacy (relative risk reduction) needed to achieve a clinically meaningful absolute survival benefit, using a number needed to treat of 50 patients for the different age strata. We also evaluated risk-benefit trade-offs in the elderly versus the young by modeling different levels of the relative efficacy and rates of fatal complication by age. RESULTS: Baseline risk (1-year all-cause mortality) was 12-fold lower in the youngest patients (age <50 years) than in oldest patients (age > or = 75 years). Given this gradient, a therapy would have to have a relative efficacy of 88% (i.e., a relative risk of 0.12) in the youngest age group, and 7% (a relative risk of 0.93) in the oldest age group, to generate a number needed to treat 50 patients. For a therapy whose relative efficacy was 25%, the fatal complication rate would have to be sevenfold greater in the oldest compared with the youngest age group to outweigh the survival benefits associated with treatment. CONCLUSION: For acute coronary syndromes, baseline mortality is so much higher for elderly patients that neither sharp reductions in the relative efficacy of therapies nor increases in the rates of serious complications are likely to negate the benefits of therapy. More attention should be paid to overall trial results and less to age-specific subgroup data, unless the latter provide very clear evidence for substantial reductions in absolute efficacy or net harm.     

Low molecular weight heparin (tinzaparin) therapy for moderate risk thromboprophylaxis during pregnancy. A pharmacokinetic study

Low molecular weight heparin (LMWH) is used increasingly for prophylaxis and treatment of venous thromboembolism during pregnancy. However, the prophylactic dose for patients at moderate risk varies between centers, and the recommended LMWH dose for the non pregnant patient is frequently used in pregnant women. The aim of this study was to investigate the effects of pregnancy on the pharmacokinetics of anti-Xa levels during moderate risk thromboprophylaxis with the LMWH, tinzaparin. In 24 pregnant women, one of three doses of tinzaparin (50, 75 or 100 IU/kg) were given according to the treating physician's assessment of their risk profile. Four-hour peak anti-Xa levels were measured throughout pregnancy and 24-hour profiles were measured at 28 and 36 weeks gestation. Doses were adjusted when peak anti-Xa levels fell below 0.1 IU/ml and, in some cases, when levels at 10 and 18 hours post injection were undetectable (<0.05 IU/ml). Our results showed that women receiving tinzaparin (50 IU/kg) frequently had peak (4 hour) anti-Xa levels below 0.1IU/ml and that 46% of these patients required dose adjustment. Similarly anti-Xa levels were also found to be low over the 24-hour period. A starting dose of 75 IU/kg, once daily, gave greater anti-Xa cover over the 24-hour period and may avoid the need for dose adjustment. The results suggest that the pharmacokinetics of tinzaparin are affected by pregnancy. Larger studies are required to determine whether an increased tinzaparin dose (75 IU/kg) would be more effective in the prevention of thrombosis during pregnancy than 50 IU/kg.     

Islet transplantation in the discordant tilapia-to-mouse model: a novel application of alginate microencapsulation in the study of xenograft rejection

BACKGROUND: Tilapia islet xenograft rejection is characterized by infiltration with macrophages (Mphis), eosinophils (Ephis), and T lymphocytes. The presence of these cells indicates they contribute to rejection; therefore, an attempt was made to assess their role through host immunomodulation. METHODS: Tilapia islet cells were transplanted under the kidney capsule of streptozotocin diabetic Balb/c mice, which were then treated with one of several immunomodulatory regimes targeting Mphis, Ephis, or T cells. Mphis were depleted using either silica or liposome-entrapped Cl2MDP. Ephi migration was blocked using monoclonal antibodies (mAbs) targeting interleukin (IL)-4 or IL-5. T-cell function was altered with mAbs targeting CD3, CD4, or CD8. Finally, T helper (Th)1 and Th2 activity was altered by depleting essential Th1 or Th2 cytokines with mAbs or by promoting a Th1 response with the injection of exogenous IL-12. The effects of antibody-mediated immunomodulation on graft survival were initially screened by cotransplanting alginate-encapsulated, mAb-secreting hybridoma cells into the peritoneal cavity at the time of islet transplantation. Significant prolongation was then confirmed using purified antibodies injected at the time of islet transplantation. Rejected grafts were examined histologically, and immunohistochemistry was used to assess the cellular infiltrates for each of the treatment groups. RESULTS: Modulation of Mphis and Ephis alone did not significantly delay functional rejection of tilapia islet grafts (maximal mean graft survival time [mGST]=7.1+/-1.7 and 9.4+/-3.4, respectively) compared with untreated controls (mGST=8.2+/-1.0). Treatment of transplanted animals with antibodies against CD3 or CD4 significantly promoted graft survival (maximal mGST=16.3+/-5.8 and 34.0+/-11.6, respectively), whereas targeting CD8 and Th1 and Th2 cytokines showed no prolonging effect (maximal mGST=7.8+/-2.9 and 9.5+/-4.3, respectively). CONCLUSION: Our results indicate that rejection in the tilapia-to-mouse model follows a pattern similar to other models of discordant islet cell xenotransplantation.     

Developmental anomaly of the inferior vena cava

Despite the many possible modes of presentation, congenital anomalies of the inferior vena cava are increasingly being found in asymptomatic patients. Although plain chest radiography may reveal enough suggestive signs, the diagnosis is usually confirmed by ultrasound, computed tomography and magnetic resonance imaging. The authors present a case of infrarenal absence of the inferior vena cava that presented as a retroperitoneal mass and discuss the embryology and clinical implications of this unusual entity.     

Acute allergic reaction due to the administration of fibrinolytic therapy for ST-segment elevation myocardial infarction: case report and discussion

Although a rare phenomenon, acute allergic reactions to fibrinolytic and heparin therapy have been described in the literature. We report the case of a 63-year-old woman who experienced a severe anaphylactic reaction while undergoing fibrinolytic therapy with tissue plasminogen activator for an ST-segment elevation myocardial infarction. Overall outcome was successful, but patient morbidity was increased because of the reaction and the subsequent therapy administered.     

Dielectric Analysis of Phosphorylcholine Head Group Mobility in Egg Lecithin Liposomes

Purpose. A knowledge of the interfacial properties of lecithin underpins our understanding of many of the physicochemical characteristics of drug delivery systems such as liposomes and lecithin stabilized microemulsions. In order to further this understanding, a high frequency dielectric study of the interfacial properties of egg lecithin liposomes was undertaken. Methods. The effect of temperature, lecithin concentration and probe sonication on the interfacial dielectric properties of liposomal suspensions was investigated by high frequency dielectric relaxation spectroscopy between 0.2–6 GHz. Results. The frequency dependent permittivity of each suspension exhibited a dielectric dispersion centred around 100 MHz, corresponding to the relaxation of zwitterionic head groups. The activation energy for head group reorientation was estimated as H = 6.3 kJ mol^–1. There was an increase in extent of inter-head group interactions on increasing the liposome volume fraction, whereas the effect of probe sonication showed that: (i) head groups in both the outer and inner lamellae contribute to the dielectric response; (ii) the head groups may be less restricted in liposomes of high surface curvature with few lamellae; (iii) the high frequency permittivity of the suspension increased on sonication, as a result of a reduction in the amount of (depolarized) interlamellar water following a reduction in the number of lamellae per liposome. Conclusions. Dielectric analysis of the zwitterionic head groups of lecithin therefore provides a means for investigating the surface of lecithin liposomes, and may be used to investigate the effect of drugs and other solutes on membranes.