Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study.

BACKGROUND: Although hormone replacement therapy (HRT) is associated with an increased risk of deep vein thrombosis (DVT), it is not clear if the risk differs in users of combined estrogen-progestin HRT and estrogen-only HRT. METHODS: We prospectively studied postmenopausal women with suspected DVT in whom HRT use status was ascertained and who subsequently had objective diagnostic testing to confirm or exclude DVT. Cases were patients with idiopathic DVT, in whom there were no DVT risk factors, and controls were patients without DVT, in whom there were also no DVT risk factors. The risk of DVT was determined in users of estrogen-progestin HRT and estrogen-only HRT by comparing the prevalence of current HRT use in cases with idiopathic DVT and controls without DVT (reference group). Multivariable regression analysis was done to adjust for factors that might confound an association between HRT use and the risk of DVT. RESULTS: One thousand one hundred and sixty-eight postmenopausal women with suspected DVT were assessed, from whom 95 cases of idiopathic DVT and 610 controls without DVT and no DVT risk factors were identified. Estrogen-only HRT was associated with an increased risk for DVT that was not statistically significant [odds ratio (OR) = 1.22; 95% confidence interval (CI) 0.57, 2.61]. Estrogen-progestin HRT was associated with a greater than 2-fold increased risk for DVT (OR = 2.70; 95% CI 1.44, 5.07). CONCLUSION: The risk of developing DVT may be higher in users of combined estrogen-progestin HRT than in users of estrogen-only HRT.

Predictors of the post-thrombotic syndrome during long-term treatment of proximal deep vein thrombosis.

BACKGROUND: The post-thrombotic syndrome is a chronic, poorly understood complication of deep venous thrombosis (DVT). OBJECTIVES: To evaluate predictors of the post-thrombotic syndrome, including intensity of long-term anticoagulation, and to assess the impact of the post-thrombotic syndrome on quality of life. PATIENTS AND METHODS: The setting was 13 Canadian hospitals and one US hospital. One hundred and forty-five patients with an unprovoked episode of proximal DVT who were initially treated with 3 months of conventional-intensity warfarin [target International Normalized Ratio (INR) of 2.5] then participated in a trial comparing two intensities of long-term warfarin therapy (target INR 2.5 vs. INR 1.7). Post-thrombotic syndrome was assessed at the end of the trial using a validated clinical scale. Generic and venous disease-specific quality of life was compared in patients with and without the post-thrombotic syndrome. Multivariable regression analyses were performed to identify predictors of the post-thrombotic syndrome and of its severity. RESULTS: After an average follow-up of 2.2 years, the prevalence of post-thrombotic syndrome was 37% and of severe post-thrombotic syndrome was 4%. Quality of life was worse in patients with the post-thrombotic syndrome compared with patients who did not have it. The presence of factor (F)V Leiden or the prothrombin gene mutation was an independent predictor of both a lower risk (P = 0.006) and reduced severity (P = 0.045) of the post-thrombotic syndrome. Intensity of anticoagulation did not influence the risk of developing the post-thrombotic syndrome. CONCLUSIONS: The post-thrombotic syndrome is a frequent and burdensome complication of proximal DVT, even among patients maintained on long-term oral anticoagulation. While the presence of FV Leiden or prothrombin gene mutation appears to be associated with a reduced risk of post-thrombotic syndrome, this finding requires further evaluation in prospective studies.

Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor.

BACKGROUND: The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor. METHODS: In this double-blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow-up. RESULTS: Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) - 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient-year in those who received warfarin for 1 month and 3.2% per patient-year in those who received warfarin for 3 months (rate difference of 3.6% per patient-year; 95% CI - 3.8, 11.0). There were no major bleeds in either group. CONCLUSION: Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding.

[Calcium channel blocking agents and albuminuria in diabetic and hypertensive patients. A pilot study]. / Agents bloqueurs des canaux calciques et albuminurie des sujets diabétiques et hypertendus. Une étude pilote.

UNLABELLED: Diltiazem tends to decrease proteinuria in hypertensive diabetic subjects in comparison to amlodipine that does not modify it. Since estimated glomerular pressure is identical in amlodipine treated and diltiazem treated subjects, differences in albuminuria may be explained by different renal tubular reabsorption rates. OBJECTIVES: To compare plasma clearances (PC) of technetium labeled albumin (albumin-Tc99m) obtained by serial plasma measurements with PC obtained by urinary excretion measurements. Indirectly evaluate tubular reabsorption of albumin-Tc99m. Test the hypothesis that amlodipine decreases renal tubular reabsorption of albumin in diabetic hypertensive subjects. METHODS: Fourteen diabetic and hypertensive subjects (DH) (average plasma creatinine: 94 mmol/L) and 6 normal subjects (average plasma creatinine: 82 mmol/L) had previously been assessed for albumin-Tc99m PC. Eleven of these 14 DH subjects were then randomized to diltiazem 300 mg/daily (6 subjects) or amlodipine 10 mg/daily (5 subjects). Their glomerular filtration, glomerular pressure and albumin-Tc99m PC were then assessed on the 3rd, 6th, and 12th month of the study. RESULTS: Albumin-Tc99m PC obtained from serial blood draws: A decrease in PC between months 0 and 3 from 14 to 10.6 cc/min was observed in subjects treated with amlodipine but subjects on diltiazem showed PC stability (from 11.9 to 12 cm3/min). PC obtained from urinary excretion: Amlodipine and diltiazem treated subjects showed PC stability. Plasma volume in amlodipine treated subjects decreased from 156 to 127% and diltiazem treated subjects from 128 to 117%. CONCLUSION: A decrease in PC obtained with plasma measurements and stability of PC based on urinary excretion measurements tends to identify a decrease in plasma volume. A decrease in albumin-Tc99m tubular reabsorption was not observed. The estimate of albumin PC with Tc 99m labelled albumin measurements still needs to be validated.

Comparison of streptokinase and urokinase in local thrombolysis of peripheral arterial occlusions for lower limb salvage.

PURPOSE: To compare the efficacy and safety of streptokinase (SK) and urokinase (UK) in the treatment of local thrombolysis. PATIENTS AND METHODS: Over a 24-month period, 40 patients with 45 lower limb arterial occlusions of less than 45 days duration underwent intraarterial fibrinolysis. Twenty occlusions were treated with recombinant UK and tissue culture-derived UK, and 25 occlusions were treated with SK. The study was retrospective, but the two groups were very homogeneous in terms of vascular surgical history, medical risk factors, and occlusion characteristics. RESULTS: Complete lysis (95% or more) was achieved in 84% of SK infusions and 89% of UK infusions. Endoluminal and surgical interventions as well as clinical outcomes of SK and UK treatment were comparable. However, infusion time was significantly longer for SK treatment: 28.5 hours versus 19.1 hours for UK treatment (P = .035). Complication rates were not statistically significantly different. Average length of stay in the intensive care unit was identical (2.2 days) for both groups, and the difference in hospital stay was not statistically significant (7.7 days for SK vs 8.7 days for UK). CONCLUSION: At the concentrations and doses used, the efficacy and safety of SK and UK were comparable, despite longer SK infusion time.

Systemic lupus erythematosus is associated with increased auto-antibody titers against calreticulin and grp94, but calreticulin is not the Ro/SS-A antigen.

Auto-antibodies against purified human calreticulin were determined by an ELISA in sera from patients with systemic lupus erythematosus (SLE) and from healthy persons or patients without an autoimmune disease. More than 80% of patients with SLE had titers exceeding the highest value obtained in the group without SLE. Almost 30% of the patients had also elevated auto-antibody titers against purified rat grp94, another resident ER-protein of the KDEL-protein family, but not against rat ERp72 (CaBP2), an ER-resident protein of the proteindisulfide isomerase family. It could, however, be excluded that calreticulin is the Ro/SS-A antigen on the basis of the following observations: 1) Calreticulin purified from rat, bovine or human liver contained far less than 1 mol of phosphate per mol of calreticulin, showed an E280/E260-absorption ratio of about 2.0, and did not contain extractable RNA; 2) Sera from patients with SLE did not react with or precipitate endogenous calreticulin from Hep G2 cells; they did, however, precipitate hY-RNA from these cells; 3) Sera from SLE-patients, but not anti-calreticulin antisera precipitated [32P]-hY-RNA from [32P]-labelled Hep G2 cells.

Hemodynamic and plasma atrial natriuretic factor responses to cardiac volume loading in young versus older normotensive humans.

To assess the effects of age on responsiveness of atrial natriuretic factor (ANF) release, and the possible contribution of cardiac sympathetic activity, in young (n = 8) and older normotensives (n = 7), the effects of cardiac volume load on plasma ANF, central venous pressure, and general hemodynamics were evaluated. Studies were performed after pretreatment with placebo or 80 mg propranolol. Cardiac volume loading increased central venous pressure by 3-5 mmHg (1 mmHg = 133.3 Pa); beta-blockade did not affect this response. Cardiac volume load caused significant increases in heart rate (10-15 beats/min) and cardiac index (by 0.7-0.8 L.min-1.m-2) and decreases in plasma catecholamines. Propranolol attenuated the increases in heart rate and cardiac index. These hemodynamic responses did not differ significantly between the two groups of subjects. Cardiac volume load significantly increased plasma ANF, by 87 +/- 21 pg/mL in the young normotensives and by 212 +/- 33 pg/mL in the older normotensives (p < 0.01, young vs. older). beta-Blockade did not affect this different response. Our results show that the plasma ANF response to volume loading is potentiated by aging. Although differences in atrial stretch cannot be excluded, this effect may relate to the decrease in clearance of plasma ANF occurring with aging.

Beta-blockade with intrinsic sympathetic activity modifies favorably exercise-induced changes in plasma lipoproteins.

The effects of beta-blockade on acute exercise-induced changes in plasma lipoprotein levels were investigated in 12 healthy normotensive subjects by use of beta-blockers of three types: a nonselective agent, a beta 1-selective agent, and a nonselective agent with intrinsic sympathomimetic activity (ISA) or partial agonist activity. Each subject received each drug and a placebo for 1 wk each according to a randomized double-blind crossover design. After placebo, exercise caused 10-20% increases in total plasma cholesterol and the high-density lipoprotein (HDL)-cholesterol fraction. The total-to-HDL cholesterol ratio fell, particularly during the 30-min recovery phase. Pindolol treatment increased resting values of HDL cholesterol (from 43 +/- 4 to 48 +/- 4 mg/dl) and potentiated the response to exercise (to 59 +/- 5 vs. 51 +/- 4 mg/dl after placebo). The total-to-HDL cholesterol ratio was significantly lower after pindolol treatment than after placebo. In contrast, neither atenolol nor timolol affected exercise-induced changes in plasma lipoprotein levels. The effects of pindolol on other study parameters (exercise endurance and exercise-induced increases in systolic blood pressure, heart rate, and potassium) were similar to the effects of the nonselective agent, timolol. We conclude that the effects of pindolol on the plasma lipid profile are due to its ISA and that the process activated (possibly plasma lecithin-cholesterol acyltransferase activity) is under minimal sympathetic control and, therefore, sensitive to the expression of ISA both at rest and in response to exercise.

Effects of beta 1- vs. beta 1 + beta 2-blockade on exercise endurance and muscle metabolism in humans.

The effects of beta-blockade on muscle utilization of glycogen and triglycerides, as well as potassium metabolism, were studied in eight healthy male subjects performing long-duration exercise to exhaustion. Subjects were studied after treatment with either placebo (PLAC), beta 1-selective (atenolol, 100 mg/day, AT), or nonselective beta-blockade (nadolol, 80 mg/day, NAD) each for 1 wk according to a randomized, double-blind, cross-over design. NAD and AT caused identical decreases in exercise heart rates, but endurance (71 +/- 8 min with PLAC) decreased significantly more with NAD (-33 +/- 4%) than with AT (-14 +/- 6%). Muscle glycogen breakdown, taking exercise time into account, was unaffected by treatment. In contrast, muscle triglyceride utilization was completely blocked by NAD whereas it was unchanged with AT as compared to PLAC. Adipose tissue lipolysis was inhibited to a similar extent by the two beta-blockers. Serum potassium increased to higher levels at exhaustion and muscle potassium decreased to lower levels with NAD than with AT or PLAC. These results suggest that decreased utilization of muscle triglycerides combined with lack of an enhanced glycogenolysis to compensate as well as alterations in potassium metabolism contribute to the decreased exercise capacity with nonselective beta-blockade compared with beta 1-selective blockade.

Cardiovascular effects of caffeine and nifedipine.

Because caffeine and nifedipine may have opposing effects on intracellular calcium concentration, a possible interaction between these agents on blood pressure and heart rate was examined. With a randomized, double-blind, crossover design, 10 normal, caffeine-abstaining subjects received caffeine, 300 mg, or placebo followed by nifedipine, 10 mg, or placebo. Caffeine increased blood pressure, whereas nifedipine reduced it and caused a reflex increase in heart rate. With caffeine pretreatment, nifedipine decreased blood pressure significantly more than with placebo pretreatment. However, nifedipine reduced blood pressure to the same absolute level on both the caffeine and placebo pretreatment days. The reflex increase in heart rate after nifedipine was not affected by prior caffeine or placebo administration. Caffeine pretreatment does not alter the cardiovascular responses to nifedipine but the pressor effect of caffeine is completely reversed by subsequent nifedipine administration.