Development of aspirin resistance in persons with previous ischemic stroke.

BACKGROUND AND PURPOSE: The ex vivo effect of aspirin (ASA) on platelet aggregation, the platelet component of thrombosis, was studied at repeated intervals in a cohort of patients taking aspirin for recurrent ischemic stroke prevention to define the maintenance of efficacy over time. METHODS: We administered increasing doses of aspirin (from 325 to 1300 mg/d) to patients with previous ischemic stroke and determined the extent of inhibition of platelet aggregation after 2 weeks and thereafter at approximately 6-month intervals. RESULTS: Over 33 months, 306 patients had platelet aggregation studies performed to define their initial response to ASA therapy. Of these, 228 had complete and 78 had partial inhibition of platelet aggregation at initial testing. To date, 119 of those who had complete inhibition and 52 who had partial inhibition have undergone repeat testing at least once. At repeat testing 39 of the 119 (32.7%) with complete inhibition at initial testing had lost part of the antiplatelet effect of ASA and converted from complete to partial inhibition without change in ASA dosage. Of the 52 with partial inhibition at initial testing, 35 achieved complete inhibition either by ASA dosage escalation (in 325 mg/d increments) or fluctuation of response at the same dosage, but 8 of those 35 (22.8%) had reverted to partial inhibition when tested again. Overall, 8.2% of patients ultimately exhibited ASA resistance to 1300 mg/d-8 of 52 (15.4%) with partial inhibition and 6 of 119 (5.0%) with complete inhibition at initial testing. CONCLUSIONS: The antiplatelet (and presumably the antithrombotic) effect of a fixed dose of ASA is not constant over time in all individuals. The mechanisms by which increased dosage requirement or ASA resistance develops and the clinical significance of this development are currently undefined.

Elective cyclosporine withdrawal 1 year after renal transplantation.

Whether the risks of acute rejection after elective cyclosporine (CsA) withdrawal in renal transplantation outweigh the potential benefits is unclear. We examined results for 236 patients who underwent transplantation between January 1986 and June 1991. Patients were treated with prophylactic CsA, prednisone, and azathioprine, and had grafts that functioned at least 1 year. We elected to withdraw CsA after 1 year in 192 patients who were rejection free for 12 months. Thirty-four patients elected to continue CsA. In 1988 a protocol that tapered CsA over 6 weeks was abandoned when eight (29.6%) of the first 27 patients developed acute rejection within 6 months. We then adopted a 12-week CsA taper preceded by 1 month of increased azathioprine (2.5 mg/d as tolerated) and followed by increased prednisone (30 mg/d for 1 week, 20 mg/d for 1 week, 15 mg/day for 6 months, then 15 mg/d on alternate days). With this protocol the incidence of postwithdrawal acute rejection within 6 months was reduced to 9.1% among 165 patients (P < 0.01 v 6-week taper). Actuarial 5-year graft survival (patients living with a functioning graft) was 81.7% for patients left on CsA, 88.9% for patients tapered over 6 weeks, and 81.5% for patients tapered over 12 weeks (P > 0.05). We also examined risk factors for acute rejection after CsA withdrawal using a Cox proportional hazards model and found that the relative risk of acute rejection within 6 months of taper was approximately two times greater for each DR mismatch (P < 0.001). We conclude that CsA withdrawal has not affected renal allograft survival at our center.(ABSTRACT TRUNCATED AT 250 WORDS)

Stroke prophylaxis: hypertension management and antithrombotic therapy.

OBJECTIVE: To review trials involving risk factor management and pharmacologic therapy for the prevention of stroke. DATA SOURCES: English-language literature published between 1966 and 1992 was analyzed; pertinent literature is reviewed. STUDY SELECTION: Studies that evaluated the impact of risk factor management on prevention of vascular events were selected. In addition, trials assessing the safety and efficacy of pharmacologic intervention in primary and secondary stroke prevention were evaluated. DATA EXTRACTION: Trials were evaluated for their ability to demonstrate a decrease in stroke occurrence. DATA SYNTHESIS: Various trials were analyzed in several categories. Studies evaluating risk factor management of hypertension and cardiogenic cerebral emboli were reviewed and recommendations made based on a consensus of these trials. The use of antiplatelet agents in stroke prevention was addressed by a review of pertinent trials and meta-analyses. CONCLUSIONS: The control of risk factors and the use of antiplatelet agents significantly reduces the risk of vascular events. Benefit from different therapies may be specific to certain patient populations and recommendations are made for these patients.

Aspirin response and failure in cerebral infarction.

BACKGROUND AND PURPOSE: The purpose of this study was to assess the biological effect of aspirin as measured by the inhibition of platelet aggregation in patients taking aspirin for stroke prevention and in patients with acute stroke. METHODS: We administered increasing doses of aspirin (325, 650, 975, and 1,300 mg daily) to 113 patients for stroke prevention and measured the inhibition of platelet aggregation in these patients and in 33 patients with acute stroke taking aspirin before stroke onset. RESULTS: Eighty-five patients on < or = 325 and six on > or = 650 mg aspirin had complete inhibition of platelet aggregation. Increase of the dose by 325 mg in nine of the 22 patients with partial inhibition of platelet aggregation produced complete inhibition in five patients at 650 mg and in one at 975 mg. At 1,300 mg, three patients still had only partial inhibition of platelet aggregation (aspirin resistance). Of the 33 inpatients with acute stroke, 24 had platelet aggregation studies done before further administration of aspirin. Of these, 19 had complete inhibition of platelet aggregation and three had partial inhibition, with production of complete inhibition of platelet aggregation at dose escalation; one patient was aspirin-resistant and the other noncompliant. CONCLUSIONS: How the inhibition of platelet aggregation relates to stroke prevention remains unclear. The ability of aspirin and the dose required to inhibit platelet aggregation may depend upon the individual.

The adverse impact of cyclosporine on serum lipids in renal transplant recipients.

The extent to which cyclosporine (CsA) directly, or indirectly, influences serum lipid levels in renal transplant patients treated with multiple-drug immunosuppression protocols is unclear. Indeed, patients treated with CsA have reduced corticosteroid requirements, fewer acute rejection episodes, and other differences from patients receiving conventional immunosuppression that may reduce serum lipid levels. We studied patients treated with low-dose CsA, corticosteroids, azathioprine, and Minnesota antilymphocyte globulin ([ALG] n = 205) versus conventional (three-drug) immunosuppression (n = 368) and evaluated the impact of CsA, acute rejection episodes, and other clinical parameters on serum lipids. Fasting serum lipid levels from stable patients transplanted between 1976 to 1989 were studied at 3 (n = 573), 12 (n = 565), 26 (n = 55), and 52 (n = 521) weeks posttransplant using multivariate, linear regression analysis. The incidence of acute rejection episodes was reduced by CsA, but patients with fewer acute rejection episodes in the early posttransplant period had higher serum total cholesterol (increased by .33 +/- .12 mmol/L [13 +/- 5 mg/dL] and .27 +/- .12 mmol/L [10 +/- 5 mg/dL], P less than 0.05, at 3 and 12 weeks, respectively) and low-density lipoprotein (LDL) (increased by .23 +/- .11 mmol/L [9 +/- 4 mg/dL] and .23 +/- .11 mmol/L [9 +/- 4 mg/dL], P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The variable nature of chronic declines in renal allograft function.

Despite having important implications for the design of therapeutic trials, the clinical setting, time of onset, and rate of progression for chronic declines in renal allograft function have not been well characterized. In the present investigation, monthly estimates of glomerular filtration rate (E-GFR) were made using creatinine clearance and interim serum creatinine levels. There were 200 patients transplanted from 1978 to 1982 (precyclosporine) who survived at least 12 months with a functioning allograft. Of these, 25 had irreversible declines in E-GFR (greater than 30%) attributable to acute rejection, 50 had gradual, chronic declines in E-GFR, and 125 maintained stable function. Patients with chronic declines in E-GFR more often returned to dialysis (56%, P less than 0.001) than those with irreversible, acute reductions (24%), or stable function (2%). Chronic declines in allograft function were modeled by one or two least-squares-fitted regression lines. In most cases, the onset was early, but in 26% chronic declines in E-GFR began 2.2 +/- 1.2 (mean +/- SD) years after transplantation. Among those with chronic declines in E-GFR, 20/50 (40%) had spontaneous improvements in the rate of progression after 2.7 +/- 1.1 years and survived 8.4 +/- 2.6 years with functioning grafts, while 30/50 (60%) continued to have progressive declines in E-GFR and survived 6.1 +/- 2.5 years (P less than 0.01). Although chronic declines in E-GFR were evident 3.2 +/- 1.7 years before graft failure, routinely measured clinical and laboratory parameters from the early posttransplant period failed to predict patients who developed chronic declines in E-GFR. Altogether these data suggest that chronic declines in allograft function have an unpredictable onset and variable clinical course.

The effects of calcium channel blockers on cyclosporine and its metabolites in renal transplant recipients.

Although calcium channel blockers have been reported to increase trough cyclosporine (CsA) blood levels, few studies have systematically examined the effects of calcium channel blockers on CsA pharmacokinetics. In the present investigation, complete pharmacokinetic profiles of CsA and its major metabolites (M1, M17, and M21) were determined in 11 verapamil-treated patients, 7 nifedipine-treated patients, and in 78 controls. Whole blood and urine levels were analyzed using high-performance liquid chromatography. Verapamil caused a 45% increase in CsA area under the curve, maximum concentration, steady-state concentration, and trough level. Metabolite 17 levels were increased in a parallel fashion, suggesting that altered CsA bioavailability rather than decreased metabolism may have caused the higher CsA levels in verapamil-treated patients. However, verapamil-induced reductions in CsA metabolism by other routes could not be ruled out. No changes in CsA or its metabolites were observed in nifedipine-treated patients. Unlike previous reports in patients treated with higher CsA doses, verapamil and nifedipine did not improve renal function in the present study. Nevertheless, the increase in CsA blood levels seen with verapamil may enhance the therapeutic cost-effectiveness of this agent in hypertensive renal transplant recipients.

Lovastatin treatment of hypercholesterolemia in renal transplant recipients.

The treatment of hypercholesterolemia in renal transplant recipients has been problematic. In the present double-blind study, 11 patients were treated with diet for at least 4 weeks. They were then randomized to placebo or the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, lovastatin (20 mg/day) for 6 weeks, followed by crossover to an additional 6 weeks of lovastatin or placebo. All patients had stable allograft function 8.4 +/- 1.2 years (mean +/- SEM) after transplantation, and received low-dose prednisone and azathioprine immunosuppression. Compared with diet alone, lovastatin caused a 21% reduction in total cholesterol from 307 +/- 14 mg/dL to 244 +/- 13 mg/dL (P less than 0.05). Lovastatin reduced LDL cholesterol 28% from 214 +/- 12 mg/dL to 155 +/- 11 mg/dL (P less than 0.05). Trends toward favorable changes in HDL cholesterol, serum triglycerides, and apolipoproteins were not statistically significant. Liver enzymes, creatine phosphokinase, and renal function remained stable. With lovastatin there was a 27% increase in the WBC (from 6220 +/- 530 cells/mm3 to 7780 +/- 510 cells/mm3, P less than 0.05) that was attributable to a 45% increase in neutrophils (P less than 0.05). This effect of lovastatin, possibly the result of reduced azathioprine bone marrow suppression, could have important implications for immunosuppressive therapy in this patient population. Altogether, these results suggest that lovastatin may be a safe and effective treatment for hypercholesterolemia in renal transplant recipients receiving conventional immunosuppression.

Polyvalent immune globulin and cytomegalovirus infection after renal transplantation.

To determine whether polyvalent, immune globulin (IgG) prevents cytomegalovirus (CMV) infection after cadaver renal transplantation, 28 patients were randomly allocated to receive 12 weekly infusions of 500 mg/kg of IgG (n = 15) or no treatment (n = 13). Both groups were similar with respect to age, sex, antigen mismatches, number of diabetics, and pretransplant donor/recipient CMV antibody titers. Moderately severe CMV infections occurred in 10 (77%) of 13 control subjects compared with 8 (53%) of 15 IgG-treated patients (not significant). Among those who developed CMV infections, prophylactic IgG had no effect on the severity or duration of fever, leukopenia, or hepatic enzyme elevations. Since none of the IgG-treated patients or control subjects in this study developed life-threatening CMV complications, a beneficial effect of prophylactic IgG in the small number of patients at risk for more severe CMV infections could not be excluded. However, this investigation suggests that the routine, prophylactic administration of polyvalent IgG, to prevent or to ameliorate CMV infection in unselected cadaver renal transplant recipients, is not warranted.

Clinical features and treatment of Lyme disease.

Lyme disease is caused by the spirochete Borrelia burgdorferi, which is carried by infected ticks. This disorder has a variable clinical course with multisystem manifestations, including dermatologic, neurologic, cardiac, and rheumatologic abnormalities. Although Lyme disease has been commonly associated with stages, the utility of staging may be limited due to the inconsistency of clinical manifestations among patients. Furthermore, stages may overlap as a result of the acute and chronic phases of the disease. The laboratory characteristics of Lyme disease are highly variable. The use of microbiologic cultures in establishing the diagnosis requires several weeks and has a low yield of positivity. Serologic assays using indirect immunofluorescence and enzyme-linked immunosorbence are preferred. Because of the highly variable features of Lyme disease, clinical and laboratory features must be correlated and interpreted in the context of the disease. Treatment should be initiated as early as possible after the onset of illness. Prompt therapeutic intervention may result in early resolution of the dermatologic hallmark, erythema chronicum migrans, as well as prevention and attenuation of subsequent complications.