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1.  Oral contraceptives and the risk of gallbladder disease: a comparative safety study 
Recent concerns have been raised about the risk of gallbladder disease associated with the use of drospirenone, a fourth-generation progestin used in oral contraceptives. We conducted a study to determine the magnitude of this risk compared with other formulations of oral contraceptives.
We conducted a retrospective cohort study using the IMS LifeLink Health Plan Claims Database. We included women who were using an oral contraceptive containing ethinyl estradiol combined with a progestin during 1997–2009. To be eligible, women had to have been taking the oral contraceptive continuously for at least six months. We computed adjusted rate ratios (RRs) for gallbladder disease using a Cox proportional hazards model. In the primary analysis, gallbladder disease was defined as cholecystectomy; in a secondary analysis, it was defined as hospital admission secondary to gallbladder disease.
We included 2 721 014 women in the cohort, 27 087 of whom underwent surgical or laparoscopic cholecystectomy during the follow-up period. Compared with levonorgestrel, an older second-generation progestin, a small, statistically significant increase in the risk of gallbladder disease was associated with desogestrel (adjusted RR 1.05, 95% confidence interval [CI] 1.01–1.09), drospirenone (adjusted RR 1.20, 95% CI 1.16–1.26) and norethindrone (adjusted RR 1.10, 95% CI 1.06–1.14). No statistically significant increase in risk was associated with the other formulations of oral contraceptive (ethynodiol diacetate, norgestrel and norgestimate).
In a large cohort of women using oral contraceptives, we found a small, statistically significant increase in the risk of gallbladder disease associated with desogestrel, drospirenone and norethindrone compared with levonorgestrel. However, the small effect sizes compounded with the possibility of residual biases in this observational study make it unlikely that these differences are clinically significant.
PMCID: PMC3091897  PMID: 21502354
2.  Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data 
Objective To compare the risk of non-fatal venous thromboembolism in women receiving oral contraceptives containing drospirenone with that in women receiving oral contraceptives containing levonorgestrel.
Design Nested case-control and cohort study.
Setting The study was based on information from PharMetrics, a United States based company that collects information on claims paid by managed care plans.
Participants The study encompassed all women aged 15 to 44 years who received an oral contraceptive containing either drospirenone or levonorgestrel after 1 January 2002. Cases were women with current use of a study oral contraceptive and a diagnosis of venous thromboembolism in the absence of identifiable clinical risk factors (idiopathic venous thromboembolism). Up to four controls were matched to each case by age and calendar time.
Main outcome measures Odds ratios comparing the risk of non-fatal venous thromboembolism in users of the two contraceptives; incidence rates and rate ratios of non-fatal venous thromboembolism for users of each of the study contraceptives.
Results 186 newly diagnosed, idiopathic cases of venous thromboembolism were identified in the study population and matched with 681 controls. In the case-control analysis, the conditional odds ratio for venous thromboembolism comparing use of oral contraceptives containing drospirenone with use of those containing levonorgestrel was 2.3 (95% confidence interval 1.6 to 3.2). The incidence rates for venous thromboembolism in the study population were 30.8 (95% confidence interval 25.6 to 36.8) per 100 000 woman years among users of oral contraceptives containing drospirenone and 12.5 (9.61 to 15.9) per 100 000 woman years among users of oral contraceptives containing levonorgestrel. The age adjusted incidence rate ratio for venous thromboembolism for current use of oral contraceptives containing drospirenone compared with those containing levonorgestrel was 2.8 (2.1 to 3.8).
Conclusions The risk of non-fatal venous thromboembolism among users of oral contraceptives containing drospirenone seems to be around twice that of users of oral contraceptives containing levonorgestrel, after the effects of potential confounders and prescribing biases have been taken into account.
PMCID: PMC3081040  PMID: 21511805
3.  Safety, efficacy, actions, and patient acceptability of drospirenone/ethinyl estradiol contraceptive pills in the treatment of premenstrual dysphoric disorder 
Premenstrual dysphoric disorder (PMDD) is estimated to affect 3%–8% of reproductive age women. Multiple therapeutic modalities have been evaluated with varying efficacy for the associated somatic and mood symptoms. The majority of older studies had shown that oral contraceptive pills (OCs) were most effective for the physical symptoms. However, newer OCs containing a novel progestin, drospirenone, have shown promise in alleviating both the somatic and affective/behavioral symptoms. This progestin, which is a derivative of spironolactone, has both antimineralocorticoid and antiandrogenic activity. A 24/4 formulation containing 20 μg of ethinyl estradiol has been found effective in randomized double-blind placebo-controlled trials utilizing established scales documenting symptoms associated with PMDD. Multiple studies have shown that drospirenone-containing OCs are safe without evidence of clinically adverse effects on carbohydrate metabolism, lipids, blood pressure, weight, serum potassium or increased thrombotic events compared to other low dose OCs. In addition, significant improvements have been demonstrated in acne, hirsutism, and fluid retention symptoms. Several open label studies demonstrated good patient compliance and reported satisfaction with the method. Because of the significant placebo effect demonstrated in the blinded placebo-controlled trials, additional large randomized placebo-controlled trials are needed to confirm the efficacy of the drospirenone OCs in the treatment of PMDD. However, this OC formulation appears to be a promising therapeutic modality.
PMCID: PMC2971718  PMID: 21072278
drospirenone; premenstrual dysphoric disorder; premenstrual syndrome; oral contraceptive pill
4.  Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database 
Objective To examine the risk of non-fatal idiopathic venous thromboembolism in current users of a combined oral contraceptive containing drospirenone, relative to current users of preparations containing levonorgestrel.
Design Nested case-control study.
Setting UK General Practice Research Database.
Participants Women aged 15-44 years without major risk factors for venous thromboembolism who started a new episode of use of an oral contraceptive containing 30 µg oestrogen in combination with either drospirenone or levonorgestrel between May 2002 and September 2009. Cases were women with a first diagnosis of venous thromboembolism; up to four controls, matched by age, duration of recorded information, and general practice, were randomly selected for each case.
Main outcome measures Odds ratios and 95% confidence intervals estimated with conditional logistic regression; age adjusted incidence rate ratio estimated with Poisson regression.
Results 61 cases of idiopathic venous thromboembolism and 215 matched controls were identified. In the case-control analysis, current use of the drospirenone contraceptive was associated with a threefold higher risk of non-fatal idiopathic venous thromboembolism compared with levonorgestrel use; the odds ratio adjusted for body mass index was 3.3 (95% confidence interval 1.4 to 7.6). Subanalyses suggested that referral, diagnostic, first time user, duration of use, and switching biases were unlikely explanations for this finding. The crude incidence rate was 23.0 (95% confidence interval 13.4 to 36.9) per 100 000 woman years in current users of drospirenone and 9.1 (6.6 to 12.2) per 100 000 woman years in current users of levonorgestrel oral contraceptives. The age adjusted incidence rate ratio was 2.7 (1.5 to 4.7).
Conclusions These findings contribute to emerging evidence that the combined oral contraceptive containing drospirenone carries a higher risk of venous thromboembolism than do formulations containing levonorgestrel.
PMCID: PMC3081041  PMID: 21511804
5.  Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9 
Objective To assess the risk of venous thromboembolism from use of combined oral contraceptives according to progestogen type and oestrogen dose.
Design National historical registry based cohort study.
Setting Four registries in Denmark.
Participants Non-pregnant Danish women aged 15-49 with no history of thrombotic disease and followed from January 2001 to December 2009.
Main outcome measures Relative and absolute risks of first time venous thromboembolism.
Results Within 8 010 290 women years of observation, 4307 first ever venous thromboembolic events were recorded and 4246 included, among which 2847 (67%) events were confirmed as certain. Compared with non-users of hormonal contraception, the relative risk of confirmed venous thromboembolism in users of oral contraceptives containing 30-40 µg ethinylestradiol with levonorgestrel was 2.9 (95% confidence interval 2.2 to 3.8), with desogestrel was 6.6 (5.6 to 7.8), with gestodene was 6.2 (5.6 to 7.0), and with drospirenone was 6.4 (5.4 to 7.5). With users of oral contraceptives with levonorgestrel as reference and after adjusting for length of use, the rate ratio of confirmed venous thromboembolism for users of oral contraceptives with desogestrel was 2.2 (1.7 to 3.0), with gestodene was 2.1 (1.6 to 2.8), and with drospirenone was 2.1 (1.6 to 2.8). The risk of confirmed venous thromboembolism was not increased with use of progestogen only pills or hormone releasing intrauterine devices. If oral contraceptives with desogestrel, gestodene, or drospirenone are anticipated to increase the risk of venous thromboembolism sixfold and those with levonorgestrel threefold, and the absolute risk of venous thromboembolism in current users of the former group is on average 10 per 10 000 women years, then 2000 women would need to shift from using oral contraceptives with desogestrel, gestodene, or drospirenone to those with levonorgestrel to prevent one event of venous thromboembolism in one year.
Conclusion After adjustment for length of use, users of oral contraceptives with desogestrel, gestodene, or drospirenone were at least at twice the risk of venous thromboembolism compared with users of oral contraceptives with levonorgestrel.
PMCID: PMC3202015  PMID: 22027398
6.  EE-drospirenone-levomefolate calcium versus EE-drospirenone + folic acid: folate status during 24 weeks of treatment and over 20 weeks following treatment cessation 
Adequate folate supplementation in the periconceptional phase is recommended to reduce the risk of neural tube defects. Oral contraceptives may provide a reasonable delivery vehicle for folate supplementation before conception in women of childbearing potential. This study aimed to demonstrate that a fixed-dose combination of an oral contraceptive and levomefolate calcium leads to sustainable improvements in folate status compared with an oral contraceptive + folic acid.
This was a double-blind, randomized, parallel-group study in which 172 healthy women aged 18–40 years received ethinylestradiol (EE)-drospirenone-levomefolate calcium or EE-drospirenone + folic acid for 24 weeks (invasion phase), and EE-drospirenone for an additional 20 weeks (folate elimination phase). The main objective of the invasion phase was to examine the area under the folate concentration time-curve for plasma and red blood cell (RBC) folate, while the main objective of the elimination phase was to determine the duration of time for which RBC folate concentration remained ≥ 906 nmol/L after cessation of EE-drospirenone-levomefolate calcium.
Mean concentration-time curves for plasma folate, RBC folate, and homocysteine were comparable between treatment groups during both study phases. During the invasion phase, plasma and RBC folate concentrations increased and approached steady-state after about 8 weeks (plasma) or 24 weeks (RBC). After cessation of treatment with levomefolate calcium, folate concentrations decreased slowly. The median time to RBC folate concentrations falling below 906 nmol/L was 10 weeks (95% confidence interval 8–12 weeks) after cessation of EE-drospirenone-levomefolate calcium treatment. Plasma and RBC folate levels remained above baseline values in 41.3% and 89.3% of women, respectively, at the end of the 20-week elimination phase.
Improvements in folate status were comparable between EE-drospirenone-levomefolate calcium and EE-drospirenone + folic acid. Plasma and RBC folate levels remained elevated for several months following cessation of treatment with EE-drospirenone-levomefolate calcium.
PMCID: PMC3628530  PMID: 23610531
drospirenone; ethinylestradiol; folic acid; levomefolate calcium; neural tube defect; oral contraception
7.  Hormonal contraception and risk of venous thromboembolism: national follow-up study 
Objective To assess the risk of venous thrombosis in current users of different types of hormonal contraception, focusing on regimen, oestrogen dose, type of progestogen, and route of administration.
Design National cohort study.
Setting Denmark, 1995-2005.
Participants Danish women aged 15-49 with no history of cardiovascular or malignant disease.
Main outcome measures Adjusted rate ratios for all first time deep venous thrombosis, portal thrombosis, thrombosis of caval vein, thrombosis of renal vein, unspecified deep vein thrombosis, and pulmonary embolism during the study period.
Results 10.4 million woman years were recorded, 3.3 million woman years in receipt of oral contraceptives. In total, 4213 venous thrombotic events were observed, 2045 in current users of oral contraceptives. The overall absolute risk of venous thrombosis per 10 000 woman years in non-users of oral contraceptives was 3.01 and in current users was 6.29. Compared with non-users of combined oral contraceptives the rate ratio of venous thrombembolism in current users decreased with duration of use (<1 year 4.17, 95% confidence interval 3.73 to 4.66, 1-4 years 2.98, 2.73 to 3.26, and >4 years 2.76, 2.53 to 3.02; P<0.001) and with decreasing dose of oestrogen. Compared with oral contraceptives containing levonorgestrel and with the same dose of oestrogen and length of use, the rate ratio for oral contraceptives with norethisterone was 0.98 (0.71 to 1.37), with norgestimate 1.19 (0.96 to 1.47), with desogestrel 1.82 (1.49 to 2.22), with gestodene 1.86 (1.59 to 2.18), with drospirenone 1.64 (1.27 to 2.10), and with cyproterone 1.88 (1.47 to 2.42). Compared with non-users of oral contraceptives, the rate ratio for venous thromboembolism in users of progestogen only oral contraceptives with levonorgestrel or norethisterone was 0.59 (0.33 to 1.03) or with 75 μg desogestrel was 1.12 (0.36 to 3.49), and for hormone releasing intrauterine devices was 0.90 (0.64 to 1.26).
Conclusion The risk of venous thrombosis in current users of combined oral contraceptives decreases with duration of use and decreasing oestrogen dose. For the same dose of oestrogen and the same length of use, oral contraceptives with desogestrel, gestodene, or drospirenone were associated with a significantly higher risk of venous thrombosis than oral contraceptives with levonorgestrel. Progestogen only pills and hormone releasing intrauterine devices were not associated with any increased risk of venous thrombosis.
PMCID: PMC2726928  PMID: 19679613
8.  Continuation rates of oral hormonal contraceptives in a cohort of first-time users: a population-based registry study, Sweden 2005–2010 
BMJ Open  2013;3(10):e003401.
To investigate if continuation rates in first-time users of oral hormonal contraceptives differed between different formulations and to measure if the rates were related to the prescribing categories, that is, physicians and midwives.
A longitudinal national population-based registry study.
The Swedish prescribed drug register.
All women born between 1977 and 1994 defined as first-time users of hormonal contraceptives from 2007 to 2009 (n=226 211).
Main outcome measures
A tendency to switch the type of hormonal contraceptive within 6 months use and repeated dispensation identical to the first were estimated as percentages and relative risks (RRs). Physicians’ and midwives’ prescription patterns concerning the women's continuation rates of oral hormonal contraceptive type.
In Sweden, there were 782 375 women born between 1977 and 1994 at the time of the study. Of these, 226 211 women were identified as first-time users of hormonal contraceptives. Ethinylestradiol+levonorgestrel, desogestrel-only and ethinylestradiol+drospirenone were the hormonal contraceptives most commonly dispensed to first-time users at rates of 43.3%, 24.4% and 11.1%, respectively. The overall rate of switching contraceptive types in the first 6 months was 11.3%, which was highest for desogestrel-only (14.3%) and lowest for ethinylestradiol+drospirenone (6.6%). The switching rate for all three products was highest in the 16-year to 19-year age group. Having a repeated dispensation identical to the initial dispensation was highest for users of ethinylestradiol either combined with levonorgestrel or drospirenone, 81.4% and 81.2%, respectively, whereas this rate for the initial desogestrel-only users was 71.5%. The RR of switching of contraceptive type within the first 6 months was 1.35 (95% CI 1.32 to 1.39) for desogestrel-only and 0.63 (0.59 to 0.66) for ethinylestradiol+drospirenone compared with ethinylestradiol+levonorgestrel as the reference category. There were no differences in the women's continuation rates depending on the prescriber categories.
Desogestrel-only users conferred the highest switcher rate to another hormonal contraceptive within a 6-month period. Users of ethinylestradiol+levonorgestrel were more prone to switch to another product within 6 months than women using ethinylestradiol+drospirenone. These findings may be of clinical importance when tailoring hormonal contraceptives on an individual basis.
PMCID: PMC3808784  PMID: 24141970
Public Health
9.  Differential Effects of 17β-Estradiol and of Synthetic Progestins on Aldosterone-Salt–Induced Kidney Disease 
Toxicologic pathology  2009;37(7):969-982.
Elevated mineralocorticoid levels and female sex hormones have been shown to confer opposing effects on renal injury, but their combined effects are still unknown.
Identify the function of estrogens and of different synthetic progestins on aldosterone salt–mediated renal disease.
The role of 17β-estradiol, medroxyprogesterone acetate (MPA), and drospirenone during renal injury was studied in Wistar rats subjected to uni-nephrectomy plus aldosterone salt treatment.
Aldo-salt treatment of intact, ovariectomized, and estradiol-treated female rats resulted in remnant kidney hypertrophy without structural damage. Co-treatment with MPA, but not with drospirenone, increased kidney hypertrophy, fluid turnover, sodium retention, and potassium excretion. Medroxyprogesterone acetate also caused glomerular, vascular, tubular, and interstitial lesions that were accompanied by increased blood pressure and enhanced NADPH oxidase (p67phox) and sodium channel (α-ENaC) expression. Drospirenone, a progestin with anti-mineralocorticoid function, and spironolactone prevented kidney hypertrophy, hypertension, and sodium retention. Drospirenone and spironolactone also increased renal angiotensin II type 2 receptor expression and relieved aldosterone-induced suppression of serum angiotensin II levels.
The choice of specific synthetic progestins has profound implications on the development of kidney injury and renal gene expression under conditions of elevated aldosterone serum levels and salt intake.
PMCID: PMC2843525  PMID: 19841131
sex; aldosterone; renal injury; progesterone; sex hormones
10.  The association between nonsteroidal anti-inflammatory drugs and potassium concentrations: A pharmacoepidemiological study in Saudi Arabia 
Several nonsteroidal anti-inflammatory drugs (NSAIDs) have been linked to cardiac death. The mechanism that is responsible for this adverse effect appears to be ischemic insult; however, another possible mechanism involves hyperkalemia. The objective of the present study was to determine the feasibility of conducting pharmacoepidemiological studies in Saudi Arabia using refill prescription data to investigate the association between NSAIDs and increased serum potassium concentrations.
This retrospective cohort study included patients from an academic medical center in Riyadh, Saudi Arabia. The patients who were recently prescribed NSAIDs were compared to a control group of paracetamol users, with respect to the drugs’ effects on serum potassium concentrations. The covariates that affected the potassium concentration or the use of NSAIDs were controlled for in the analysis. The studied outcome was the first serum potassium concentration of more than 5 mEq/L.
A total of 184 patients were prescribed NSAIDs (n = 101) or paracetamol (n = 83) and met the inclusion criteria. Compared to the control group, the patients who received NSAIDs were more likely to be women, were less likely to use angiotensin-converting enzyme inhibitors, and were more likely to have lower baseline serum creatinine concentrations. The other baseline characteristics were similar between the patients in the NSAID group and the patients who received paracetamol. Compared to the patients who were prescribed paracetamol, those who were prescribed NSAIDs did not have an increased risk of hyperkalemia (odds ratio, 1.1, 95% confidence interval, 0.17–6.7, P = 0.95).
In the present, small feasibility study, no increase in the risk of hyperkalemia was associated with NSAIDs compared to paracetamol. The present study was exploratory and included only a small number of patients; therefore, this study may not be sufficiently powered to detect small differences between the groups. Future studies with larger sample sizes are needed to investigate the association between NSAIDs and hyperkalemia.
PMCID: PMC3745074  PMID: 23960778
Pharmacoepidemiology; NSAIDs; Potassium
11.  The comparative study of Yaz and Ovocept-ld on patients with simple ovarian cysts referring to Iran-Isfahan Shariati Hospital 
Functional ovarian cysts include follicular, corpus luteum, and theca lutein cysts are the most common adnexal masses (about 50%) in women of reproductive age. Treatment with the combined monophasic oral contraceptives reduces functional ovarian cysts. Yaz (drospirenone/ethinyl estradiol) is a low-dose combined oral contraceptive pill containing 20 μg ethinyl estradiol and 3 mg drospirenone. In addition to contraceptive effects, Yaz has anti-mineralocorticoid and anti-adrenergic effects. Ovocept- low-dose LD is also a low-dose combined oral contraceptive drug containing 30 μg ethinyl estradiol and 3 mg norgestrol. Ovocept-LD has some side-effects such as weight gain, spotting, breast tenderness, nausea, and headache.
Materials and Methods:
Being a clinical study, the present research was carried out on 42 patients with the simple ovarian cysts from 2010 to 2012. 84 Patients were assigned to A and B groups. Group A received Yaz once a day for a period of 28 days and group B received Ovocept-LD once a day for a period of 21 days. After treating by Yaz and Ovocept-LD, Cysts were evaluated by ultrasound. Results were analyzed by the SPSS software. A P < 0.05 was considered the significance threshold.
Obtained results indicated that both Yaz and Ovocept-LD had an effect on the simple ovarian cysts. Statistical tests, however, has shown that the effect of Yaz has been significantly more than that of Ovocept-LD.
Given the faster and better recovery effect, and the lesser side effects of Yaz as compared to Ovocept-LD, it is recommended to use Yaz for the simple ovarian cysts.
PMCID: PMC4202506  PMID: 25337535
Ovocept-LD; simple ovarian cyst; Yaz
12.  A combined oral contraceptive containing 30 mcg ethinyl estradiol and 3.0 mg drospirenone does not impair endothelium-dependent vasodilation 
Contraception  2010;82(4):366-372.
Ethinyl estradiol (EE) increases endothelium-dependent vasodilation in young women, but certain progestins paired with EE in combination OCPs have been shown to antagonize the vasodilatory effects of EE. Therefore, the purpose of this study was to investigate how endothelial function, serum biomarkers, and resting blood pressures change across an OCP cycle in women using a monophasic OCP formulation containing the progestin drospirenone.
Study Design
Twelve women were studied during two hormone phases of their OCP cycle; once at the end of three weeks of active pills (30 mcg EE and 3.0 mg drospirenone), and once at the end of a week of placebo pills (no exogenous hormones).
Endothelium-dependent vasodilation was greater during the active phase compared to the placebo phase (p < 0.001). In contrast, there was no difference in endothelium-independent dilation between hormone phases.
These data suggest that the combination of 30 mcg EE and 3.0 mg drospirenone used in the active phase of this OCP increases endothelium-dependent vasodilation compared to a placebo phase.
PMCID: PMC2943430  PMID: 20851231
progestin; estrogen; vasodilation; birth control pills; drospirenone; blood pressure
13.  Efficacy and safety of combined ethinyl estradiol/drospirenone oral contraceptives in the treatment of acne 
Acne is a common disorder affecting the majority of adolescents and often extends into adulthood. The central pathophysiological feature of acne is increased androgenic stimulation and/or end-organ sensitivity of pilosebaceous units leading to sebum hypersecretion and infundibular hyperkeratinization. These events lead to Propionibacterium acnes proliferation and subsequent inflammation. Hormonal therapy, including combined oral contraceptives (OCs), can attenuate the proximate androgenic trigger of this sequence. For many women, hormonal therapy is a rational option for acne treatment as it may be useful across the spectrum of severity. Drospirenone (DRSP) is a unique progestin structurally related to spironolactone with progestogenic, antimineralocorticoid, and antiandrogenic properties. It is available in 2 combined OC preparations (30 μg EE/3 mg DRSP; Yasmin® in a 21/7 regimen; and 20 μg EE/3 mg DRSP; Yaz® in a 24/4 regimen). These preparations are bereft of the fluid retentional side effects typical of other progestins and their safety has been demonstrated in large epidemiological studies in which no increased risk of vascular thromboembolic disease or arrhythmias was observed. In acne, the efficacy of DRSP-containing OCs has been shown in placebo-controlled superiority trials and in active-comparator non-inferiority trials.
PMCID: PMC2971705  PMID: 21072290
acne vulgaris; combined oral contraceptives; drosperinone; ethinyl estradiol; efficacy; safety; treatment
14.  Diabetes and Drug-Associated Hyperkalemia: Effect of Potassium Monitoring 
Renin-angiotensin-aldosterone system (RAAS) inhibitors are associated with hyperkalemia, but there is little evidence demonstrating patients who receive potassium monitoring have a lower rate of hyperkalemia.
To evaluate the association between potassium monitoring and serious hyperkalemia-associated adverse outcomes among patients with diabetes newly initiating RAAS inhibitor therapy.
Retrospective observational study.
Patients with diabetes without end-stage renal disease initiating RAAS inhibitor therapy between 2001 and 2006 at three integrated health care systems.
Potassium monitoring and first hyperkalemia-associated adverse event during the initial year of therapy. Hyperkalemia-associated adverse events included hospitalizations, emergency department visits or deaths within 24 h of hyperkalemia diagnosis and/or diagnostic potassium ≥6 mmol/l. Incidence rates were calculated in person-years (p-y). We used inverse probability propensity score weighting to adjust for differences between patients with and without monitoring; Poisson regression was used to obtain adjusted relative risks.
A total of 19,391 of 27,355 patients (71%) received potassium monitoring. Serious hyperkalemia-associated events occurred at an incidence rate of 10.2 per 1,000 p-y. Compared to patients without monitoring, adjusted relative risk of hyperkalemia-associated adverse events among all patients with monitoring was 0.50 (0.37, 0.66); in the subset of patients who also had chronic kidney disease (n = 2,176), adjusted relative risk was 0.29 (0.18, 0.46).
Patients prescribed RAAS inhibitors who have both diabetes and chronic kidney disease and receive potassium monitoring are less likely to experience a serious hyperkalemia-associated adverse event compared to similar patients who did not receive potassium monitoring. This evidence supports existing consensus-based guidelines.
PMCID: PMC2842549  PMID: 20087674
hyperkalemia; hyperpotassemia; angiotensin-converting enzyme inhibitor; ACEi; angiotensin receptor blocker; ARB; spironolactone; RAAS inhibitor
15.  A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers 
Background and objectives
Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are increasingly used in a variety of settings including heart failure, renal failure, arterial hypertension, and diabetic nephropathy. The objective of this study was to investigate the prevalence of hyperkalemia with ACEI and ARB use, in a population of the United States veterans.
Design, settings, material, and measurements
Retrospective observational cohort study of 1163 patients on ACEIs and 1168 patients on ARBs in a single Veterans Affairs Medical Center. Electronic medical records were reviewed over a 12-month period with data collected on various demographic, laboratory, comorbidity, and medication related variables.
Hyperkalemia (>5 mEq/L) was observed in 20.4% of patients on ACEIs and 31.0% on ARBs. Severe hyperkalemia (6 mEq/L or higher), was observed in 0.8% of ACEI and 2.8% of ARB users. In univariate logistic regression analyses, diabetes mellitus; serum glucose, total carbon dioxide content, creatinine, and estimated glomerular filtration rate (GFR) were significantly associated with hyperkalemia. ARB use, when compared to ACEI, was associated with a 42% increase in odds of hyperkalemia (odds ratio [OR] = 1.42; p = 0.001) in a model including adjustment for GFR and a 56% increase in odds of hyperkalemia (OR = 1.56; p < 0.001) in a model including adjustment for serum creatinine.
Hyperkalemia, associated with the use of ACEIs and ARBs, is usually mild and severe hyperkalemia is rare. Hyperkalemia is more common with ARBs than ACEIs. ARB use, when compared to ACEI use, may significantly and independently be associated with increased odds of hyperkalemia.
PMCID: PMC2710386  PMID: 19707264
hyperkalemia; angiotensin-converting enzyme inhibitors; angiotensin receptor blockers
16.  The Positive Predictive Value of a Hyperkalemia Diagnosis in Automated Health Care Data 
Pharmacoepidemiology and drug safety  2010;19(11):1204-1208.
Our objectives were to determine performance of coded hyperkalemia diagnosis at identifying 1) clinically-evident hyperkalemia and 2) serum potassium ≥ 6 mmol/liter.
This retrospective observational study included 8,722 patients with diabetes within an integrated healthcare system who newly-initiated an angiotensin converting enzyme inhibitor, angiotensin receptor blocker, or spironolactone. The primary outcome was first hyperkalemia-associated event (hospitalization, emergency department visit or death within 24 hours of coded diagnosis and/or potassium ≥ 6 mmol/liter) during the first year of therapy. Medical records were reviewed.
Among a random sample of 99 patients not coded as having hyperkalemia, none had hyperkalemia upon record review. Among all 64 patients identified as having hyperkalemia, all had hospitalization or emergency department visit associated with coded diagnosis or elevated potassium. Of 55 with coded diagnosis, 42 (PPV 76%) had clinically-evident hyperkalemia; 32 (PPV 58%) had potassium ≥ 6. Of 9 identified using only potassium ≥ 6, 7 (PPV 78%) had clinically-evident hyperkalemia.
Nearly one-fourth of patients with coded diagnosis do not have clinically-evident hyperkalemia and nearly one-half do not have potassium ≥ 6. Because both false positives and negatives occur with coded diagnoses, medical record validation of hyperkalemia-associated outcomes is necessary.
PMCID: PMC2996391  PMID: 20878650
Hyperkalemia; positive predictive value; sensitivity; specificity; ACEi; ARB
17.  Risk of Hyperkalemia in Nondiabetic Patients With Chronic Kidney Disease Receiving Antihypertensive Therapy 
Transplantation  2011;92(7):10.1097/TP.0b013e31822dc36b.
The incidence and factors associated with hyperkalemia in patients with chronic kidney disease (CKD) treated with angiotensin converting enzyme inhibitors (ACEIs) and other antihypertensive drugs was investigated using the African American Study of Kidney Disease and Hypertension (AASK) database.
A total of 1094 nondiabetic adults with hypertensive CKD (glomerular filtration rate [GFR], 20–65 mL/min/1.73 m2) were followed for 3.0 to 6.4 years in the AASK trial. Participants were randomly assigned to ACEI, β-blocker (BB), or dihydropyridine calcium channel blocker (CCB). The outcome variables for this analysis were a serum potassium level higher than 5.5 mEq/L (to convert to millimoles per liter, multiply by 1.0), or a clinical center initiated hyperkalemia stop point.
A total of 6497 potassium measurements were obtained, and 80 events in 51 subjects were identified (76 events driven by a central laboratory result and 4 driven by a clinical center–initiated hyperkalemia stop point). Compared with a GFR higher than 50 mL/min/1.73 m2, after multivariable adjustment, the hazard ratio (HR) for hyperkalemia in patients with a GFR between 31 and 40 mL/min/1.73 m2 and a GFR lower than 30 mL/min/1.73 m2 was 3.61 (95% confidence interval [CI], 1.42–9.18 [P=.007]) and 6.81 (95% CI, 2.67–17.35 [P<.001]), respectively; there was no increased risk of hyperkalemia if GFR was 41 to 50 mL/min/1.73 m2. Use of ACEIs was associated with more episodes of hyperkalemia compared with CCB use (HR, 7.00; 95% CI, 2.29–21.39 [P<.001]) and BB group (HR, 2.85; 95% CI, 1.50–5.42 [P=.001]). Diuretic use was associated with a 59% decreased risk of hyperkalemia.
In nondiabetic patients with hypertensive CKD treated with ACEIs, the risk of hyperkalemia is small, particularly if baseline and follow-up GFR is higher than 40 mL/min/1.73 m2. Including a diuretic in the regimen may markedly reduce risk of hyperkalemia.
PMCID: PMC3831506  PMID: 21832957
18.  Severe hyperkalemia requiring hospitalization: predictors of mortality 
Critical Care  2012;16(6):R225.
Severe hyperkalemia, with potassium (K+) levels ≥ 6.5 mEq/L, is a potentially life-threatening electrolyte imbalance. For prompt and effective treatment, it is important to know its risk factors, clinical manifestations, and predictors of mortality.
An observational cohort study was performed at 2 medical centers. A total of 923 consecutive Korean patients were analyzed. All were 19 years of age or older and were hospitalized with severe hyperkalemia between August 2007 and July 2010; the diagnosis of severe hyperkalemia was made either at the time of admission to the hospital or during the period of hospitalization. Demographic and baseline clinical characteristics at the time of hyperkalemia diagnosis were assessed, and clinical outcomes such as in-hospital mortality were reviewed, using the institutions' electronic medical record systems.
Chronic kidney disease (CKD) was the most common underlying medical condition, and the most common precipitating factor of hyperkalemia was metabolic acidosis. Emergent admission was indicated in 68.6% of patients, 36.7% had electrocardiogram findings typical of hyperkalemia, 24.5% had multi-organ failure (MOF) at the time of hyperkalemia diagnosis, and 20.3% were diagnosed with severe hyperkalemia at the time of cardiac arrest. The in-hospital mortality rate was 30.7%; the rate was strongly correlated with the difference between serum K+ levels at admission and at their highest point, and with severe medical conditions such as malignancy, infection, and bleeding. Furthermore, a higher in-hospital mortality rate was significantly associated with the presence of cardiac arrest and/or MOF at the time of diagnosis, emergent admission, and intensive care unit treatment during hospitalization. More importantly, acute kidney injury (AKI) in patients with normal baseline renal function was a strong predictor of mortality, compared with AKI superimposed on CKD.
Severe hyperkalemia occurs in various medical conditions; the precipitating factors are similarly diverse. The mortality rate is especially high in patients with severe underlying disease, coexisting medical conditions, and those with normal baseline renal function.
PMCID: PMC3672605  PMID: 23171442
19.  Mild hyperkalemia and outcomes in chronic heart failure: A propensity matched study 
International journal of cardiology  2009;144(3):383-388.
Compared with serum potassium levels 4–5.5 mEq/L, those <4 mEq/L have been shown to increase mortality in chronic heart failure (HF). Expert opinions suggest that serum potassium levels >5.5 mEq/L may be harmful in HF. However, little is known about the safety of serum potassium 5–5.5 mEq/L.
Of the 7788 chronic HF patients in the Digitalis Investigation Group trial, 5656 had serum potassium 4–5.5 mEq/L. Of these, 567 had mild hyperkalemia (5–5.5 mEq/L) and 5089 had normokalemia (4–4.9 mEq/L). Propensity scores for mild hyperkalemia were used to assemble a balanced cohort of 548 patients with mild hyperkalemia and 1629 patients with normokalemia. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for association between mild hyperkalemia and mortality during a median follow-up of 38 months.
All-cause mortality occurred in 36% and 38% of matched patients with normokalemia and mild hyperkalemia respectively (HR, 1.07; 95% CI, 0.90–1.26; P= 0.458). Unadjusted, multivariable-adjusted, and propensity-adjusted HRs for mortality associated with mild hyperkalemia were 1.33 (95% CI, 1.15–1.52; P<0.0001), 1.16 (95% CI, 1.01–1.34; P=0.040) and 1.13 (95% CI, 0.98–1.31; P=0.091) respectively. Mild hyperkalemia had no association with cardiovascular or HF mortality or all-cause or cardiovascular hospitalization.
Serum potassium 4–4.9 mEq/L is optimal and 5–5.5 mEq/L appears relatively safe in HF. Despite lack of an intrinsic association, the bivariate association of mild-hyperkalemia with mortality suggests that it may be useful as a biomarker of poor prognosis in HF.
PMCID: PMC2888731  PMID: 19500863
Mild hyperkalemia; heart failure; mortality; hospitalization
20.  Implementation and evaluation of a nurse-centered computerized potassium regulation protocol in the intensive care unit - a before and after analysis 
Potassium disorders can cause major complications and must be avoided in critically ill patients. Regulation of potassium in the intensive care unit (ICU) requires potassium administration with frequent blood potassium measurements and subsequent adjustments of the amount of potassium administrated. The use of a potassium replacement protocol can improve potassium regulation. For safety and efficiency, computerized protocols appear to be superior over paper protocols. The aim of this study was to evaluate if a computerized potassium regulation protocol in the ICU improved potassium regulation.
In our surgical ICU (12 beds) and cardiothoracic ICU (14 beds) at a tertiary academic center, we implemented a nurse-centered computerized potassium protocol integrated with the pre-existent glucose control program called GRIP (Glucose Regulation in Intensive Care patients). Before implementation of the computerized protocol, potassium replacement was physician-driven. Potassium was delivered continuously either by central venous catheter or by gastric, duodenal or jejunal tube. After every potassium measurement, nurses received a recommendation for the potassium administration rate and the time to the next measurement. In this before-after study we evaluated potassium regulation with GRIP. The attitude of the nursing staff towards potassium regulation with computer support was measured with questionnaires.
The patient cohort consisted of 775 patients before and 1435 after the implementation of computerized potassium control. The number of patients with hypokalemia (<3.5 mmol/L) and hyperkalemia (>5.0 mmol/L) were recorded, as well as the time course of potassium levels after ICU admission. The incidence of hypokalemia and hyperkalemia was calculated. Median potassium-levels were similar in both study periods, but the level of potassium control improved: the incidence of hypokalemia decreased from 2.4% to 1.7% (P < 0.001) and hyperkalemia from 7.4% to 4.8% (P < 0.001). Nurses indicated that they considered computerized potassium control an improvement over previous practice.
Computerized potassium control, integrated with the nurse-centered GRIP program for glucose regulation, is effective and reduces the prevalence of hypo- and hyperkalemia in the ICU compared with physician-driven potassium regulation.
PMCID: PMC2826292  PMID: 20100342
21.  Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: a population-based cohort study 
Combined oral contraceptives are a common method of contraception, but they carry a risk of venous and arterial thrombosis. We assessed whether use of drospirenone was associated with an increase in thrombotic risk relative to third-generation combined oral contraceptives.
Using computerized records of the largest health care provider in Israel, we identified all women aged 12 to 50 years for whom combined oral contraceptives had been dispensed between Jan. 1, 2002, and Dec. 31, 2008. We followed the cohort until 2009. We used Poisson regression models to estimate the crude and adjusted rate ratios for risk factors for venous thrombotic events (specifically deep vein thrombosis and pulmonary embolism) and arterial thromboic events (specifically transient ischemic attack and cerebrovascular accident). We performed multivariable analyses to compare types of contraceptives, with adjustment for the various risk factors.
We identified a total of 1017 (0.24%) venous and arterial thrombotic events among 431 223 use episodes during 819 749 woman-years of follow-up (6.33 venous events and 6.10 arterial events per 10 000 woman-years). In a multivariable model, use of drospirenone carried an increased risk of venous thrombotic events, relative to both third-generation combined oral contraceptives (rate ratio [RR] 1.43, 95% confidence interval [CI] 1.15–1.78) and second-generation combined oral contraceptives (RR 1.65, 95% CI 1.02–2.65). There was no increase in the risk of arterial thrombosis with drospirenone.
Use of drospirenone-containing oral contraceptives was associated with an increased risk of deep vein thrombosis and pulmonary embolism, but not transient ischemic attack or cerebrovascular attack, relative to second- and third-generation combined oral contraceptives.
PMCID: PMC3255137  PMID: 22065352
22.  Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis 
Objective To provide a comprehensive overview of the risk of venous thrombosis in women using different combined oral contraceptives.
Design Systematic review and network meta-analysis.
Data sources PubMed, Embase, Web of Science, Cochrane, Cumulative Index to Nursing and Allied Health Literature, Academic Search Premier, and ScienceDirect up to 22 April 2013.
Review methods Observational studies that assessed the effect of combined oral contraceptives on venous thrombosis in healthy women. The primary outcome of interest was a fatal or non-fatal first event of venous thrombosis with the main focus on deep venous thrombosis or pulmonary embolism. Publications with at least 10 events in total were eligible. The network meta-analysis was performed using an extension of frequentist random effects models for mixed multiple treatment comparisons. Unadjusted relative risks with 95% confidence intervals were reported. The requirement for crude numbers did not allow adjustment for potential confounding variables.
Results 3110 publications were retrieved through a search strategy; 25 publications reporting on 26 studies were included. Incidence of venous thrombosis in non-users from two included cohorts was 1.9 and 3.7 per 10 000 woman years, in line with previously reported incidences of 1-6 per 10 000 woman years. Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). The relative risk of venous thrombosis for combined oral contraceptives with 30-35 µg ethinylestradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk.
Conclusion All combined oral contraceptives investigated in this analysis were associated with an increased risk of venous thrombosis. The effect size depended both on the progestogen used and the dose of ethinylestradiol.
PMCID: PMC3771677  PMID: 24030561
23.  Treatment of premenstrual dysphoric disorder (PMDD) with a novel formulation of drospirenone and ethinyl estradiol 
Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS). Pharmacologic options studied for treating severe PMS and PMDD may include selective serotonin reuptake inhibitors, anxiolytic agents, gonadotropin-releasing hormone agonists and the diuretic spironolactone. However, the use of combined oral contraceptives (COC) may be a therapeutic option in treating PMS and PMDD. The combination of drospirenone with ethinylestradiol (EE/drospirenone) was approved for marketing as an oral contraceptive in Europe and the United States. The preparation is characterized by a high contraceptive efficacy in combination with excellent cycle control, good tolerability, and a favourable impact on lipid and glucose metabolism. Recently, some placebo-controlled, randomized studies have tested clinical efficacy and tolerability of this COC in the treatment of PMDD. The aim of the present review was to elucidate the possible benefits or disadvantages of PMDD treatment with this novel formulation of EE/drospirenone. The results of trials evaluating the use of EE/drospirenone combination in the treatment of PMDD are encouraging but further studies are needed. However, the reported clinical efficacy and the relative good tolerability of EE/drospirenone may contribute to widen the therapeutic spectrum of PMDD.
PMCID: PMC2374943  PMID: 18472980
Premenstrual dysphoric disord©er; oral contraceptives; drospirenone; ethinylestradiol; efficacy; tolerability
24.  International Active Surveillance Study of Women Taking Oral Contraceptives (INAS-OC Study) 
A 24-day regimen of contraceptive doses of drospirenone and ethinylestradiol (DRSP/EE 24d) was recently launched. This regimen has properties which may be beneficial for certain user populations (e.g., women suffering from premenstrual dysphoric disorder or acne). However, it is unknown whether this extended regimen has an impact on the cardiovascular risk associated with the use of oral contraceptives (OCs). The INternational Active Surveillance study of women taking Oral Contraceptives (INAS-OC) is designed to investigate the short- and long-term safety of the new regimen in a population which is representative for the typical user of oral contraceptives.
A large, prospective, controlled, non-interventional, long-term cohort study with active surveillance of the study participants has been chosen to ensure reliable and valid results. More than 2,000 gynecologists in the US and 5 European countries (Austria, Germany, Italy, Poland, and Sweden) will recruit more than 80,000 OC users. The two to five year follow-up of these women will result in at least 220,000 documented women-years.
The main clinical outcomes of interest for the follow-up are deep venous thrombosis, pulmonary embolism, acute myocardial infarction and cerebrovascular accidents. Secondary objectives are general safety, effectiveness and drug utilization pattern of DRSP/EE 24d, return to fertility after stop of OC use, as well as the baseline risk for users of individual OC formulations.
Because of the non-interference character of this study, potential participants (first-time users or switchers) are informed about the study only after the decision regarding prescription of a new OC. There are no specific medical inclusion or exclusion criteria. Study participation is voluntary and a written informed consent is required. After the baseline questionnaire, follow-up questionnaires will be mailed to the participants every 6 months for up to 5 years after baseline. Self-reported serious adverse events will be validated by contacting the relevant physician and by reviewing relevant source documents. At the end of the study an independent blinded adjudication of relevant clinical outcomes will be conducted.
Meanwhile, this study has received ethical approval from the Western Institutional Review Board (USA) and the Medical Association in Berlin (Germany).
The feasibility of the study is considered to be very high because of its similar design to the EURAS-OC study. All relevant methodological and logistical features of the study were successfully tested in the EURAS study.
The chosen design minimizes the impact of referral and misclassification bias, healthy user effect and loss to follow-up. Overall, it is expected that the study design is robust enough to interpret hazard ratios of 1.5 or higher.
PMCID: PMC2784801  PMID: 19922634
25.  The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study 
Objective To assess the thrombotic risk associated with oral contraceptive use with a focus on dose of oestrogen and type of progestogen of oral contraceptives available in the Netherlands.
Design Population based case-control study.
Setting Six participating anticoagulation clinics in the Netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht).
Participants Premenopausal women <50 years old who were not pregnant, not within four weeks postpartum, and not using a hormone excreting intrauterine device or depot contraceptive. Analysis included 1524 patients and 1760 controls.
Main outcome measures First objectively diagnosed episodes of deep venous thrombosis of the leg or pulmonary embolism. Odds ratios calculated by cross-tabulation with a 95% confidence interval according to Woolf’s method; adjusted odds ratios estimated by unconditional logistic regression, standard errors derived from the model.
Results Currently available oral contraceptives increased the risk of venous thrombosis fivefold compared with non-use (odds ratio 5.0, 95% CI 4.2 to 5.8). The risk clearly differed by type of progestogen and dose of oestrogen. The use of oral contraceptives containing levonorgestrel was associated with an almost fourfold increased risk of venous thrombosis (odds ratio 3.6, 2.9 to 4.6) relative to non-users, whereas the risk of venous thrombosis compared with non-use was increased 5.6-fold for gestodene (5.6, 3.7 to 8.4), 7.3-fold for desogestrel (7.3, 5.3 to 10.0), 6.8-fold for cyproterone acetate (6.8, 4.7 to 10.0), and 6.3-fold for drospirenone (6.3, 2.9 to 13.7). The risk of venous thrombosis was positively associated with oestrogen dose. We confirmed a high risk of venous thrombosis during the first months of oral contraceptive use irrespective of the type of oral contraceptives.
Conclusions Currently available oral contraceptives still have a major impact on thrombosis occurrence and many women do not use the safest brands with regard to risk of venous thrombosis.
PMCID: PMC2726929  PMID: 19679614

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