Oral contraceptives and thromboembolism: A reassessment

The relationship between oral contraceptive usage and thromboembolism is controversial. Since thromboembolism is often undiagnosed, both clinically and at routine autopsy, most epidemiologic analyses rest on a very uncertain factual base. There are increases in blood coagulation factors in oral contraceptive users similar to, but less than, those seen in pregnancy, which isnot associated with increased thromboembolism. Hematologists emphasize that these changes do not define a “hypercoagulable” state, and they do not define or predict the occurrence of thrombosis. Intrinsic vascular wall changes, unrelated to drug use, may play a role in sporadic cases of thromboembolism. When the incidence of thromboembolism in very large Phase III trials of conventional oral contraceptives is compared to that in other populations (patients admitted to the hospital, women who visit a physician, pregnant women, or users of nonestrogenic oral contraceptives), no difference is seen. Epidemiologic studies by the “case-control” (“trohoc”) method consistently show an increased “relative risk” associated with oral contraceptive use in subjects with “idiopathic” thromboembolism but no increased risk in thromboembolism patients as a whole or in those with predisposing factors. This retrospective epidemiologic technique, its particular applications, and the inferences drawn are open to serious criticism, as are studies claiming a relationship between estrogen dose and thromboembolism incidence. An Australian prospective survey found no increased risk among users, and a large British study which initially reported an increased risk is currently undergoing recalculation. The only controlled clinical experiment (with random assignment of subjects to vaginal versus high-estrogen contraceptives) showed no increased incidence in the drug-treated group. Statistical associations derived from “trohoc” studies do not establish causal relationships; moreover, their risk estimates are in conflict with the findings of large Phase III clinical surveys including subjects using estrogen-free contraceptives, with at least one prospective clinical survey, and with a randomized, controlled clinical trial. The data relating estrogen dosage to thromboembolism incidence are ambiguous, at best. Thus, the claim of a causal relationship between oral contraceptive steroids and thromboembolism does not appear to be firmly founded, and the belief that predisposing factors increase the risk to contraceptive users is equally insubstantial.     

Psychiatric consultation: A survey and review of utilization

Regardless of what has been written of the need for evaluation of the psychiatric consultation service in the general hospital, there is a dearth of such studies.¹ In a 400-bed university-affiliated general hospital, we have recently increased the staffing and scope of consultation service. In a period of 2 mo, two and one-half staff positions were added. Here was a point at which to take stock of prior performance and future course. One evaluative approach herein involves a survey of recipients of the consultation service, staff physicians of the hospital. We were also interested in the relationship between the findings of such a survey instrument and the actual clinical practice.To that end, we used our service records to explore the following possible associations: Would concurrent use of consultation services by various subgroups within the staff reflect survey support and approval? How would survey respondents' declared profile of reasons to request consultation compare with actual practice?     

Plasma levels and pharmacokinetics of ethynyl estrogens in various populations: II. Mestranol

A total of 89 adult women from Nigeria, Singapore, Sri Lanka, Thailand and the USA were given single oral doses of mestranol ranging from 50 to 100 μg; the subsequent plasma levels of free mestranol and ethynylestradiol were determined by radioimmunoassay, and certain pharmacokinetic parameters calculated. Mestranol is absorbed very rapidly from the digestive tract and maximum plasma levels are attained in 1–4 hours, the majority at 1–2 hours. Detectable levels of mestranol are present 24 hours postingestion in 58% of subjects after a 50 μg dose and in 79% after a 100 μg dose. At all dose levels, highest plasma mestranol levels and area under the curve of plasma levels (AUC) occurred in Sri Lankan women, and lowest plasma levels in Nigerian women, even when corrected for body surface differences. Plasma levels of ethynylestradiol derived from mestranol rose earlier and reached higher values than those of mestranol itself in every locality. The plasma levels of ethynylestradiol derived from mestranol were lowest and total body clearance highest in the Nigerian group at all dose levels; total body clearance was similar in the other localities. The AUC of plasma levels of ethynylestradiol was compared, by locality, on a dose-for-dose basis for the administration of mestranol or of ethynylestradiol itself. There was no significant difference between the two drugs, except at one dosage level in Thailand. These findings suggest that ethynylestradiol and mestranol are similar in terms of AUC; a higher peak and a faster decline are observed after administration of the former compound. Substantial differences between localities in the clearance rates of mestranol are suggested; whether these are due to differences in distribution or rate of metabolism or to differences in absorption remains to be determined.     

Pharmacologically induced changes in wall thickening dynamics and mid-ventricular volumes in dogs assessed by prospectively gated computed tomography

Assessment of regional wall thickening dynamics is important for monitoring the response of normal and ischemic myocardium to pharmacologic interventions. Because regional wall thickness can be measured on computed tomographic (CT) scans of the heart, the ability of electrocardiogram-gated computed tomography to determine the effects of pharmacologic agents on global and segmental left ventricular (LV) function was assessed. Eight conditioned dogs were studied at a control state and during drug-induced changes in contractility and loading conditions brought about by the use of isoproterenol (0.15 μg/kg/min), phenylephrine (0.3 μg/kg/min), and verapamil (0.2 mg/kg infused over 10 minutes). Ten contrast-enhanced CT slices (1 cm thick) at the same mid-LV level were reconstructed for each 10% of the R-R interval throughout an average cardiac cycle using prospectively gated CT scans. End-diastolic and end-systolic frames were selected and analyzed for the following: septal, apical, and lateral wall thickness, percent wall thickening, end-diastolic and end-systolic mid-LV volume, and percent change in mid-LV volume.

During control, end-diastolic and end-systolic LV wall thicknesses (in millimeters) were 12 ± 2 and 15 ± 2 for the septal wall, 8 ± 1 and 11 ± 2 for the apical wall, and 10 ± 1 and 12 ± 1 for the lateral wall, respectively. The percent thickening in these respective segments was 24 ± 8, 36 ± 10, and 28 ± 13. The control end-diastolic and end-systolic mid-LV volumes were 16 ± 3 and 12 ± 3 ml, resulting in a percent change of 27 ± 7%. Phenylephrine induced significant thinning of the walls and impairment of systolic thickening, whereas isoproterenol induced opposite effects. Verapamil produced a significant decrease in mean blood pressure (123 ± 9 versus 99 ± 23 mm Hg, p < 0.025), but end-diastolic wall thicknesses were mildly thicker or showed no change and end-systolic wall thicknesses showed no change compared with those in the control state. Similarly, mid-LV volumes and percent change in mid-LV volumes were not different from those during control. Thus, electrocardiogram-gated computed tomography can be used to assess the effects of pharmacologic interventions on global and segmental LV function.     

Clinical assessment and follow-up of functional capacity in patients with chronic congestive cardiomyopathy

The presumption that the results of left ventricular systolic function tests performed at rest are related to the symptoms of chronic congestive heart failure or to exercise capacity is unproved. Thirty-three patients with chronic congestive Cardiomyopathy underwent serial exercise tests, determinations of ejection fraction and systolic time intervals, echocardiograms, assessment of symptom score, chest roentgenogram, and physical examination over a mean (± standard deviation) of 24.8 ± 14.1 months. Maximal exercise performance achieved correlation with symptoms (r = −0.66) but not with indexes of left ventricular function. Edema, elevated jugular venous pressure, rales and radiologic evidence of pulmonary venous hypertension were more common in patients with severe limitation of exercise capacity. In 17 patients whose functional capacity changed during the follow-up period, congruent changes in left ventricular function measured at rest were not consistently observed.

Thus the findings on history, physical examination and radiologic examination correlate with exercise capacity, but indexes of left ventricular performance at rest do not and therefore are of limited use in assessing treatment. The clinical course of patients with chronic congestive cardiomyopathy can be followed up safely, effectively and economically by simple clinical observations. Serial laboratory testing of left ventricular function can be reserved for specific indications, research and patients with valvular heart disease.     

Migraine

Instead of representing two sharply different entities, migraine and tension headache may best be thought of as occupying the two ends of a continuum, with mixed tension and vascular headache in the center. The author's assessment of current knowledge of mechanisms, symptoms, and acute and prophylactic treatments supports his statement that the major clinical difference between the variants of headache is differential pharmacologic effectiveness of the drugs used.