Mary Jane Geiger

Relationship Between Osteoporosis and Cardiovascular Disease in Postmenopausal Women

In the placebo group of the MORE study, including 2576 postmenopausal women (mean age, 66.5 years), the authors describe a strong linear association between the severity grade of osteoporosis (from low BMD to presence of severe vertebral fractures) and the future risk of cardiovascular events. Accordingly, treatment of postmenopausal osteoporosis should include consideration of measures to prevent adverse cardiovascular outcomes.

ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia

Aims To assess long-term (78 weeks) alirocumab treatment in patients with heterozygous familial hypercholesterolaemia (HeFH) and inadequate LDL-C control on maximally tolerated lipid-lowering therapy (LLT). Methods and results In two randomized, double-blind studies (ODYSSEY FH I, n = 486; FH II, n = 249), patients were randomized 2 : 1 to alirocumab 75 mg or placebo every 2 weeks (Q2W). Alirocumab dose was increased at Week 12 to 150 mg Q2W if Week 8 LDL-C was ≥1.8 mmol/L (70 mg/dL). Primary endpoint (both studies) was percentage change in calculated LDL-C from baseline to Week 24. Mean LDL-C levels decreased from 3.7 mmol/L (144.7 mg/dL) at baseline to 1.8 mmol/L (71.3 mg/dL; −57.9% vs. placebo) at Week 24 in patients randomized to alirocumab in FH I and from 3.5 mmol/L (134.6 mg/dL) to 1.8 mmol/L (67.7 mg/dL; −51.4% vs. placebo) in FH II (P < 0.0001). These reductions were maintained through Week 78. LDL-C <1.8 mmol/L (regardless of cardiovascular risk) was achieved at Week 24 by 59.8 and 68.2% of alirocumab-treated patients in FH I and FH II, respectively. Adverse events resulted in discontinuation in 3.4% of alirocumab-treated patients in FH I (vs. 6.1% placebo) and 3.6% (vs. 1.2%) in FH II. Rate of injection site reactions in alirocumab-treated patients was 12.4% in FH I and 11.4% in FH II (vs. 11.0 and 7.4% with placebo). Conclusion In patients with HeFH and inadequate LDL-C control at baseline despite maximally tolerated statin ± other LLT, alirocumab treatment resulted in significant LDL-C lowering and greater achievement of LDL-C target levels and was well tolerated. Clinical trial registration Cinicaltrials.gov (identifiers: NCT01623115; NCT01709500).

Implantable Cardioverter-Defibrillators and Pregnancy A Safe Combination?

BACKGROUND The purpose of this investigation was to evaluate the outcome of pregnancy in women with implantable cardioverter-defibrillators (ICDs). METHODS AND RESULTS A multicenter retrospective analysis was performed on women with an ICD who became pregnant. Data were collected on 44 patients. The mean age and ejection fraction at the time of the initial ICD implant were 25.6+/-4.9 years and 49.8+/-9.7%, respectively. The mean follow-up after the ICD implant was 4.8+/-2.8 years. Forty-two women had abdominally implanted generators, and 2 had a prepectoral device. Thirty had epicardial lead sensing systems, and 14 had transvenous. Thirty-six (82%) experienced no complications, and 8 (18%) had a medical or device-related complication. The ICD-related problems included tenderness at the ICD pocket scar (2 patients), generator migration (1), and pericarditis secondary to the epicardial patches (1). Medical complications were pulmonary embolism (1), therapeutic abortion (1), worsening hyperthyroidism (1), congestive heart failure (1), and weight loss (1). Thirty-seven women delivered vaginally, and 7 underwent cesarean section. Thirty-nine babies were born healthy, 1 was stillborn, 2 were small for gestational age, 1 had transient hypoglycemia, and 1 woman had a therapeutic abortion unrelated to the ICD. During pregnancy, 33 women received no ICD therapy, 8 had 1 shock, 1 had 5 discharges, 1 had 11 shocks, and 1 had 5 shocks. The total number of shocks during pregnancy ranged from 0 to 11, with an average of 0.66+/-1.9 discharges. Five women had 7 additional pregnancies without an ICD shock. CONCLUSIONS The mere presence of an ICD should not defer a women from becoming pregnant unless she has an underlying structural cardiac disease that is considered a contraindication. Pregnancy does not increase the risk of major ICD-related complications or result in a high number of ICD discharges.

Effects of the Selective Estrogen Receptor Modulator Raloxifene on Coronary Outcomes in The Raloxifene Use for the Heart Trial: Results of Subgroup Analyses by Age and Other Factors

Background— The Raloxifene Use for The Heart (RUTH) trial showed that raloxifene, a selective estrogen receptor modulator, had no overall effect on the incidence of coronary events in women with established coronary heart disease or coronary heart disease risk factors. We provide detailed results of the effect of raloxifene on coronary outcomes over time and for 24 subgroups (17 predefined, 7 post hoc). Methods and Results— Postmenopausal women (n=10 101; mean age, 67 years) were randomized to raloxifene 60 mg/d or placebo for a median of 5.6 years. Coronary outcomes were assessed by treatment group in women with coronary heart disease risk factors and those with established coronary heart disease. Raloxifene had no effect on the incidence of coronary events in any subgroup except in the case of a post hoc age subgroup analysis using age categories defined in the Womens Health Initiative randomized trials. The effect of raloxifene on the incidence of coronary events differed significantly by age (interaction P=0.0118). The incidence of coronary events in women <60 years of age was significantly lower in those assigned raloxifene (50 events) compared with placebo (84 events; hazard ratio, 0.59; 95% confidence interval, 0.41 to 0.83; P=0.003; absolute risk reduction, 36 per 1000 women treated for 1 year). No difference was found between treatment groups in the incidence of coronary events in women ≥60 and <70 or ≥70 years of age. Conclusions— In postmenopausal women at increased risk of coronary events, the overall lack of benefit of raloxifene was similar across the prespecified subgroups.

Effect of Raloxifene on Stroke and Venous Thromboembolism According to Subgroups in Postmenopausal Women at Increased Risk of Coronary Heart Disease

Background and Purpose— Raloxifene, a selective estrogen receptor modulator, reduces risk of invasive breast cancer and osteoporosis, but the effect on risk for stroke and venous thromboembolism in different patient subgroups is not established. The purpose of this analysis was to evaluate the effect of raloxifene on the incidence of all strokes, stroke deaths, and venous thromboembolic events according to participant subgroups. Methods— This was a secondary end point analysis of an international, randomized, placebo-controlled clinical trial of 10 101 postmenopausal women with or at increased risk of coronary heart disease followed a median of 5.6 years. Strokes, venous thromboembolic events, and deaths were adjudicated by expert centralized committees. Strokes were categorized as ischemic, hemorrhagic, or undetermined and venous thromboembolic events were subclassified. Results— The incidences of all strokes did not differ between raloxifene (incidence rate per 100 woman-years=0.95) and placebo (incidence rate=0.86) treatment groups (P=0.30). In women assigned raloxifene versus placebo, there was a higher incidence of fatal strokes (incidence rates=0.22 and 0.15, respectively, P=0.0499) and venous thromboembolic events (incidence rates=0.39 and 0.27, respectively, P=0.02). No significant subgroup interactions were found except that there was a higher incidence of stroke associated with raloxifene use among current smokers. Conclusions— In postmenopausal women at increased risk for coronary events, the incidences of venous thromboembolism and fatal stroke but not all strokes were higher in those assigned raloxifene versus placebo. Raloxifene’s effect did not differ across subgroups, except that the risk of stroke differed by smoking status. Treatment decisions about raloxifene should be based on a balance of projected absolute risks and benefits.

Risk-benefit profile for raloxifene: 4-year data from the multiple outcomes of Raloxifene Evaluation (MORE) randomized trial

Posthoc analysis of the MORE osteoporosis treatment trial assessed risk‐benefit profile of raloxifene in 7705 postmenopausal women. A major disease outcomes global index resulted in annual rates of 1.39% and 1.83% in the raloxifene and placebo groups, respectively (HR, 0.75; 95% CI, 0.62‐0.92), compatible with a favorable risk‐benefit profile for raloxifene for treating postmenopausal osteoporosis.

Effects of the Once-Weekly Glucagon-Like Peptide-1 Receptor Agonist Dulaglutide on Ambulatory Blood Pressure and Heart Rate in Patients With Type 2 Diabetes Mellitus

Glucagon-like peptide-1 receptor agonists, used to treat type 2 diabetes mellitus, are associated with small reductions in systolic blood pressure (SBP) and increases in heart rate. However, findings based on clinic measurements do not adequately assess a drug’s 24-hour pharmacodynamic profile. The effects of dulaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, on BP and heart rate were investigated using ambulatory BP monitoring. Patients (n=755; 56±10 years; 81% white; 48% women), with type 2 diabetes mellitus, taking ≥1 oral antihyperglycemic medication, with a clinic BP between 90/60 and 140/90 mm Hg were randomized to dulaglutide (1.5 or 0.75 mg) or placebo subcutaneously for 26 weeks. Ambulatory BP monitoring was performed at baseline and at 4, 16, and 26 weeks. The primary end point was change from baseline to week 16 in mean 24-hour SBP, a tree gatekeeping strategy compared the effects of dulaglutide to placebo. Both doses of dulaglutide were noninferior to placebo for changes in 24-hour SBP and diastolic blood pressure, and dulaglutide 1.5 mg significantly reduced SBP (least squares mean difference [95% confidence interval]), −2.8 mm Hg [−4.6, −1.0]; P⩽0.001). Dulaglutide 0.75 mg was noninferior to placebo (1.6 bpm; [0.3, 2.9]; P⩽0.02) for 24-hour heart rate (least squares mean difference [95% confidence interval]), but dulaglutide 1.5 mg was not (2.8 bpm [1.5, 4.2]). Dulaglutide 1.5 mg was associated with a reduction in 24-hour SBP and an increase in 24-hour heart rate. The mechanisms responsible for the observed effects remain to be clarified.

Recurrence of neurocardiogenic syncope without pharmacologic interventions

In 54 patients with positive tilt and who refused medical therapy, we observed a significant decrease in the frequency of syncopal spells after diagnosis and counseling. However, symptoms were reported at follow-up by 64.8% of the patients and were predicted by the frequency and total number of syncope episodes before upright tilt.

Reduced Incidence of Invasive Breast Cancer With Raloxifene Among Women at Increased Coronary Risk

BACKGROUND In the Raloxifene Use for The Heart trial, 10 101 postmenopausal women with coronary heart disease (CHD) or multiple CHD risk factors were randomly assigned to 60 mg/d raloxifene or to placebo and followed for a median of 5.6 years. Raloxifene, a selective estrogen receptor modulator, was found to reduce the risk of invasive breast cancer and vertebral fractures but not the risk of cardiovascular events. Here, we provide further details about breast cancer incidence by tumor characteristics, duration of treatment, and subgroup. METHODS Reported breast cancer was adjudicated by an independent committee based on medical records and pathology reports. The primary analyses used Cox proportional hazards models with time to first breast cancer as the outcome. Subgroup effects were analyzed using similar models with terms for treatment by subgroup. All statistical tests were two-sided. RESULTS As previously reported, raloxifene reduced the incidence of invasive breast cancer by 44% (hazard ratio [HR] = 0.56; 95% confidence interval [CI] = 0.38 to 0.83; absolute risk reduction = 1.2 invasive breast cancers per 1000 women treated for 1 year). The lower incidence of invasive breast cancer reflected a 55% lower incidence of invasive estrogen receptor (ER)-positive tumors (HR = 0.45; 95% CI = 0.28 to 0.72). However, raloxifene treatment did not reduce the incidence of noninvasive breast cancer or of invasive ER-negative breast cancer. The reduced incidence of invasive breast cancer was similar across subgroups, including those defined by age, body mass index, family history of breast cancer, prior use of postmenopausal hormones, and 5-year estimated risk of invasive breast cancer. CONCLUSION Raloxifene reduces risk of invasive ER-positive breast cancer regardless of a womans baseline breast cancer risk but does not reduce risk of noninvasive or ER-negative breast cancers. These results confirm those of the Multiple Outcomes of Raloxifene Evaluation, a previous randomized trial among women with osteoporosis.

Undetected Ventricular Fibrillation in Transvenous Implantable Cardioverter-Defibrillators Prospective Comparison of Different Lead System–Device Combinations

BACKGROUND The purpose of this study was to prospectively analyze redetection problems after unsuccessful shock with different lead systems and devices. METHODS AND RESULTS We prospectively analyzed detection and redetection characteristics among transvenous implantable cardioverter-defibrillators (ICDs) using standard bipolar and integrated bipolar sensing. Monophasic and biphasic ICDs were included. Subthreshold shocks were intentionally delivered, and redetection of ventricular fibrillation (VF) was assessed before discharge and at 1, 3, 6, and 12 months later. Sensing of VF resulting from antitachycardia pacing and low-energy cardioversion ( < or = 2 J) also was analyzed. Before inclusion in the study, each patient underwent subthreshold shock testing at three different time intervals. Among the 160 ICDs with standard bipolar sensing, 530 VF inductions were analyzed. After the failed shocks, undersensing was more frequent (3% versus 20%, P<.01) but did not remarkably prolong redetection (3.1 +/- 0.8 versus 3.3 +/- 1.1 seconds). Among the 201 ICDs with integrated bipolar sensing, 80 were connected to a CPI device (60 Ventak 1600-Endotak 60 series and 20 PRx II 1715-Endotak 70 series) and 121 to the Ventritex defibrillator (91 Endotak 60 series, 14 TVL systems, and 16 Endotak 70 series). After 252 failed shocks, redetection was prolonged with the CPI system (3.1 +/- 1.4 versus 4.6 +/- 3.6 seconds, P<.05) but did not change after 396 failed shocks with the Ventritex ICD (5.4 +/- 1.9 versus 4.9 +/- 2.2 seconds). This may reflect different nominal settings for detection and redetection. In 9 of 121 patients with Ventritex and 1 of 80 with the CPI ICDs, the devices failed to redetect VF. However, redetection malfunction was never observed in patients with integrated bipolar systems with >6-mm electrode separation. After antitachycardia pacing in 1 patient and a 2-J shock in 1 patient, ventricular tachycardia turned into VF, which was undetected. Both patients used the Endotak 60 series-Cadence combination. None of the patients showing VF undersensing had sudden death at follow-up. Only 3 of the 12 patients with sensing malfunction were on antiarrhythmia drugs at the time of testing. Analysis of endocardial electrograms showed that failure to redetect VF is not associated with a uniform reduction but with a rapid and repetitive change of electrogram amplitude. CONCLUSIONS Standard bipolar sensing redetects VF more effectively than integrated bipolar sensing. Endocardial electrogram analysis provides insights into the understanding of the mechanism of undersensing, and certain lead-device combinations result in a higher occurrence of VF undersensing. The clinical relevance of this phenomenon remains unknown.