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Protrhombotic Effects of Contraceptives
Abstract
The use of oral contraceptives first became widespread some 40 years ago, and reports of an excess risk of cardiovascular disease among women who used these agents soon followed. Few drugs have been the object of such intensive epidemiological research, the outcome of which has provided clinicians with detailed information about risks not only of specific thrombotic diseases but also important non-contraceptive benefits from the pill. Recently, oral contraceptives have been classified by some according to "generation" (first, second, third, and most recently, fourth generation): first-generation formulations containing lynestrenol or norethindrone, second-generation formulations containing levonorgestrel, third-generation formulations containing desogestrel or gestodene, and oral contraceptives containing an estrogen and other progestagens (cyproterone or norgestimate) or a progestagen alone. The results of several study was that the use of the older high-dose oral contraceptives increased the risk of cardiovascular disease by modifying the Low-density lipoprotein and High-Density lipoprotein cholesterol level, increasing triglyceride serum level, reducing glucose tolerance, raising blood pressure, and promoting clotting mechanisms. In this review we investigate the mechanism of the oral contraceptives and performed a risk assessment of every generation.
... The most accepted type of birth control and widely used is Combined Oral Contraceptive Pills (COCPs) it has been introduced in 1960, Its use is on increasing by women in child bearing age all over the world, especially in the recent years when various organizations and government are encouraging it's use for spacing pregnancy in developing countries [4]. It is reported that COCPs can be classified into first-, second-, thirdand fourth generation, according to the type of progestogen [5]. Firstgeneration COCPs preparations combined high dose ethanol estradiol (>50 µg) and androgenic progestin are associated with adverse effects, such as strokes and thromboembolic events [6]. ...
... Lipid and lipoproteins disorder in hormonal contraceptive users has been studied and reported significant changes in the lipid profile levels by various researchers [5,6,14,19]. These changes can be due to the lipogenic effect of estrogen hormone which increases liver lipogenesis and results in raising LDL-C and TG levels [20]. ...
Background: Globally, the use of contraception has been increased due to a serious problem facing the world which is population explosion. It has been suggested that the use of contraceptives is beneficial, but it has some side effects and metabolism impairment too. The most accepted and widely used birth control to avoid unintended pregnancy is Combined Oral Contraceptive Pills (COCPs).
... 11 The elevated risk of stroke is likely due to the hypercoagulable effects of estrogen. 12 The joint effects of migraine and CHCs on risk of stroke are not well understood. Several studies found that the risk of stroke among women with migraine was increased with use of COCs compared with nonuse. ...
... 20 Estrogen has several biological effects including changes in coagulation factors, lipid levels, and blood pressure, which may contribute to the increased risk of stroke. 12 It is therefore not surprising that our study found the highest OR of ischemic stroke among women with migraine with aura currently using CHCs. ...
(Abstracted from Am J Obstet Gynecol 2017;216:489.e1–489.e7)
Migraine headaches occur commonly in women; more than 40% will have a migraine during their lifetime. Women of reproductive age who experience migraine, especially those with aura are at increased risk of ischemic stroke.
... Epidemiological data from OC users in the 1960s clearly associated the high-dose formulations used in that era with increased risk of ischemic stroke, myocardial infarction, and pulmonary embolism in healthy young women, particularly smokers ( 50,51 ). Several studies of older high-dose OC formulations, including those containing lynestrenol, typically showed detrimental effects on cardiovascular risk factors, including reduced HDL levels and increased LDL and triglyceride levels [reviewed in ( 50 )]. ...
... Epidemiological data from OC users in the 1960s clearly associated the high-dose formulations used in that era with increased risk of ischemic stroke, myocardial infarction, and pulmonary embolism in healthy young women, particularly smokers ( 50,51 ). Several studies of older high-dose OC formulations, including those containing lynestrenol, typically showed detrimental effects on cardiovascular risk factors, including reduced HDL levels and increased LDL and triglyceride levels [reviewed in ( 50 )]. However, note that these changes in lipid levels are reported to be due to effects on hepatic lipase, which is generally stimulated by estrogens and inhibited by progestins, including lynestrenol ( 51 ). ...
Apolipoprotein E is the major lipid carrier in the central nervous system. As apoE plays a major role in the pathogenesis of Alzheimer's Disease (AD) and also mediates repair pathways after several forms of acute brain injury, modulating the expression, secretion or function of apoE may provide potential therapeutic approaches for several neurological disorders. Here we show that progesterone and a synthetic progestin, lynestrenol, significantly induce apoE secretion from human CCF-STTG1 astrocytoma cells, whereas estrogens and the progesterone metabolite allopregnanolone have negligible effects. Intriguingly, lynestrenol also increases expression of the cholesterol transporter ABCA1 in CCF-STTG1 astrocytoma cells, primary murine glia, and immortalized murine astrocytes that express human apoE3. The progesterone receptor (PR) inhibitor RU486 attenuates the effect of progestins on apoE expression in CCF-STTG1 astrocytoma cells but has no effect on ABCA1 expression in all glial cell models tested, suggesting that the PR may participate in apoE but does not affect ABCA1 regulation. These results suggest that selective reproductive steroid hormones have the potential to influence glial lipid homeostasis through LXR-dependent and PR-dependent pathways.
... The higher risk of cardiovascular events has been associated with changes in lipid metabolism caused by oral contraceptives through the modification of low-density lipoprotein (LDL) and highdensity lipoprotein cholesterol (HDL-C) levels 12 addition, they act like procoagulant agents, favoring a hypercoagulability state, and then raising the risk of thromboembolic diseases. 14 Inflammation is an uninterrupted effect of the atherosclerotic process, which promotes the formation of the lipid stria, and even the movement and rupture of the atherosclerotic plaque. ...
Myocardial infarction, colloquially known as "heart attack," is caused by decreased or complete cessation of blood flow to a portion of the myocardium. Myocardial infarction may be silent, and go undetected, or it could be a catastrophic event leading to hemodynamic deterioration and sudden death. Most myocardial infarctions are due to underlying coronary artery disease and the risk to suffer from this deadly event is linked to the presence of several risk factors like hypertension, diabetes, obesity, dyslipidemia, smoking or stress. Combined oral contraceptives (COCs) have been associated with an increased risk of arterial thrombosis, myocardial infarction or ischemic stroke. However, as these diseases are rare in young women and as many types of combined oral contraception exist, the magnitude of the risk and the effect of different hormonal contents of COC preparations remain unclear.
... These findings could be explained by the development of age-related changes in microcirculation and blood coagulation, which contribute to generate a hypercoagulability status and a gradual increase of D-Dimer levels with aging, as well as by the use of hormonal contraceptives in most of women. Such contraceptives can promote clotting mechanisms and increase D-Dimer levels (29,30). Increased frequency of antihypertensive use was observed in patients with high D-Dimer levels, which was expected, since these patients also showed an increased frequency of renal disease. ...
Objective
This study aimed to evaluate the association between different renal biomarkers with D-Dimer levels in diabetes mellitus (DM1) patients group classified as: low D-Dimer levels (< 318 ng/mL), which included first and second D-Dimer tertiles, and high D-Dimer levels (≥ 318 ng/mL), which included third D-Dimer tertile.
Materials and methods
D-Dimer and cystatin C were measured by ELISA. Creatinine and urea were determined by enzymatic method. Estimated glomerular filtration rate (eGFR) was calculated using CKD-EPI equation. Albuminuria was assessed by immunoturbidimetry. Presence of renal disease was evaluated using each renal biomarker: creatinine, urea, cystatin C, eGFR and albuminuria. Bivariate logistic regression analysis was performed to assess which renal biomarkers are associated with high D-Dimer levels and odds ratio was calculated. After, multivariate logistic regression analysis was performed to assess which renal biomarkers are associated with high D-Dimer levels (after adjusting for sex and age) and odds ratio was calculated.
Results
Cystatin C presented a better association [OR of 9.8 (3.8–25.5)] with high D-Dimer levels than albuminuria, creatinine, eGFR and urea [OR of 5.3 (2.2–12.9), 8.4 (2.5–25.4), 9.1 (2.6–31.4) and 3.5 (1.4–8.4), respectively] after adjusting for sex and age. All biomarkers showed a good association with D-Dimer levels, and consequently, with hypercoagulability status, and cystatin C showed the best association among them.
Conclusion
Therefore, cystatin C might be useful to detect patients with incipient diabetic kidney disease that present an increased risk of cardiovascular disease, contributing to an early adoption of reno and cardioprotective therapies.
... These differences did not reach statistical significance. Levonorgestrel is part of the second generation of OCs and generally considered safer with regard to thrombosis risk compared with third-generation OCs including desogestrel and norgestimate [24]. Second-generation OCs still tend to have a residual androgenic effect which, in some users, can lead to bothersome side effects such as acne, hirsutism, and weight gain [25]. ...
Recent studies showed differences in the risk of venous thrombosis between different combined hormonal contraceptives. Database studies comprising large cohorts can add relevant aspects from daily clinical practice. The purpose of this study was to evaluate different progestogen in combination with ethinylestradiol on the risk of venous thrombosis in Germany.
Computerized data from 68,168 contraceptive users in gynecological practices throughout Germany (Disease Analyzer Database) were analyzed. The adjusted odds ratios for risk of thrombosis were estimated in users of different oral contraceptive (OC) formulations relative to users of levonorgestrel-containing preparations.
In total, 38 (0.06 %) of the 68,168 contraceptive users had a recorded diagnosis of thrombosis within 365 days after the initial prescription. The adjusted risk was 1.95 for desogestrel (95 % CI 0.52-7.29), 2.97 for dienogest (95 % CI 0.96-9.24), 1.57 for drospirenone (95 % CI 0.46-5.38), 2.54 for chlormadinone (95 % CI 0.72-9.04), and 3.24 for norgestimate (95 % CI 0.59-17.75) compared to levonorgestrel. None of those findings reached statistical significance. The maximum absolute increase versus levonorgestrel was 6 cases per 10,000 women (n.s.).
The study shows the low incidence rates of thrombosis in OC users. Since there is no significant difference, this study does not confirm an increased risk but shows only a tendency for this risk of third- and fourth-generation OC versus levonorgestrel-containing products.
Migraine is a global neurologic disease that is highly prevalent, especially in women. Studies have observed a predisposition for the development of migraine in women, although the mechanisms involved have yet to be fully elucidated. This review aimed to summarize the recent evidence regarding the epidemiology, pathophysiology, and treatment of migraine and highlight key sex differences. We also identify gaps in care for both women and men living with migraine and discuss the presence of migraine-related stigma and how this may impact the efficacy of clinical care.
Background
Comparative safety data on the risk of pseudotumor cerebri syndrome (PTCS) with different hormonal contraceptives is absent. We sought to quantify the risk of PTCS with eight different types of hormonal contraceptives compared with oral levonorgestrel.
Methods
A retrospective cohort study with a case‐control analysis was used on 4,871,504 women aged 15‐45 from 2008‐2015 using data from IQVIA Ambulatory EMR data from the United States was undertaken. Patients who used nine different contraceptive agents including intrauterine levonorgestrel, medroxyprogesterone injection, etonogestrel/ethinyl estradiol vaginal ring and combination oral contraceptives (COCs) that contained ethinyl estradiol and the following progestins: levonorgestrel, norgestimate, desogestrel, norethindrone, drospirenone were included. Diagnosis of PTCS defined as the first international classification for disease code 9th or 10th edition for intracranial hypertension who had also received an imaging code in the 30 days prior to the index date.
Results
3,323 PTCS cases and 13,292 matched controls were identified. No increase in risk was found when comparing levonorgestrel IUD or COCs containing desogestrel, norethindrone, drospirenone, norgestimate or norgestrel to COC levonorgestrel. The adjusted incident rate ratio (IRR) for etonogestrel/EES vaginal ring and medroxyprogesterone suspension compared with levonorgestrel COC were 4.45, (95% CI:1.98‐9.96) and 2.20, (95% CI:1.33‐3.64) respectively.
Conclusions
This study found an elevated risk for PTCS among users of etonogestrel vaginal ring and medroxyprogesterone suspension when compared with oral levonorgestrel. Future studies are needed to confirm these findings.
Due to the circadian rhythm regulation of almost every biological process in the human body, physiological and biochemical conditions vary considerably over the course of a 24-h period. Thus, optimal drug delivery and therapy should be effectively controlled to achieve the desired therapeutic plasma concentrations and therapeutic drug responses at the required time according to chronopharmacological concepts, rather than continuous maintenance of constant drug concentrations for an extended time period. For many drugs, it is not always necessary to constantly deliver a drug into the human body under disease conditions due to rhythmic variations. Pulsatile drug delivery systems (PDDSs) have been receiving more attention in pharmaceutical development by providing a predetermined lag period, followed by a fast or rate-controlled drug release after application. PDDSs are characterized by a programmed drug release, which may release a drug at repeatable pulses to match the biological and clinical needs of a given disease therapy. This review article focuses on thermoresponsive gating membranes embedded with liquid crystals (LCs) for transdermal drug delivery using PDDS technology. In addition, the principal rationale and the advanced approaches for the use of PDDSs, the marketed products of chronotherapeutic DDSs with pulsatile function designed by various PDDS technologies, pulsatile drug delivery designed with thermoresponsive polymers, challenges and opportunities of transdermal drug delivery, and novel approaches of LC systems for drug delivery are reviewed and discussed. A brief overview of all academic research articles concerning single LC- or binary LC-embedded thermoresponsive membranes with a switchable on-off permeation function through topical application by an external temperature control, which may modulate the dosing interval and administration time according to the therapeutic needs of the human body, is also compiled and presented. In the near future, since thermal-based approaches have become a well-accepted method to enhance transdermal delivery of different water-soluble drugs and macromolecules, a combination of the thermal-assisted approach with thermoresponsive LCs membranes will have the potential to improve PDDS applications but still poses a great challenge.
Migraine headache (MH) is a common disorder affecting millions of people in the United States. MH is substantially more prevalent in women compared to men. An association between migraine with or without aura and risk of cardiovascular disease (CVD) has been extensively reported. There are several proposed theories that may explain the pathophysiologic relationship between MH and CVD. This review will summarize the recent literature on this topic and provide an evidence-based perspective regarding the current knowledge and controversies regarding association of MH and CVD.
All women of reproductive age with psychiatric and neurologic disease should be screened for contraceptive need, and offered counseling on options compatible with their medications and medical conditions. While non-hormonal methods are appropriate for all patients, hormonal contraception may interact with some medications used by women in treatment of epilepsy, multiple sclerosis and mood disorders. Women at risk for or with a history of stroke should avoid estrogen-containing options; similarly, women who report migraine with aura are also discouraged from use of any estrogen-based contraception due to the potential increase in risk of stroke. Fortunately, the highly effective reversible contraceptive options that include intrauterine devices (IUDs) and the progestin-only implant are appropriate for almost all these women. This chapter provides evidence and guidance for selection of appropriate, safe contraceptive options in women with migraine disease, epilepsy, stroke, multiple sclerosis and psychiatric disease.
Background:
Migraine with aura and combined hormonal contraceptives are independently associated with an increased risk of ischemic stroke. However, little is known about whether there are any joint effects of migraine and hormonal contraceptives on risk of stroke.
Objective:
We sought to estimate the incidence of stroke in women of reproductive age and examine the association among combined hormonal contraceptive use, migraine type (with or without aura), and ischemic stroke.
Study design:
This study used a nationwide health care claims database and employed a nested case-control study design. Females ages 15-49 years with first-ever stroke during 2006 through 2012 were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification inpatient services diagnosis codes. Four controls were matched to each case based on age. Migraine headache with and without aura was identified using inpatient or outpatient diagnosis codes. Current combined hormonal contraceptive use was identified using the National Drug Code from the pharmacy database. Conditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals of ischemic stroke by migraine type and combined hormonal contraceptive use.
Results:
From 2006 through 2012, there were 25,887 ischemic strokes among females ages 15-49 years, for a cumulative incidence of 11 strokes/100,000 females. Compared to those with neither migraine nor combined hormonal contraceptive use, the odds ratio of ischemic stroke was highest among those with migraine with aura using combined hormonal contraceptives (odds ratio, 6.1; 95% confidence interval, 3.1-12.1); odds ratios were also elevated for migraine with aura without combined hormonal contraceptive use (odds ratio, 2.7; 95% confidence interval, 1.9-3.7), migraine without aura and combined hormonal contraceptive use (odds ratio, 1.8; 95% confidence interval, 1.1-2.9), and migraine without aura without combined hormonal contraceptive use (odds ratio, 2.2; 95% confidence interval, 1.9-2.7).
Conclusion:
The joint effect of combined hormonal contraceptives and migraine with aura was associated with a 6-fold increased risk of ischemic stroke compared with neither risk factor. Use of combined hormonal contraceptives did not substantially further increase risk of ischemic stroke among women with migraine without aura. Determining migraine type is critical in assessing safety of combined hormonal contraceptives among women with migraine.
The Meso-Rex shunt (MRS) procedure was first described in 1992 by de VILLE et al. for the treatment of extrahepatic portal vein obstruction (EHPVO) in paediatric liver transplant patients. This technique provides more physiological relief of portal hypertension compared to the porto-systemic shunts, which can lead to long-term complications such as hyperammonaemia and hepato-pulmonary syndrome. Different conduits as autologous and cryopreserved veins or prosthetic grafts have been previously reported. We present herein the first case of a MRS using the autologous deep femoral vein in a 17-year-old female patient affected by EHPVO from unknown reasons.
In the last decade, a number of new antithrombotic therapies as well as new approaches have been appearing for the management of patients with or at risk for arterial and venous thrombosis. Considering new drugs, direct thrombin inhibitors (dabigatran etixilate) or Factor Xa inhibitors (rivaroxaban and apixaban) are now available for the prophylaxis for venous thromboembolism (VTE) during orthopedic procedures. Hopefully soon, new oral anticoagulants (dabigatran etexilate) will replace warfarin in the prevention of stroke in patients with chronic atrial fibrillation (AF). What are the advantages of these new drugs over warfarin? Mainly, they do not need laboratory monitoring, since direct thrombin or factor Xa inhibitors are administered at fixed doses. Some investigations showed also a greater efficacy without increasing the risk for bleeding; however, most of the studies were designed as non-inferiority trials, therefore strong conclusions about their superiority are not easy to attempt. In this issue, all the most relevant topics on new approaches for the management of arterial and venous thrombosis are discussed. Dr. Douketis [1] analyses the pharmacological profiles of the new anticoagulants and, very interestingly, implications for their use during perioperative management. This topic is still debated in patients who receive warfarin and several approaches have been published. Dr. Lyp et coworkers [2, 3] addressed in two papers new issues related to arterial thrombosis. Particularly, Dr. Butt [2] evaluated the role of endothelial dysfunction as a marker for cardiovascular diseases, while Dr. Potpara [3] highlighted the strategies and future perspectives for the prevention of arterial thromboembolism in patients with AF. New issues on VTE were analyzed by Dr Lepic and Dr. Garcia [4, 5]. The first author reports on new anticoagulants for the prevention of venous thrombosis during orthopedic surgery [4], a population at high-risk for postoperative Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) in whom heparin antithrombotic prophylaxis can be further ameliorate in terms of efficacy. Dr. Garcia analyzed the new oral anticoagulants for the treatment of DVT and PE, highlighting the potential advantages over coumarin specially in case of long-term treatment [5]. Dr. Romualdi addressed a very important topic: how to manage anticoagulated patients receiving warfarin or the new thrombin or factorXa inhibitors [6]. This topic is extremely important, especially in case of therapy with the new anticoagulants, since they do not have a specific antagonist. Along with new drugs, new approaches to establishing the individual risk for recurrent VTE are discussed. Malato et al. briefly analyzes the use of well reproducible markers as D-dimer (D-d) and detection of residual vein thrombosis (RVT) that has been demonstrated to drive the optimal duration of oral anticoagulants in patients with a first episode of DVT [7]. Finally, Dr. Huisman explores the potential advantages of administering new anticoagulants in settings, where indications are still under evaluation or await for approval or areas, where these novel drugs have not yet been evaluated [8]. In the last two review Fazio et al. analyzed the importance of thrombotic complications in the presence of PFO or in patients that used some oral contraceptives [9-10]. In general, this issue furnishes a comprehensive framework of the most recent approaches for the management of patients with or at highrisk for venous or arterial thrombosis....
The past several decades have seen the development of many controlled-release preparations featuring constant release rates to maintain drug concentrations in the human body, regardless of the patient's physiological condition. However, long-term constant drug concentrations in the blood and tissue can cause problems such as resistance, tolerability, and drug side effects. People vary considerably in their physiological and biochemical conditions during any 24 h period, due to the circadian rhythm, and thus, the constant delivery of a drug into the body seems both unnecessary and undesirable. If the drug release profile mimics a living system's pulsatile hormone secretion, then it may improve drug efficacy, and reduce the toxicity of a specific drug administration schedule. Medication and treatments provided according to the body's circadian rhythms will result in better outcomes. This may be provided by a chronopharmaceutical dosage regimen with pulsatile release that matches the circadian rhythm resulting from a disease state, so optimizing the therapeutic effect while minimizing side effects. The press coating technique is a simple and unique technology used to provide tablets with a programmable lag phase, followed by a fast, or rate-controlled, drug release after administration. The technique offers many advantages, and no special coating solvent or coating equipment is required for manufacturing this type of tablet. The present review article introduces chronopharmaceutical press-coated products from a patient physiological needs perspective. The contents of this article include biological rhythms and pulsatile hormone secretion in humans, the reasons for using pulsatile drug delivery for disease treatment, recent chronopharmaceutical preparations appearing on the market, updated compilation of all research articles and press-coated delivery techniques, factors affecting the performance and drug release characteristics of press-coated delivery systems, and recent challenges for the press coating technique. We also provide a brief overview of press-coating approaches intended for chronotherapy.
To determine the influence of oral contraceptives (particularly those containing modern progestins) on the risk for ischaemic stroke in women aged 16-44 years.
Matched case-control study.
16 Centres in the United Kingdom, Germany, France, Switzerland, and Austria.
Cases were 220 women aged 16-44 who had an incident ischaemic stroke. Controls were 775 women (at least one hospital and one community control per case) unaffected by stroke who were matched with the corresponding case for 5 year age band and for hospital or community setting. Information on exposure and confounding variables were collected in a face to face interview.
Odds ratios derived with stratified analysis and unconditional logistic regression to adjust for potential confounding.
Adjusted odds ratios (95% confidence intervals) for ischaemic stroke (unmatched analysis) were 4.4 (2.0 to 9.9), 3.4 (2.1 to 5.5), and 3.9 (2.3 to 6.6) for current use of first, second, and third generation oral contraceptives, respectively. The risk ratio for third versus second generation was 1.1 (0.7 to 2.0) and was similar in the United Kingdom and other European countries. The risk estimates were lower if blood pressure was checked before prescription.
Although there is a small relative risk of occlusive stroke for women of reproductive age who currently use oral contraceptives, the attributable risk is very small because the incidence in this age range is very low. There is no difference between the risk of oral contraceptives of the third and second generation; only first generation oral contraceptives seem to be associated with a higher risk. This small increase in risk may be further reduced by efforts to control cardiovascular risk factors, particularly high blood pressure.
Combined oral contraceptives (OC) are known to increase the risk of venous thromboembolism. The aim of this randomized, cycle-controlled, cross-over study in 28 healthy volunteers was to assess potential differences between the effects of an OC containing 150 microg levonorgestrel (as representative of the so-called second generation OC) and an OC containing 150 microg desogestrel (as representative of the third generation OC) in combination with 30 microg ethinylestradiol on several coagulation factors and markers of thrombin formation. All participants used each OC for two cycles, and were switched to the other OC after a washout period of two menstrual cycles. The plasma concentrations of factors II, VII, X, and fibrinogen significantly increased during use of both the levonorgestrel- and desogestrel-containing OC's. The plasma concentrations of factor VIII increased, and of factor V decreased, changes which only reached statistical significance during the use of the desogestrel-containing OC. During exposure to the desogestrel-containing OC, as compared with the levonorgestrel-containing OC, both factor VII and factor II showed a greater increase (FVII: 32% and 12% respectively; p <0.0001; FII: 16% and 12% respectively; p = 0.048), whereas factor V showed a greater decrease (-11% and -3% respectively; p = 0.010). Only one of the markers for ongoing coagulation (prothrombin fragment 1+2) showed a significant increase during OC use, whereas concentrations of thrombin-antithrombin complexes and soluble fibrin remained unchanged. For these markers, there was no difference between the tested OC's. We conclude that there are differences between the effects of levonorgestrel and desogestrel-containing OC's on some coagulation factors. Whether these changes provide a biological explanation for the reported differences in venous thromboembolic risk is as yet unclear. The real challenge now becomes to define a pattern of changes in the various systems which, if affected simultaneously, may tip the hemostatic balance towards a prethrombotic state and may lead to overt clinical venous thromboembolism.
In the early 1960s, shortly after the introduction of oral contraceptives, the first case reports appeared describing venous thrombosis and pulmonary emboli in women using this method of birth control. Later, myocardial infarction and stroke were also found to be associated with the use of oral contraceptives. These observations led to numerous epidemiologic and clinical studies of oral-contraceptive pills and thrombosis and subsequently to the development of new oral contraceptives with a lower estrogen content. These lower-estrogen contraceptives were considered safer: changes in hemostatic factors remained small, inconsistent in direction, and mostly within the normal range.1–4 Recent studies have . . .
An association between the use of oral contraceptives and the risk of myocardial infarction has been found in some, but not all, studies. We investigated this association, according to the type of progestagen included in third-generation (i.e., desogestrel or gestodene) and second-generation (i.e., levonorgestrel) oral contraceptives, the dose of estrogen, and the presence or absence of prothrombotic mutations
In a nationwide, population-based, case-control study, we identified and enrolled 248 women 18 through 49 years of age who had had a first myocardial infarction between 1990 and 1995 and 925 control women who had not had a myocardial infarction and who were matched for age, calendar year of the index event, and area of residence. Subjects supplied information on oral-contraceptive use and major cardiovascular risk factors. An analysis for factor V Leiden and the G20210A mutation in the prothrombin gene was conducted in 217 patients and 763 controls
The odds ratio for myocardial infarction among women who used any type of combined oral contraceptive, as compared with nonusers, was 2.0 (95 percent confidence interval, 1.5 to 2.8). The adjusted odds ratio was 2.5 (95 percent confidence interval, 1.5 to 4.1) among women who used second-generation oral contraceptives and 1.3 (95 percent confidence interval, 0.7 to 2.5) among those who used third-generation oral contraceptives. Among women who used oral contraceptives, the odds ratio was 2.1 (95 percent confidence interval, 1.5 to 3.0) for those without a prothrombotic mutation and 1.9 (95 percent confidence interval, 0.6 to 5.5) for those with a mutation
The risk of myocardial infarction was increased among women who used second-generation oral contraceptives. The results with respect to the use of third-generation oral contraceptives were inconclusive but suggested that the risk was lower than the risk associated with second-generation oral contraceptives. The risk of myocardial infarction was similar among women who used oral contraceptives whether or not they had a prothrombotic mutation.
Recent randomized clinical trials have suggested that estrogen plus progestin does not confer cardiac protection and may increase the risk of coronary heart disease (CHD). In this report, we provide the final results with regard to estrogen plus progestin and CHD from the Women's Health Initiative (WHI).
The WHI included a randomized primary-prevention trial of estrogen plus progestin in 16,608 postmenopausal women who were 50 to 79 years of age at base line. Participants were randomly assigned to receive conjugated equine estrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. The primary efficacy outcome of the trial was CHD (nonfatal myocardial infarction or death due to CHD).
After a mean follow-up of 5.2 years (planned duration, 8.5 years), the data and safety monitoring board recommended terminating the estrogen-plus-progestin trial because the overall risks exceeded the benefits. Combined hormone therapy was associated with a hazard ratio for CHD of 1.24 (nominal 95 percent confidence interval, 1.00 to 1.54; 95 percent confidence interval after adjustment for sequential monitoring, 0.97 to 1.60). The elevation in risk was most apparent at one year (hazard ratio, 1.81 [95 percent confidence interval, 1.09 to 3.01]). Although higher base-line levels of low-density lipoprotein cholesterol were associated with an excess risk of CHD among women who received hormone therapy, higher base-line levels of C-reactive protein, other biomarkers, and other clinical characteristics did not significantly modify the treatment-related risk of CHD.
Estrogen plus progestin does not confer cardiac protection and may increase the risk of CHD among generally healthy postmenopausal women, especially during the first year after the initiation of hormone use. This treatment should not be prescribed for the prevention of cardiovascular disease.
Mammalian reproduction is a complex physiological process involving a tightly regulated hypothalamic-pituitary-gonadal axis and the integration of a diverse array of molecular signals. Oral contraceptives (OCs) were introduced over 40 years ago and have evolved over the years through the discovery of new estrogens and progestins, the development of progestin-only pills and the reduction of the estrogen content in combined OCs. Despite the developments that improved the safety profile of current OCs, adverse metabolic and vascular effects caused by the estrogen component and possible neoplastic effects of OCs remain and, thus, necessitate efforts to develop newer, possibly non-steroidal and non-hormonal, contraceptives. Recent advances in our understanding of ovarian endocrinology, coupled with molecular biology and transgenic technology, have enabled identification of several factors that are functionally critical in the regulation of female fertility. Progress in the area of female reproduction is showing great promise for identifying new contraceptive drug targets. In this article, the authors review the field of female contraception with emphasis on novel targets involved in reproductive function and identified through genomics and proteomics. In addition, the usefulness of these targets for contraception purposes will be discussed.
There is a strong relationship between cigarette smoking and haemostatic parameters to increase the risk of cardiovascular events. Smoking influences negatively coagulation-fibrinolysis cascade at any level, although it acts primarily on those pathways that are most important for an effective clot formation: endothelium, platelets, and fibrinogen. Endothelial dysfunction is a main consequence of smoke compounds with significant changes in initiating physiologic coagulation process; platelet adhesiveness and aggregation increases as a result of smoking; finally, fibrinogen/fibrin framework strengthens clot thickness. Therefore, the whole coagulation cascade activates the thrombi formation pathway under smoking action. The risk of thrombotic cardiovascular events increases its frequency with more severe atherosclerotic alterations if compared to similar events in nonsmokers. Changes in haemostatic factors produced by smoking appear to be related to female sex, especially for those women who use oral contraceptives. Thrombosis of coronary and cerebral arteries are found with a major incidence in young women who are users. In conclusion, cigarette smoking modifies haemostatic parameters via thrombosis with consequently more rate of cardiovascular events.
Papers p 820New evidence on myocardial infarction and the recent statement from the Medicines Commission giving a greater role to clinical judgment in choosing a contraceptive pill1 call for a reassessment of the role of third generation oral contraceptives containing desogestrel or gestodene. The shift to third generation pills in the early 1990s was largely based on claims of superior cardiovascular safety. We now have evidence on which to assess these claimsA lower risk of myocardial infarction in users of third compared with users of second generation pills was found in the Transnational study, although not in the British subgroup or in women aged under 35.2 However, the results did not take account of product specific differences in screening for hypertension before women started using the pill, which had a large effect in users of second generation pills (MA Lewis, personal communication). A similar influence had previously been found in the World Health Organisation study: in women whose blood pressure had been checked, the difference between the pill generations disappeared.3 It seems that undiagnosed hypertension was more common in second generation users …
PIP
Plasma fibrinogen was assayed in 4837 plasma specimens from women who took part in the Scottish Heart Health Study and the Scottish WHO MONICA survey. These samples included 13 women taking oral contraceptives, 210 women who had taken the pill, 2192 women still menstruating, and 2619 post-menopausal women. 66 women were taking hormone replacement medications (HRT). Fibrinogen levels did not differ significantly between current and former pill users. Menstruating women also had lower fibrinogen levels than postmenopausal women. The 66 women taking HRT, after than women not taking hormone replacement therapy, and had lower total cholesterol, blood pressure, and body mass index. Former oral contraceptive users had significantly lower fibrinogen than never users, even when age and smoking were controlled (p 0.001). Pill users also had significantly lower cholesterol, blood pressure and body mass index than never users, and a higher proportion of smokers. Premenopausal women had lower total and HDL cholesterol, blood pressure, body mass index than postmenopausal women. Some of these results could be accounted for by selection of healthier women for either oral contraception or HRT.
We examined the effects of past use of oral contraceptives on risks of cardiovascular diseases prospectively in the Nurses' Health Study cohort. The 119,061 participants were 30 to 55 years old and free of coronary disease or stroke in 1976. They provided information on biennial questionnaires and were followed for 8 years. There were 380 nonfatal myocardial infarctions and 105 deaths from coronary disease, 282 strokes, and 48 other cardiovascular deaths. We observed virtually no differences in the rates of various cardiovascular diseases between never and past users of oral contraceptives, regardless of duration of use or time since last use. For major coronary disease, the relative risk was 0.8 (95% confidence intervals, 0.6 to 1.0). A quantitative meta-analysis of 13 studies yielded an estimated relative risk of 1.01 (95% confidence intervals, 0.91 to 1.13) for coronary heart disease. Past use of oral contraceptives has little or no impact on risks of subsequent cardiovascular diseases.
Atherosclerosis, lipoprotein structure, lipoprotein metabolism and role in atherogenesis, epidemiology of lipoproteins and coronary artery disease, and current public health guidelines for cholesterol control are described. Low density lipoprotein cholesterol levels rise with age in both men and women. High density lipoprotein (HDL) levels decline after menopause. Special aspects of coronary risk in women include the stronger role of diabetes, hypertriglyceridemia and HDL. In addition, the effects of exogenous hormone therapy, both in the form or oral contraceptives and post menopausal hormone replacement should be considered. Careful attention to these issues may reduce cardiovascular morbidity in adult women.
In discussing the possible vascular complications of oral contraception, one must differentiate between venous and arterial effects. Different estrogen-progestogen combinations have different effects on the hemostatic system.
In 1969 this department reported on 42 women who had developed "idiopathic" venous thromboembolism while using oral contraceptives and 42 women who had developed the disease in the absence of such exposure. We have traced the subsequent history of these women to obtain information about recurrence of the disease.During the follow-up period the risk of recurrence of thromboembolism during pregnancy or the puerperium appeared to be much the same irrespective of whether or not oral contraceptives had been in use at the time of the index attack. Recurrences unassociated with childbearing however, occurred about four times more often among women who had not been using oral contraceptives at the time of the index attack than among women who had been doing so. None of these findings was influenced by the use of oral contraceptives during the follow-up period, since exposure to the preparations was negligible after the index attack.
Vital statistics and epidemiologic studies in Great Britain and the U.S. have shown that among nonpregnant women of reproductive age who are not using OCs (oral contraceptives) the risks of myocardial infarction and stroke increase substantially with age and in the presence of such risk factors as cigarette smoking and hypertension. The same statistics and studies show that OCs multiply instead of adding to the effects of age and these other risk factors. The pathogenesis of myocardial infarction that is attributable to OCs involves the effects of current use which are unrelated to duration and which disappear when OCs are discontinued and the effects of past use which are related to duration of use and which persist when OCs are discontinued. OCs are known to elevate blood pressure and decrease glucose tolerance slightly in most women. The net effect on high-density-lipoprotein cholesterol depends on the composition of the specific OC compounds. Among women under 35 who do not smoke the risks of death associated with OC cardiovascular effects are lower than the risks associated with complications of pregnancy and risks associated with other methods of contraception. Over 35 the risk of OC-related mortality rises substantially. For smokers the risk is even greater. Introduction of the very low dose estrogenic compounds may reduce these risks. Screening of susceptible high-risk women may also reduce OC-associated mortality.
Several studies suggest an association between the use of third-generation oral contraceptives (OCs) containing either desogestrel or gestodene and an increased risk of venous thromboembolism. Current users of third-generation OCs faced about a two-fold increased risk of thromboembolism than users of other OCs even after researchers controlled for possible confounding factors that increase the risk for thromboembolism e.g. smoking. These latest findings suggest that these OCs actually induce the increased risk of thromboembolism. One study showed that body mass index did not account for the added risk of thromboembolism to users of third-generation OCs. Another study found that family history of venous thrombosis did not increase the risk in third-generation OC users. It did find that nulligravidity and the factor V Leiden mutation contributed to the increased risk of venous thromboembolism in third-generation OC users. Health professionals should consider the size of both risks and benefits linked to various OCs when advising women to discontinue or not to begin using third-generation OCs. The increased risk of venous thromboembolism linked to a third generation OC beyond that linked to the use of an earlier OC is 10-15/100000 woman-years of use. Assuming a typical case fatality rate of around 1% the increased rate of fatal thromboembolism would range from 1 to 1.5/million woman-years. One study found that mortality from vascular diseases among current users of third-generation OCs is essentially the same as that of users of other OCs. No studies have examined any possible benefits from third-generation OC use in terms of incidence and mortality related to myocardial infarction or diabetes mellitus. Women and their health providers need to make their decision by weighing an increase albeit small in thromboembolism-related death against a possible decrease in the risk of other serious conditions.
Coronary heart disease has long been recognized as the leading cause of death among middle-aged men, but it is an equally important cause of death and disability among older women. By the age of 60 years, only 1 in 17 women in the United States has had a coronary event, as compared with 1 in 5 men. After the age of 60, however, coronary heart disease is the primary cause of death among women. In this age group, one in four women, as well as one in four men, die of coronary heart disease.1 The annual numbers of American women . . .
The risks of cardiovascular disease associated with dyslipidemia differ in women and men, being more strongly associated with triglyceride/high-density lipoprotein in middle-aged women than in men. Although the incidence of heart disease is lower in women because they live longer, over a lifetime, cardiovascular disease in women is equal to that in men, with the greatest incidence after age 65 years. Major coronary events are rare among reproductive-age women who use oral contraceptives and are related to the concomitant effects of age, smoking, diabetes, hypertension, and obesity. Low estrogen-progestin dose oral contraceptives appear not to promote cardiovascular disease and can be used in women with controlled cholesterol elevations. Alternative contraceptive measures should be considered for patients with severe uncontrolled hypercholesterolemia or a lipid disorder that carries a high risk of coronary heart disease. In these conditions, thrombotic propensity associated with supraphysiologic doses of estrogen in oral contraceptives might accelerate coronary thrombosis should an arteriosclerotic plaque rupture. Treatment of hypercholesterolemia should follow the guidelines of the National Cholesterol Education Program and emphasize hygienic measures. Contraceptive selection in hyperlipidemic patients should reflect a balance between the risks--and their management--of developing cardiovascular disease versus the risks of pregnancy.
The alterations in lipid metabolism that occur with the use of oral contraceptives (OCs) have aroused considerable concern that OCs might increase the risk of premature atherosclerosis. However, most studies examining the role of OCs in atherogenesis were performed using earlier-generation preparations employing larger doses of sex hormones than present formulation. Therefore, we undertook a comparative and standardized determination of the effects on lipid metabolism of six modern, low-dose OCs. This open, randomized, comparative study included patients recruited at 21 study centers throughout Europe. Four hundred sixty-six women, aged 18-38 years, participated. They were randomly assigned to the following OC formulations:(1) norgestimate 250 micrograms + ethinyl estradiol (EE) 35 micrograms (Cilest); (2) norgestimate 180/215/250 micrograms + EE 35 micrograms (Tricilest); (3) desogestrel 150 micrograms + EE 20 micrograms = (Marvelon); (4) desogestrel 150 micrograms + EE 30 micrograms (Mercilon); (5) gestodene 75 micrograms + EE 30 micrograms (Femovan); and (6) gestodene 50/70/100 micrograms + EE 30/40/30 micrograms (Trifemovan). There were three parallel studies with six parallel patient groups. Fasting blood samples were drawn at baseline (between days 24 and 28) and on days 18-22 of cycle 6, and cycle 12. Sample were analyzed for total cholesterol,high-density lipoprotein (HDL) cholesterol, HDL2 cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, apolipoprotein (apo)A1, and apoB at one central laboratory. Two hundred eighty-two women completed all 12 cycles and were included in the final evaluation. As expected, triglyceride and total cholesterol concentrations increased in all study groups but to lesser levels with the formulations containing gestodene. All OCs, except the monophasic gestodene preparation, slightly but significantly increased HDL. The HDL2 subfraction did ot change significantly except in the group using the monophasic gestodene preparation; in this group, the HDL2 subfraction slightly but significantly decreased. The LDL concentration increased slightly with the monophasic and triphasic norgestimate preparations and with desogestrel + 20 micrograms EE. The LDL/HDL ratio did not change significantly except with the use of the triphasic norgestimate preparation, in which case it decreased slightly. ApoA1 and apoB levels increased only slightly with all formulations. Importantly, while all of the OCs tested altered lipid levels to some extent, after 12 cycles there were no statistically significant differences in lipid effects among OC preparations. Modern, combined OCs that contain norgestimate, desogestrel, or gestodene all have some impact on lipid levels. However, it would appear likely that they do not contribute to atherogenesis in healthy women.
Recently, new information has been published about: a) the relationship between combination oral contraceptives (OCs), estrogen dose, cigarette smoking, and the risk of myocardial infarction (MI) and stroke; and b) the effect of different progestins on the risk of venous thromboembolism (VTE). We review the epidemiologic data. Regardless of age, in the absence of smoking, use of sub-50 micrograms OCs is not associated with any meaningful increase in risk of MI or stroke. If the small, statistically nonsignificant elevations in risk for these diseases are assumed (for the sake of argument) to be causal, then the incidence of MI and stroke associated with use of OCs containing less than 50 micrograms ethinyl estradiol (EE) would be approximately 2 per 100,000 per year. For women less than 35 years of age who do not smoke or do not have a history of hypertension, the risk would be even lower. Any woman over the age of 35 who smokes should be advised to use a non-estrogen or nonhormonal contraceptive. There are now two reports, from jick et al. and Lewis et al., that demonstrate that the relative risk of MI is certainly no greater for users of OCs containing desogestrel or gestodene than for users of OCs containing older progestins. In fact, both show reduced relative risks for the newer progestins compared to the older ones. With respect to progestins, four recent epidemiologic studies have indicated a twofold increased risk of nonfatal VTE with use of OCs containing desogestrel or gestodene compared with levonorgestrel. A fifth report, which showed an increased relative risk for norgestimate, is based on use among only 19 cases and 31 controls and is not statistically significant. As the authors themselves caution and as subsequent follow-up analyses and editorials conclude, these studies do not provide evidence for a cause-and-effect relationship between OCs containing desogestrel or gestodene, and VTE. The recommendation with respect to desogestrel- and gestodene-containing OCs is that no change in prescribing practices is warranted for either current or new-start patients. There is a growing body of evidence demonstrating that OCs containing 30 or 35 micrograms of EE have lower risks of MI, stroke, and VTE than higher dose OCs. However, there is no epidemiologic study that demonstrates a greater risk of vascular events among women using OCs containing 30 or 35 micrograms EE compared with preparations containing 20 micrograms EE. Users of sub-50 micrograms OCs of any age have no clinically meaningful increase in incidence of MI or stroke compared with non-OC users. This is also true for smokers under the age of 35 years who use OCs. However, smokers over the age of 35 years who use OCs still have an unacceptably high incidence rate of MI and stroke and should not use combination OCs. Sub-50 micrograms OCs of all types are associated with a small excess risk of VTE, about 15 per 100,000 events per year. Until there is biologic explanation of the twofold greater risk of VTE in users of OCs containing desogestrel or gestodene compared with users of those containing older progestins, this association should not be accepted as one of cause and effect.
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A review of the recent epidemiologic evidence indicates that use of low-dose combined oral contraceptives (OCs) is not associated with any clinically significant increase in risk of myocardial infarction (MI) or stroke, including for smokers under 35 years of age. Even if the small elevation in risk for these diseases is assumed to be causal, the incidence of both MI and stroke associated with use of OCs containing under 50 mcg of ethinyl estradiol would be only 2 per 100,000 events per year. This risk would be even lower for women under 35 years of age who do not smoke and have no history of hypertension. Two new reports have identified even lower relative risks of MI and stroke among users of OCs containing the progestins desogestrel and gestodene compared with users of second-generation OCs. However, four additional epidemiologic studies have revealed a two-fold increased risk of non-fatal venous thromboembolism for OCs containing desogestrel or gestodene compared to levonorgestrel; the excess risk is about 15 per 100,000 events per year. Until there is a biologic explanation of the greater thromboembolism risk in users of third-generation OCs, this association should not be viewed as causal and no change in OC prescribing practices is warranted for either current or new acceptors. However, smokers over 35 years of age should not use any combination OCs.
The objective of this study was to assess the risk of myocardial infarction (MI) associated with the use of new and old combination oral contraceptives (OC). A matched case-control study in 16 centers in Germany, the United Kingdom, France, Austria, and Switzerland explored the association of current use of combination OC with the occurrence of MI. Our subjects were 182 women aged 16-44 years with MI; the controls were 635 women without MI (at least one hospital control and one community control per case) matched for 5-year age group and region. The main outcome measures were odds ratios comparing current use of a specific group of OC against current use of other groups or against no current use. The adjusted overall odds ratio (OR; 95% confidence intervals) for MI for second generation OC versus no current use was 2.35 (1.42 to 3.89) and 0.82 (0.29 to 2.31) for third generation OC (low dose ethinyl estradiol, gestodene, and desogestrel). A direct comparison of third generation users with second generation users yielded an OR of 0.28 (0.09 to 0.86). In subgroup analyses, the odds ratio for the UK alone was 1.25 (0.36 to 4.29), while for continental Europe it was 0.10 (0.02 to 0.48). For hospital controls, the risk estimated was 0.98 (0.22 to 4.44), and 0.18 (0.04 to 0.65) for community controls. The independent risk of MI among current smokers adjusted for OC use was 7.21 (4.58 to 11.36). Among users of third generation OC, the OR for current smokers was 3.75 (0.65 to 21.74) and among users of second generation it was 9.50 (2.93 to 30.96). A comparison of OC use in the UK for the time before and after regulatory action was taken in October 1995 shows that the likelihood of a control (last control accrued June 1996) being treated with second generation OC is seven times higher after 1 November 1995 than it was before. Third generation OC are the first to be associated with no excess risk of MI. A significantly lower risk of MI is found when comparing use of third generation OC with use of second generation OC. There seems to be an impressive amelioration of risk among smokers using newer OC. An impact of regulatory action in the UK was found in the OC use spectrum of controls.
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The risk of myocardial infarction associated with use of second- and third-generation oral contraceptives (OCs) was investigated in a matched case-control study conducted at 16 centers in Germany, the UK, France, Austria, and Switzerland. 182 women 18-44 years old with myocardial infarction were matched for 5-year age group and region with 635 controls (at least 1 hospital control and 1 community control per case). 57 cases and 156 controls reported exposure to OCs, of whom 7 cases and 49 controls had taken third-generation formulations. The adjusted overall odds ratio (OR) for myocardial infarction was 2.35 (95% confidence interval [CI], 1.42-3.89) for second-generation OC use versus no use but only 0.82 (95% CI, 0.29-2.31) for third-generation OC use versus no use. A direct comparison of third-generation and second-generation OC users yielded an OR of 0.28 (95% CI, 0.09-0.86). 80% of cases, compared with 37% of controls, were current smokers. The independent risk of myocardial infarction among current smokers adjusted for OC use was 7.21 (95% CI, 4.58-11.36). The OR for current smokers was 3.75 (95% CI, 0.65-21.74) among users of third-generation OCs and 9.50 (95% CI, 2.93-30.96) among users of second-generation formulations. These Transnational Study findings indicate that third-generation formulations are the first OCs to be associated with no excess risk of myocardial infarction; moreover, they substantially reduce this risk among smokers. The reduced risk of myocardial infarction associated with OCs containing desogestrel and gestodene compared with levonorgestrel may reflect the failure of third-generation progestins to inhibit the estrogen-related increase in sex hormone binding globulin.
Four epidemiologic studies showed a twofold increase in risk of deep venous thrombosis with the use of oral contraceptives containing third-generation progestins, relative to second-generation products. These findings have been strongly debated ever since, and new studies have been added. In the current article we examine whether the findings can be explained by potential biases or other shortcomings of the epidemiologic studies. We conclude that complete certainty cannot exist but that the most rational conclusion from the epidemiologic findings and their discussion is that an increased risk of deep venous thrombosis with third-generation contraceptives is likely, especially in first-time and young users. The controversy has recently led to new insights in coagulation: Women who use third-generation contraceptives acquire a resistance to the blood's own anticoagulation system, similar to the activated protein C resistance that is seen in persons who carry the factor V Leiden mutation but different from that in women using second-generation contraceptives.
The most frequent major adverse effect of hormonal contraception is an increased risk of cardiovascular disease. The effect on the risk of venous thromboembolism (VTE), ischemic and hemorrhagic stroke, and myocardial infarction (MI) differs and is strongly influenced by smoking and the presence of other cardiovascular risks factors, such as hypertension and diabetes mellitus. The incidence of each disease rises with age and there are differences in risk among hormonal contraceptive preparations. This article provides a framework within which to assess the balance of risks among types of hormonal contraceptives according to individual circumstances.
Many lifestyle-related risk factors for coronary heart disease have been identified, but little is known about their effect on the risk of disease when they are considered together.
We followed 84,129 women participating in the Nurses' Health Study who were free of diagnosed cardiovascular disease, cancer, and diabetes at base line in 1980. Information on diet and lifestyle was updated periodically. During 14 years of follow-up, we documented 1128 major coronary events (296 deaths from coronary heart disease and 832 nonfatal infarctions). We defined subjects at low risk as those who were not currently smoking, had a body-mass index (the weight in kilograms divided by the square of the height in meters) under 25, consumed an average of at least half a drink of an alcoholic beverage per day, engaged in moderate-to-vigorous physical activity (which could include brisk walking) for at least half an hour per day, on average, and scored in the highest 40 percent of the cohort for consumption of a diet high in cereal fiber, marine n-3 fatty acids, and folate, with a high ratio of polyunsaturated to saturated fat, and low in trans fat and glycemic load, which reflects the extent to which diet raises blood glucose levels.
Many of the factors were correlated, but each independently and significantly predicted risk, even after further adjustment for age, family history, presence or absence of diagnosed hypertension or diagnosed high cholesterol level, and menopausal status. Women in the low-risk category (who made up 3 percent of the population) had a relative risk of coronary events of 0.17 (95 percent confidence interval, 0.07 to 0.41) as compared with all the other women. Eighty-two percent of coronary events in the study cohort (95 percent confidence interval, 58 to 93 percent) could be attributed to lack of adherence to this low-risk pattern.
Among women, adherence to lifestyle guidelines involving diet, exercise, and abstinence from smoking is associated with a very low risk of coronary heart disease.
The use of oral contraceptives first became widespread some 40 years ago, and reports of an excess risk of cardiovascular disease among women who used these agents soon followed. Because the risks seemed to be dose related, manufacturers created new formulations with a lower hormone content. Nonetheless, their use still carried an increased risk of myocardial infarction, mainly attributable to a striking synergistic interaction with cigarette smoking. Heavy smokers who used oral contraceptives had risks that were at least 30 times as high as those of women with neither risk factor.1,2 These extreme relative risks contrasted with the excess . . .
A healthy, sexually active, 35-year-old woman presents for advice about the use of oral contraceptives. She does not smoke cigarettes and has no personal or family history of venous thromboembolism, myocardial infarction, or stroke. Her blood pressure is 120/80 mm Hg. Should an oral contraceptive be prescribed, and if so, how should a formulation be chosen?
Lipid markers are well established predictors of vascular disease. The most frequently measured lipid variables are total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides. In this review we consider the predictive value of these variables and other more specialised related tests. We also discuss the effect of lipid altering drugs on these markers. The interaction of other vascular risk factors and the lipid effects of non-lipid altering drugs (e.g. blood pressure lowering agents) are also briefly described. Similarly, we discuss the effects of lipid lowering drugs on non-lipid vascular risk factors. Finally, we briefly consider the effect of altering the lipid profile on surrogate markers and events associated with atherosclerosis.
A 33 year old woman suffered a lateral myocardial infarction for the first time, and was treated by pre-hospital thrombolysis and secondary angioplasty on the diagonal artery. Fifteen days before the cardiac event she had undergone a left ovarian cyst excision and left salpingectomy for an ectopic pregnancy. She was a moderate smoker and had been taking a second-generation biphasic minidose oral contraceptive (ethinyl-estradiol 30-40mg and levonorgestrel 150-200 mg) for about ten years. Fifteen days before the myocardial infarction and due to the ectopic pregnancy she had changed to a combined monophasic minidose oral contraceptive pill containing ethinylestradiol (30 mg) and drospirenone (3 mg). The eventual outcome was favourable, with no complications. In this article we discuss the possible implications of the various factors (oral contraceptive, tobacco use, and surgical intervention) in this young woman with a myocardial infarction.
The mechanisms for drug interactions with smoking and clinically significant pharmacokinetic and pharmacodynamic drug interactions with smoking are reviewed.
Polycyclic aromatic hydrocarbons (PAHs) are some of the major lung carcinogens found in tobacco smoke. PAHs are potent inducers of the hepatic cytochrome P-450 (CYP) isoenzymes 1A1, 1A2, and, possibly, 2E1. After a person quits smoking, an important consideration is how quickly the induction of CYP1A2 dissipates. The primary pharmacokinetic interactions with smoking occur with drugs that are CYP1A2 substrates, such as caffeine, clozapine, fluvoxamine, olanzapine, tacrine, and theophylline. Inhaled insulin's pharmacokinetic profile is significantly affected, peaking faster and reaching higher concentrations in smokers compared with nonsmokers, achieving significantly faster onset and higher insulin levels. The primary pharmacodynamic drug interactions with smoking are hormonal contraceptives and inhaled corticosteroids. The most clinically significant interaction occurs with combined hormonal contraceptives. The use of hormonal contraceptives of any kind in women who are 35 years or older and smoke 15 or more cigarettes daily is considered contraindicated because of the increased risk of serious cardiovascular adverse effects. The efficacy of inhaled corticosteroids may be reduced in patients with asthma who smoke.
Numerous drug interactions exist with smoking. Therefore, smokers taking a medication that interacts with smoking may require higher dosages than nonsmokers. Conversely, upon smoking cessation, smokers may require a reduction in the dosage of an interacting medication.