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John A Glaspy,1 Michelle Z Lim-Watson,2 Michael A Libre,3 Swagata S Karkare,3 Nandini Hadker,3 Aleksandra Bajic-Lucas,2 William E Strauss,2 Naomi V Dahl2 1UCLA School of Medicine, Los Angeles, CA, USA; 2AMAG Pharmaceuticals, Inc., Waltham, MA, USA; 3Trinity LifeSciences, Waltham, MA, USACorrespondence: Naomi V DahlAMAG Pharmaceuticals, Inc., 1100 Winter Street, Waltham, MA 02451, USATel +1 617-498-7650Email ndahl@amagpharma.comBackground: Iron deficiency anemia (IDA) is a prevalent yet underdiagnosed condition with a significant impact on quality of life. Oral iron supplementation is often poorly tolerated or yields inadequate response, requiring the use of intravenous iron (IVI) in some patients. Administration of certain IVI preparations has been associated with decreases in serum phosphate levels and clinically significant hypophosphatemia, which has been reported to lead to adverse events including serious fatigue and osteomalacia.Objective: The purpose of this study was to systematically assess the prevalence, clinical consequences, and reporting of treatment-emergent hypophosphatemia within literature investigating IVI therapies marketed in the United States (US).Methods: A systematic literature review (SLR) was conducted using the PubMed database to identify publications reporting serum phosphate levels or rates of hypophosphatemia within adult IDA patient populations receiving current US-marketed IVIs.Results: The SLR yielded 511 unique publications, with 40 records meeting the final inclusion criteria. Most studies did not report phosphate monitoring methodology or an explicit definition of hypophosphatemia. Hypophosphatemia rates ranged from 0.0% to 92.1% for ferric carboxymaltose (FCM), 0.0% to 40.0% for iron sucrose, 0.4% for ferumoxytol, and 0.0% for low-molecular-weight (LMW) iron dextran. Randomized controlled studies described hypophosphatemia as “asymptomatic” or did not report on other associated sequelae. Eleven case reports detailed treatment-emergent hypophosphatemia in patients treated with FCM. Patients with acute hypophosphatemia primarily developed severe fatigue; those with repeated FCM dosing developed chronic hypophosphatemia associated with osteomalacia and bone deformities.Conclusion: Studies analyzed in this SLR reported a range of hypophosphatemia rates, with the highest consistently seen in patients treated with FCM. Across the clinical literature, there appeared to be minimal standardization of phosphate monitoring and definitions of hypophosphatemia. Although multiple cases have documented serious clinical consequences of hypophosphatemia associated with certain IVIs, current trials neither consistently nor adequately assess the frequency and severity of treatment-emergent hypophosphatemia and may underestimate its prevalence.Keywords: IDA, phosphate, hypophosphatemia, iron supplementation

William E Strauss,1 Michael Auerbach2 1AMAG Pharmaceuticals, Inc., Waltham, MA, USA; 2Auerbach Hematology and Oncology, Baltimore, MD, USA Abstract: Most physicians appear to be aware of the health consequences of advanced anemia, especially in the acute setting, frequently responding with a not inconsequential therapeutic default of transfusion. In contrast, the profound impact that chronic anemia, of any degree, may have on a patient’s performance is underappreciated. The focus of this review is to 1) delineate the consistent and broad impact of anemia on patient quality of life as documented by multiple well-validated patient-reported outcome instruments and 2) demonstrate the essential normalization of the debilitation as assessed by these instruments following the administration of intravenous iron. Keywords: anemia, health-related quality of life, intravenous iron, iron deficiency anemia

Saroj Vadhan-Raj,1 Naomi V Dahl,2 Kristine Bernard,2 Zhu Li,2 William E Strauss2 1Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA; 2AMAG Pharmaceuticals, Inc., Waltham, MA, USA Purpose: Iron deficiency anemia (IDA) is common in cancer patients due to blood loss and inflammation. Many do not tolerate oral iron or adequately respond. Intravenous (IV) iron is commonly used as an adjunct to erythropoiesis-stimulating agents; data on the use of IV iron monotherapy in these patients are limited. This study aimed to evaluate IV ferumoxytol for the treatment of cancer patients with IDA with a history of unsatisfactory oral iron therapy or in whom oral iron could not be used. Patients and methods: This post hoc analysis of pooled data from two multicenter, randomized, controlled, Phase III trials evaluating IV ferumoxytol (510 mg ×2) vs placebo or iron sucrose (200 mg ×5) included a subgroup of 98 patients with cancer that the investigator identified as the primary cause of their IDA, or with cancer whose IDA was attributed to another comorbid condition (ferumoxytol, n=75; iron sucrose, n=13; placebo, n=10). Gastrointestinal cancers were most common (42), followed by breast (14), cervix (ten), and lung (nine). The primary endpoint was the mean change in hemoglobin (Hgb) from baseline to week 5. Results: At week 5, both ferumoxytol and iron sucrose produced significant increases in Hgb from baseline (1.8 g/dL [P20% nor initiated in any treatment group. Overall rates of adverse events and serious adverse events in the cancer subgroup mirrored those in the overall study population. Conclusion: Monotherapy with IV iron appears to be an effective option for cancer patients with IDA who do not respond to or cannot tolerate oral iron therapy. Keywords: anemia, cancer, ferumoxytol, hemoglobin, efficacy, intravenous iron

Naomi V Dahl,1 Robert F Kaper,2 William E Strauss,1 Frank A Corvino,3 Marko Zivkovic3 1Medical Affairs, 2Medical & Scientific Affairs, AMAG Pharmaceuticals, Inc., Waltham, MA, 3Genesis Research, Hoboken, NJ, USA Objective: Ferumoxytol has demonstrated superior efficacy compared with oral iron in treating iron deficiency anemia in chronic kidney disease (CKD) patients. However, an economic evaluation of ferumoxytol has not been conducted. The aim of this study was to analyze the cost-effectiveness of treating iron deficiency anemia in adult non-dialysis-dependent CKD patients with ferumoxytol as compared with oral iron, alone or in combination with erythropoietin-stimulating agents (ESAs). Methods: A decision analytic model compared health outcomes and costs associated with 5-week outpatient treatment of adult non-dialysis-dependent CKD patients with ferumoxytol or oral iron, each as monotherapy or in combination with ESAs in the USA. Direct costs include the following: drug acquisition and administration, adverse events, and medical management. Efficacy was determined as mean increase in hemoglobin (g/dL) from baseline over the 5-week period. Clinical inputs were derived from patient-level data from two Phase III randomized controlled trials of ferumoxytol vs. oral iron in non-dialysis-dependent CKD patients, and cost inputs from RED BOOKTM and Centers for Medicare and Medicaid Services data. Sensitivity analyses were performed to identify cost drivers and assess the stability of results. Results: The 5-week treatment cost was $2,489, $5,216, $1,298, and $4,263 per patient for ferumoxytol, ferumoxytol with ESAs, oral iron, and oral iron with ESAs, respectively. The corresponding incremental costs per g/dL increase in hemoglobin, relative to ferumoxytol alone, were $398, $3,558, and $4,768 per patient. Efficacy was the main driver of cost-effectiveness for all treatments. Adverse event and medical management costs were the principal drivers of oral iron monotherapy costs, while drug acquisition substantially contributed to the overall cost for the remaining treatments. Conclusion: These results suggest that ferumoxytol is a cost-effective treatment for iron deficiency anemia in non-dialysis-dependent CKD patients over a 5-week period compared with oral iron with or without ESAs. Ferumoxytol is more cost-effective as monotherapy. Keywords: incremental cost-effectiveness ratio, ICER, health care costs, intravenous iron, iron therapy, erythropoietin

N Franklin Adkinson,1 William E Strauss,2 Kristine Bernard,2 Robert F Kaper,2 Iain C Macdougall,3 Julie S Krop2 1Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2AMAG Pharmaceuticals, Inc., Waltham, MA, USA; 3Department of Renal Medicine, King’s College Hospital, London, UK Background: Intravenous (IV) iron is often used to treat iron deficiency anemia in patients who are unable to tolerate or are inadequately managed with oral iron. However, IV iron treatment has been associated with acute hypersensitivity reactions. The comparative risk of adverse events (AEs) with IV iron preparations has been assessed by a few randomized controlled trials, which are most often limited by small patient numbers, which lack statistical power to identify differences in low-frequency AE such as hypersensitivity reactions.Materials and methods: Ferumoxytol versus Ferric Carboxymaltose for the Treatment of Iron Deficiency Anemia (FIRM) is a randomized, double-blind, international, multicenter, Phase III study designed to compare the safety of ferumoxytol and ferric carboxymaltose (FCM). The study includes adults with hemoglobin

David C Ford,1 Naomi V Dahl,2 William E Strauss,2 Charles F Barish,3 David J Hetzel,4 Kristine Bernard,2 Zhu Li,2 Lee F Allen,2 1Toronto Digestive Disease Associates, Inc, Vaughan Endoscopy Clinic, Vaughan, ON, Canada; 2AMAG Pharmaceuticals, Inc, Waltham, MA, 3Wake Gastroenterology, Wake Research Associates, Raleigh, NC, USA; 4Department of Gastroenterology, Royal Adelaide Hospital, Adelaide, SA, Australia Introduction: Iron deficiency anemia (IDA) is common in patients with gastrointestinal (GI) disorders and can adversely affect quality of life. Oral iron is poorly tolerated in many patients with GI disorders. Ferumoxytol is approved for the intravenous treatment of IDA in patients with chronic kidney disease. This study aimed to evaluate the efficacy and safety of ferumoxytol in patients with IDA and concomitant GI disorders. Patients and methods: This analysis included 231 patients with IDA and GI disorders from a Phase III, randomized, double-blind, placebo-controlled trial evaluating ferumoxytol (510 mg ×2) versus placebo in patients who had failed or were intolerant of oral iron therapy. The primary study end point was the proportion of patients achieving a ≥20 g/L increase in hemoglobin (Hgb) from baseline to Week 5. Other end points included mean change in Hgb, proportion of patients achieving Hgb ≥120 g/L, mean change in transferrin saturation, and patient-reported outcomes (PROs). Results: Significantly more patients with IDA receiving ferumoxytol achieved a ≥20 g/L increase in Hgb versus placebo (82.1% vs 1.7%, respectively; P

Some, but not all, intravenous iron formulations have been recognized to induce renal phosphate wasting syndrome. Most commonly this has been reported following treatment of iron deficiency anemia (IDA) with ferric carboxymaltose (FCM). A search of PubMed identified relevant randomized controlled trials (RCTs), and case studies evaluating hypophosphatemia (HPP) resulting from intravenous iron treatment. While more recent larger comparative RCTs have confirmed that the majority of patients receiving FCM, especially those with normal renal function, may experience severe HPP, complete documentation is hampered by inconsistent reporting of serum phosphate in such trials. Similarly, while case series and RCTs have documented the persistence of HPP for several weeks or even months, the lack of studies lasting beyond 5-6 weeks has constrained full understanding of the duration of effect. Clinical trials have established that the mechanism involves the bone/metabolic axis with the elevation of intact fibroblast growth factor 23 playing the central role. Reports continue to accumulate of the clinical consequences of severe HPP which are, most commonly, bone abnormalities following repetitive dosing. Case reports and studies, however, have also shown that symptomatic hypophosphatemia can occur after a single FCM dose. The frequency of such events remains unknown, in part due to lack of awareness of hypophosphatemia coupled with the fact that the most common acute symptoms of HPP (fatigue and weakness) are the same for IDA and for many of the chronic diseases that cause IDA. Changes to US and European prescribing information for FCM should raise awareness of the potential for HPP and need to monitor patients at risk for it., (© 2021. The Author(s).)

Background: Patients with chronic kidney disease (CKD) undergoing dialysis often require intravenous iron for iron deficiency anemia (IDA)., Materials and Methods: The Ferumoxytol for Anemia of CKD Trial (FACT), a randomized, multicenter, open-label, phase 4 study, compared the long-term safety and efficacy of ferumoxytol with iron sucrose for the treatment of IDA in patients with CKD undergoing hemodialysis. Patients with IDA and CKD undergoing hemodialysis were randomized 2:1 to ferumoxytol 1.02 g (2 × 510 mg) or iron sucrose 1.0 g (10 × 100 mg) for a 5-week treatment period (TP). Over 11 months, patients underwent additional 5-week TPs whenever IDA (hemoglobin < 11.5 g/dL and transferrin saturation < 30%) was detected. The primary efficacy endpoint was mean change in hemoglobin from baseline to week 5 for each TP. Adverse events were recorded during the study., Results: Overall, 293 patients received ferumoxytol (n = 196) or iron sucrose (n = 97). Ferumoxytol was noninferior to iron sucrose regarding hemoglobin change from baseline to week 5. The mean change in hemoglobin in the ferumoxytol and iron sucrose groups was 0.5 and 0.4 g/dL, respectively, in TP 1 (least-squares mean difference, 0.13; 95% confidence interval, -0.11 to 0.36) and 0.6 and 0.3 g/dL, respectively, in TP 2 (0.30; 0.06 - 0.55). Treatment-related and serious adverse events were similar in both groups; no new safety signals emerged., Conclusion: Long-term administration of ferumoxytol has noninferior efficacy and a similar safety profile to iron sucrose when used to treat IDA in patients with CKD undergoing hemodialysis.
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Few trials have examined rates of hypersensitivity reactions (HSRs) with intravenous iron formulations used to treat iron deficiency anemia (IDA). This randomized, multicenter, double-blind clinical trial compared the safety, and efficacy of ferumoxytol versus ferric carboxymaltose (FCM), focusing on rates of HSRs and hypotension as the primary end point. Patients with IDA of any etiology in whom oral iron was unsatisfactory or intolerable received ferumoxytol (n = 997) or FCM (n = 1000) intravenously over ≥15 minutes on days 1 and 8 or 9 for total respective doses of 1.02 g and 1.50 g. Composite incidences of moderate-to-severe HSRs, including anaphylaxis, or moderate-to-severe hypotension from baseline to week 5 (primary safety end point) were 0.6% and 0.7% in the ferumoxytol and FCM groups, respectively, with ferumoxytol noninferior to FCM. No anaphylaxis was reported in either group. The secondary safety end point of incidences of moderate-to-severe HSRs, including anaphylaxis, serious cardiovascular events, and death from baseline to week 5 were 1.3% and 2.0% in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Least-squares mean changes in hemoglobin at week 5 were 1.4 g/dL and 1.6 g/dL in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Incidence of hypophosphatemia was 0.4% for ferumoxytol and 38.7% for FCM., (© 2018 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.)

Following publication of the original article [1], the authors reported that one of the authors' name is spelled incorrectly. In this Erratum the incorrect and correct author name are shown. The original publication of this article has been corrected.

Background: Iron deficiency anemia (IDA) is a common manifestation of chronic kidney disease (CKD), affecting most patients on hemodialysis and imposing a substantial clinical burden. Treatment with iron supplementation increases hemoglobin levels and can reduce the severity of anemia in patients with CKD. While correcting anemia in these patients is an important therapeutic goal, there is a lack of long-term trials directly comparing intravenous iron therapies in patients with CKD receiving hemodialysis., Methods/design: The Ferumoxytol for Anemia of CKD Trial (FACT) is a 13-month, open-label, randomized, multicenter, international, prospective study with 2 substudies. Entry criteria for the main study include adults with IDA (defined as hemoglobin <11.5 g/dL [<115.0 g/L] and a transferrin saturation <30%), serum ferritin <800 ng/mL (<1798 pmol/L), and receiving hemodialysis for ≥3 months. Patients are randomized to receive ferumoxytol (1.02 g over 2 doses) or iron sucrose (1.0 g over 10 doses) during the initial 5-week treatment period. Those with persistent/recurrent IDA over the 11-month observation period will receive additional 5-week treatment periods, as appropriate. The primary efficacy endpoint of the main study is the mean change in hemoglobin from Baseline to Week 5 for each treatment period. The secondary efficacy endpoints include the mean change in transferrin saturation from Baseline to Week 5 and the proportion of patients with a hemoglobin increase of ≥1.0 g/dL at any time from Baseline to Week 5. Safety will be assessed through an examination of the adverse event profile over the course of the study. An "oxidative stress" substudy in approximately 100 patients will assess the effects of treatment on biomarkers of oxidative stress/inflammation during the initial 5-week treatment period, and a magnetic resonance imaging substudy in approximately 70 patients will assess the potential for iron deposition in target tissues over 24 months., Discussion: FACT fulfills the need for a long-term comparative trial in patients with IDA and CKD receiving hemodialysis. The efficacy and safety results will provide useful information for guiding therapy in this population. Two hundred ninety-six patients have been enrolled, and completion of the main study is expected soon., Trial Registration: ClinicalTrials.gov identifier: NCT01227616 (registered October 22, 2010); EudraCT number: 2010-022133-28.

Background: Iron deficiency anemia is highly prevalent in patients with chronic kidney disease and is often treated with intravenous iron. There are few trials directly comparing the safety and efficacy of different intravenous iron products., Methods: This post-hoc analysis pooled data from 767 patients enrolled in two randomized, controlled, open-label trials of similar design comparing the treatment of iron deficiency anemia with ferumoxytol and iron sucrose across patients with all stages of renal function. One trial was conducted in adults with CKD either on or not on dialysis and the second in adults with IDA of any underlying cause and a history of unsatisfactory oral iron therapy or in whom oral iron could not be used who had normal to no worse than moderately impaired renal function. Patients were categorized by chronic kidney disease stage (i.e., estimated glomerular filtration rate), and the primary efficacy endpoint was the mean change in hemoglobin from Baseline to Week 5., Results: The overall incidence of adverse events was numerically lower in ferumoxytol-treated patients compared to those treated with iron sucrose (42.4 vs. 50.2 %, respectively); the incidence of treatment-related adverse events was generally similar between the two treatment groups (13.6 vs. 16.0 %, respectively). Adverse events of Special Interest (i.e., hypotension, hypersensitivity) occurred at lower rates in those treated with ferumoxytol compared to those treated with iron sucrose (2.5 vs. 5.3 %, respectively). Overall, mean hemoglobin increased in both treatment groups, regardless of degree of renal insufficiency, although greater increases were seen among those with less severe kidney damage. Mean increases in hemoglobin from Baseline to Week 5 were significantly greater with ferumoxytol than with iron sucrose treatment in the subgroup with an estimated glomerular filtration rate ≥90 mL/min (Least Squares mean difference = 0.53 g/dL; p < 0.001). There were no other consistent, significant differences in hemoglobin levels between treatment groups for the other chronic kidney disease categories except for isolated instances favoring ferumoxytol., Conclusions: The efficacy and safety of ferumoxytol is at least comparable to iron sucrose in patients with varying degrees of renal function., Trial Registration: (CKD-201; ClinicalTrials.gov identifier: NCT01052779; registered 15 January, 2010), (IDA-302; ClinicalTrials.gov identifier: NCT01114204; registered 29 April, 2010).

Background and Objectives: Few randomized controlled trials have compared intravenous iron products head to head in CKD patients with iron deficiency anemia. This study compared the efficacy and safety of two intravenous iron products (ferumoxytol [Feraheme injection] and iron sucrose [Venofer]) in patients with CKD and iron deficiency anemia., Design, Setting, Participants, & Measurements: In this phase II, randomized, open-label, active-controlled, multicenter clinical trial, patients were randomized 1:1 to either 1.02 g ferumoxytol (2 × 510-mg injections) or 1.0 g iron sucrose administered as either a slow injection or infusion (10 doses for dialysis patients and 5 doses for nondialysis patients). Inclusion criteria included hemoglobin<11.0 g/dl, transferrin saturation<30%, and eGFR<60 ml/min per 1.73 m(2) or a diagnosis of underlying CKD (e.g., nephropathy or nephritis). The primary end point was change in hemoglobin from baseline to week 5., Results: In total, 162 patients were randomized. Demographics were balanced between the treatment groups. Adverse event profiles of the two regimens were fairly similar: overall adverse events, 48% ferumoxytol versus 65% iron sucrose; related adverse events, 10% ferumoxytol versus 16% iron sucrose; and adverse events leading to study discontinuation, 1% ferumoxytol versus 5% iron sucrose. Rates of serious adverse events and related serious adverse events were similar between the ferumoxytol and iron sucrose groups: serious adverse events, 9% versus 7%, respectively and related serious adverse events, 1% versus 1%, respectively. Overall, increases in hemoglobin were similar between treatment groups. Based on an ANOVA model adjusted for baseline hemoglobin level and dialysis status, the least squares mean change from baseline to week 5 was 0.8 ± 0.1 g/dl in the ferumoxytol-treated group and 0.7 ± 0.1 g/dl in the iron sucrose group. The difference in the mean change from baseline between the two treatment groups was 0.1 g/dl (95% confidence interval, -0.2 to 0.4)., Conclusion: In this randomized, controlled trial, ferumoxytol and iron sucrose showed comparable efficacy and adverse events rates.

We compared 1-year outcomes in patients treated with paclitaxel-eluting stents (PESs) or sirolimus-eluting stents (SESs) in "real-world" clinical practice. Clinical outcomes were evaluated in 1,558 consecutive, unselected, retrospectively collected patients treated with drug-eluting stents (DESs; PES = 816, SES = 742) at 19 United States centers. The primary end point was 1-year target vessel revascularization (TVR). The study included a prespecified diabetic cohort (PES = 289, SES = 247), for which efficacy comparisons between DESs were analyzed according to vessel diameter and presence of chronic kidney disease. Baseline demographic, angiographic, and procedural characteristics were similar between patients treated with PESs and those treated with SESs. At 1 year, there were no overall statistical differences in death, myocardial infarction, TVR, or stent thrombosis. In the diabetic cohort, however, the cumulative incidence of TVR was significantly lower for patients treated with PESs (3%) compared with SESs (9%, p <0.01), which persisted after adjustment for baseline differences (hazard ratio 0.29, 95% confidence interval 0.12 to 0.67). This decrease in TVR with PES was similar in insulin- and noninsulin-requiring diabetic patients. In multivariate analysis, independent predictors of TVR included diabetes, bifurcation stenting, and overlapping stents; in the diabetic cohort, treatment with SESs was also a multivariate predictor of TVR. In conclusion, in this observational, retrospective analysis of DES-treated patients, PESs and SESs demonstrated similar overall safety and efficacy, but PESs were associated with a significant decrease in 1-year TVR rates in diabetic patients.

Background: The HMG CoA reductase inhibitors have quickly become the most widely prescribed family of agents for the treatment of patients with elevated low-density lipoprotein (LDL) cholesterol. The incidence of side effects with these agents increases as the dose increases within the recommended dosage range. A lower dosage presumably would have a lower incidence of adverse effects. In addition, lower doses should translate into reduced drug costs., Methods and Results: We compared the efficacy of 10 mg of pravastatin and 10 mg of lovastatin in a randomized, crossover design trial among 30 patients with hypercholesterolemia. At baseline, their total cholesterol and LDL cholesterol levels were 249.0 +/- 27.3 and 185.1 +/- 25.5 mg/dL. After 4 weeks of treatment with lovastatin, the total cholesterol and LDL cholesterol levels fell to 202.8 +/- 29.6 and 141.0 +/- 25.3 mg/dL, decreases of 19% and 24%, respectively. Four weeks of pravastatin treatment resulted in levels of 212.6 +/- 30.8 and 150.5 +/- 25.5 mg/dL, or 15% and 19%, respectively., Conclusions: There were highly significant changes in total cholesterol and LDL cholesterol levels with each agent and no differences in effect between the 2 agents. In 13 (43%) of the 30 patients, LDL levels were reduced to

Despite abundant evidence of the benefits of lipid lowering in reducing mortality from all causes in high-risk patients with or without coronary artery disease (CAD) and the wide availability of guidelines for targeting such patients more aggressively, there are indications that this population is still being treated suboptimally. Our study sought to ascertain the appropriateness of prescribing practices of the hydroxymethylglutaryl coenzyme A-reductase (HMG-CoA) inhibitor pravastatin that was used at our facility at the time. We conducted a drug utilization review of a randomly chosen sample of patients receiving prescriptions for pravastatin at the outpatient clinics of a tertiary care, academically affiliated Veterans Affairs medical center. The algorithm we used was based on National Cholesterol Education Program Adult Treatment Panel-2 guidelines. Patient charts were reviewed for the presence of CAD and standard cardiac risk factors and for lipid determinations performed since 1986, when laboratory test results began to be compiled electronically. The initial review was performed by a pharmacist; cases the pharmacist identified as involving possible suboptimal prescribing practices were subsequently reviewed and classified by a cardiologist. From the pharmacy database, we derived a random sample of 118 patients who were receiving doses >20 mg (high-dose cases) and 100 patients receiving doses of < or =20 mg (standard-dose cases). The pharmacist's review found 57 (48%) high-dose cases and 47 (47%) standard-dose cases that were questionable; the cardiologist's review of these cases determined that 43 (36%) high-dose cases and 38 (38%) standard-dose cases involved suboptimal prescribing practices. The deficiencies noted in patients receiving standard-dose pravastatin were generally minor; however, 23% of the deficiencies noted in patients receiving high-dose therapy were serious ones that may have exposed the patients to unnecessary therapy or caused a delay in their receiving appropriate therapy. In conclusion, slightly more than one third of a randomly selected sample of patients treated with an HMG-CoA reductase inhibitor at a tertiary care medical center were receiving suboptimal therapy. Suboptimal prescribing practices have both clinical and economic implications, and a tiered, multidisciplinary review process allows convenient monitoring of prescribing practices.

Platelet factor 4 (PF4) and tissue factor pathway inhibitor (TFPI) are two proteins with high affinity for heparin. They are each stored in platelets, as well as on endothelial cell surfaces, from where both are displaced or released following an injection of heparin with a rapid and marked increase in serum levels. Prior work has demonstrated that the platelet count is one of the factors affecting the levels of heparin-releasable PF4. We therefore characterized the response to a dose of intravenous heparin previously demonstrated to completely displace PF4 from the non-platelet pool in subjects with normal or increased platelet counts. Seventeen patients with essential thrombocytosis (ET), 10 patients with polycythemia vera and high platelet counts (PV-H), 7 patients with polycythemia vera and normal platelet counts (PV-N) and 10 controls received an initial bolus of 40 I.U./kg of unfractionated heparin, followed 2 hours later by a 2nd bolus of a fixed dose of 1000 I.U. TFPI activity did not show any variation among the different groups, either before (TFPI) or after (HR-TFPI) the first bolus of heparin: ET, TFPI 92.6 ± 21.5%, HR-TFPI 298.3 ± 165.8; PV-H, TFPI 91.5 ± 32.0, HR-TFPI 210 ± 1.0; PV-N, TFPI 69.4 ± 24.0, HR-TFPI 203.0 ± 79.0; C, TFPI 109.5 ± 33.5, HR-TFPI 234.0 ± 60.4. TFPI activity returned to basal values prior to the 2nd injection of heparin, which again elicited a rise in TFPI, albeit smaller due to the lower level of heparin injected. In contrast to the lack of any difference between groups with respect to TFPI, the level of heparin-releasable PF4 (HR-PF4) was significantly higher in ET and PV-H patients compared to PV-N patients or controls. However when normalized for platelet count, both PV-H and PV-N had HR-PF4 levels after the 1st heparin injection that were significantly higher than observed in ET patients (PV-H 1.163 + 0.108, PV-N 1.411 + 0.019, ET 0.737 + 0.086 ng/10/3 platelets) supporting an increased platelet activation in PV. Thus, although platelets contain approximately 5-10% of the total amount of TFPI in plasma, they do not affect the major intravascular pool of TFPI mobilizable by heparin. However, since the concentration at the site of vessel wall injury is enhanced several-fold, TFPI could play a role in competing with PF4 to limit thrombus formation in patients with high platelet count.

We tested whether patients presenting with atrial fibrillation (AF) or flutter (AFl) with a rapid ventricular response could maintain control of heart rate while transferring from a bolus and continuous infusion of intravenous diltiazem to oral diltiazem. Forty patients with AF or AFI and sustained ventricular rate > or = 120 beats/min received intravenous diltiazem "bolus" (20 to 25 mg for 2 minutes) and "infusion" (5 to 15 mg/hour for 6 to 20 hours). Oral long-acting diltiazem (diltiazem CD 180, 300, or 360 mg/24 hours) was administered in patients in whom stable heart rate control was attained during constant infusion. Intravenous diltiazem infusion was discontinued 4 hours after the first oral dose, and patients were monitored during 48 subsequent hours of "transition" to oral therapy. Response to diltiazem was defined as heart rate <100 beats/min, > or = 20% decrease in heart rate from baseline, or conversion to sinus rhythm. Other rate control or antiarrhythmic medications were not allowed during the study period. Thirty-seven of 40 patients maintained heart rate control during the bolus, and 35 of the remaining 37 maintained control during the infusion of intravenous diltiazem. Of the 35 patients achieving heart rate control with intravenous diltiazem who entered the transition to oral therapy, 27 maintained heart rate control (response rate of 77%/, 95% confidence interval 63% to 91%). The median infusion rate of intravenous diltiazem was 10 mg/hour, and the median dose of oral diltiazem CD was 300 mg/day. Oral long-acting diltiazem was 77% effective in controlling ventricular response over 48 hours in patients with AF or AFl in whom ventricular response was initially controlled with intravenous diltiazem.

We studied tissue factor pathway inhibitor (TFPI) activity during hemodialysis in 10 uremic patients who were not receiving anticoagulant for at least 120 minutes. TFPI activity before dialysis was normal (patients 107 +/- 5.8%, controls 104 +/- 4.5%). During extracorporeal circuit it rose progressively with a statistically significant difference, reaching a plateau between 60 and 120 minutes. Since thrombin induces a marked redistribution and release of TFPI from stimulated endothelial cells and platelets contain about 10% of TFPI activity that is secreted following activation it is possible that thrombin-induced release of TFPI by endothelium and platelets could account for the increased TFPI we found during hemodialysis. To investigate this possibility we measured during dialysis beta-thromboglobulin (beta-TG), thrombin-antithrombin complex (TAT) and prothrombin fragment 1.2 (F 1.2). The increased levels of beta-TG, TAT and F1.2 we noted during extracorporeal circuit are in keeping with this concept. One hundred eighty minutes after initiation of dialysis, by which time all patients were receiving heparin there was a further increase in TFPI (to more than 200% of baseline), due to the presence of the glycosaminoglycan. This was due the previously reported displacement by heparin of the major intravascular pool of TFPI, from endothelial cell surfaces.

Background: Evaluations of therapy for the treatment of angina have traditionally consisted of a combination of objective measures, such as exercise tolerance, and subjective markers, such as angina attack rate. Recently, the need to assess "how patients feel"--their quality of life (QOL)--has been regarded with increasing importance. Standard instruments are available to assess QOL and its change after therapeutic intervention. Although QOL instruments have been used to assess the efficacy of percutaneous transluminal coronary angioplasty (PTCA), they have not been used previously to compare the impact of PTCA with that of medical therapy in patients with angina pectoris. We report on the changes in self-assessed QOL among patients randomly assigned to treatment by PTCA or medical therapy and relate these measurements to changes in exercise performance and coronary angiograms., Methods and Results: Patients with stable angina, a positive exercise tolerance test, and at least 70% stenosis (index lesion) in the proximal two thirds of one major coronary artery were randomly assigned to receive PTCA or medical therapy. Six months after randomization, each patient underwent repeat exercise testing and coronary angiography. Before randomization and at the 6-month visit, patients completed a self-administered QOL questionnaire that measured physical functioning and psychological well-being. We compared the changes in QOL with changes between the baseline and 6-month exercise tests, stratified by terciles (decrease in duration, 0- to 2-minute increase, and > 2-minute improvement). We also stratified patients by whether there was more or less than 2 SD change (18.8%) in diameter stenosis of the index lesion (initial minus follow-up angiogram), and we related these to changes in QOL measures. One hundred eighty-two patients with one-vessel disease completed baseline and 6-month questionnaires. At baseline, there were no differences in any QOL measurements between treatment groups. At the 6-month follow-up visit, there was greater improvement in both physical functioning and psychological well-being scores for patients receiving PTCA (+7.36 +/- 15.6, PTCA; +1.98 +/- 14.7, medical therapy; P < .02). Improvement in QOL variables was noted only in patients demonstrating an increase in exercise performance. Also, patients assigned to either treatment whose angiograms demonstrated more than 18.8% improvement in index lesion percent stenosis experienced a significant increase in their QOL scores., Conclusions: This was the first study of the relative changes in QOL measures assessed with the use of previously validated and standardized instruments in patients randomly assigned to treatment with PTCA or medical therapy. Patients assigned to PTCA demonstrated a significantly greater improvement in both physical and psychological measures. This improvement was noted in patients whose exercise performance improved and whose angiograms demonstrated an improvement in lesion severity.

Background: It has been hypothesized that the pathogenesis of diseases induced by cigarette smoking involves oxidative damage by free radicals. However, definitive evidence that smoking causes the oxidative modification of target molecules in vivo is lacking. We conducted a study to determine whether the production of F2-isoprostanes, which are novel products of lipid peroxidation, is enhanced in persons who smoke., Methods: We measured the levels of free F2-isoprostanes in plasma, the levels of F2-isoprostanes esterified to plasma lipids, and the urinary excretion of metabolites of F2-isoprostanes in 10 smokers and 10 nonsmokers matched for age and sex. The short-term effects of smoking (three cigarettes smoked over 30 minutes) and the effects of two weeks of abstinence from smoking on levels of F2-isoprostanes in the circulation were also determined in the smokers., Results: Plasma levels of free and esterified F2-isoprostanes were significantly higher in the smokers (242 +/- 147 and 574 +/- 217 pmol per liter, respectively) than in the nonsmokers (103 +/- 19 and 345 +/- 65 pmol per liter; P = 0.02 for free F2-isoprostanes and P = 0.03 for esterified F2-isoprostanes). Smoking had no short-term effects on the circulating levels of F2-isoprostanes. However, the levels of free and esterified F2-isoprostanes fell significantly after two weeks of abstinence from smoking (250 +/- 156 and 624 +/- 214 pmol per liter, respectively, before the cessation of smoking, as compared with 156 +/- 67 and 469 +/- 108 pmol per liter after two weeks' cessation; P = 0.03 for free F2-isoprostanes and P = 0.02 for esterified F2-isoprostanes)., Conclusions: The increased levels of F2-isoprostanes in the circulation of persons who smoke support the hypothesis that smoking can cause the oxidative modification of important biologic molecules in vivo.

This study examines the efficacy of various doses of intravenous diltiazem to control the ventricular response during atrial fibrillation or atrial flutter. Control of the ventricular response of patients with atrial fibrillation and a rapid ventricular response can provide patients with relief of symptoms and improve hemodynamics. Eighty-four consecutive patients with atrial fibrillation or atrial flutter, or both, received an intravenous bolus dose of diltiazem followed by a continuous infusion of diltiazem at 5, 10, and 15 mg/hour. The mean ventricular response and blood pressure were monitored. Overall, 94% of patients (79 of 84) responded to the bolus dose with a > 20% reduction in heart rate from baseline, a conversion to sinus rhythm, or a heart rate < 100 beats/min. Seventy-eight patients received the continuous infusion. After 10 hours of infusion, 47% of patients (confidence interval [CI]: 36%, 59%) had maintained response with the 5 mg/hour infusion, 68% (CI: 57%, 79%) maintained response after the infusion was titrated to 10 mg/hour, and 76% (CI: 66%, 85%) after titration from the 5 and 10 mg/hour infusion to the 15 mg/hour dose. For the 3 diltiazem infusions studied, mean (+/- SD) heart rate was reduced from a baseline value of 144 +/- 14 beats/min to 98 +/- 19, 107 +/- 25, 107 +/- 22, 101 +/- 22, 91 +/- 17, and 88 +/- 18 beats/min at infusion times 0, 1, 2, 4, 8, and 10 hours, respectively. By the end of the infusion, 18% of patients (14 of 78) had conversion to sinus rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)

Nicorandil (nicotinamidoethyl nitrate) is a novel vasodilator. Its vasodilator properties are related both to the nicotinamide and nitrate moieties. Classic nitrates such as nitroglycerin (NTG) and isosorbide dinitrate demonstrate in vitro inhibition of ADP-induced platelet aggregation. Such effects have been shown to occur in a dose-related manner, are potentiated by reduced thiols and by increasing preincubation time, and are associated with increases in intracellular cyclic GMP. We explored the effect of nicorandil on ADP-induced human platelet aggregation and the role of reduced thiol N-acetylcysteine (NAC) in modulating this response. Nicorandil significantly inhibited aggregation to ADP dose dependently (IC50 3.0 mM). These effects were associated with inhibition of fibrinogen binding to the platelet surface (IC50 2 mM). Addition of nicorandil after maximal ADP-induced aggregation was achieved resulted in disaggregation. Addition of a source of reduced thiol (NAC) potentiated the antiaggregatory effects of nicorandil threefold (p < 0.05). Platelet inhibition by nicorandil was also augmented by increase in duration of preincubation, with maximal effects observed at 180 min. Preincubation of platelets with 10 mM nicorandil resulted in attenuated inhibition of platelet aggregation on gel filtration and subsequent exposure to additional nicorandil, indicative of tolerance induction. Methylene blue (MB), an inhibitor of guanylate cyclase, significantly reversed nicorandil-induced inhibition of platelet aggregation. Moreover, in accordance with this mechanism, nicorandil increased intracellular platelet cyclic GMP levels. Although the antiplatelet effect of nicotinamide was partially reversed by the K+ channel inhibitor iberotoxin, preincubation with iberotoxin had no impact on inhibition of platelet aggregation by nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)

Although congestive heart failure has been reported with the combination of a beta blocker and either verapamil or nifedipine, it has not previously been reported for combination therapy that includes diltiazem. The following case documents the occurrence of clinical congestive failure in a patient with baseline left ventricular dysfunction and severe angina pectoris. Although the patients had tolerated propranolol therapy for years without difficulty, and high-dose diltiazem monotherapy with an excellent clinical response, the combination of diltiazem and propranolol resulted in the development of congestive heart failure. Thus, although generally well tolerated, given the suitable scenario of reduced left ventricular function, the combination of diltiazem and a beta blocker may adversely affect left ventricular performance.

Mesothelioma of the atrioventricular node are rare benign tumors with well-described potential for resulting in sudden death. The presentations have varied: the majority of patients have been predominantly female aged 15 to 40, dying suddenly; however, other patients have had documented heart block for many decades and a noncardiac cause of death. A 19-year-old female expired after presenting with ventricular fibrillation and was subsequently discovered to have a mesothelioma involving the AV node. Although high degree heart block is present in many patients, most episodes of sudden death probably are secondary to ventricular tachyarrhythmias. Either form of dysrhythmia may potentially benefit from ventricular pacing.

During the past decade, the therapy for stable angina pectoris has greatly expanded with the introduction of the calcium-channel blockers. Initially studied as monotherapy, these agents have been regularly used in combination with other antianginal medications, most notably the beta-adrenergic blockers. Although there are pharmacologic rationales for combining these agents, in daily practice, the major impetus for combination therapy is continuing angina during monotherapy. At least one well-conducted double-blind study was done to confirm that diltiazem, verapamil, and nifedipine each can markedly improve both subjective and objective measures of efficacy when used in combination with a beta-blocker. However, individual patient responses are of chief importance. Many persons do better with monotherapy than with combination treatment. The offsetting hemodynamic effects of nifedipine and a beta-blocker generally work well together; however, minor side effects are not infrequent. In the patient with underlying conduction system disease, this combination is clearly preferable. Diltiazem with a beta-blocker is usually well-tolerated, with a low incidence of adverse effects, similar to the experience with diltiazem monotherapy. Verapamil in conjunction with a beta-blocker warrants the greatest concern; approximately 10% to 15% of patients will have significant bradycardia, heart block, hypotension, or congestive failure. When these agents are used concurrently, reduced dosages, especially of the beta-blocker, will likely result in a lower incidence of adverse effects with maintained efficacy.

In vivo activation of platelets can be accurately measured by radioimmunoassays of platelet factor 4 (PF4) and beta thromboglobulin (beta TG). Studies that attempt to correlate increases in PF4 and beta TG levels with exercise-induced myocardial ischemia have yielded conflicting results. To further examine the natural history of release of PF4 and beta TG we used a method of serial samplings of these proteins during and after exercise in nine normal subjects and 24 patients with coronary artery disease (CAD). Mean values for PF4 and beta TG at rest, during each stage, and immediately after treadmill exercise were the same for normal subjects and for patients with positive and negative responses to exercise-tolerance tests (ETTs). However, nonparametric analysis and regression equations disclosed differences in trends of PF4 level during exercise; PF4 levels increased in normal subjects during exercise, while patients with positive ETTs had no change in PF4 levels and patients with negative ETTs actually showed a decrease in PF4. This investigation confirmed that exercise-induced myocardial ischemia is not associated with platelet aggregation as manifested by the release of the platelet-specific proteins PF4 and beta TG. Statistical analysis suggested that prior reports of elevated levels of PF4 during exercise could have been caused by technical and methodologic difficulties that were associated with the collection and handling of the samples.

Sixty-three patients completed a multicenter 10 week, double-blind, parallel group protocol evaluating the efficacy of diltiazem versus placebo with respect to rate of attacks of angina, nitroglycerin consumption and duration of treadmill exercise. An additional 36 patients were evaluated for drug safety. A 4 week placebo lead-in phase was followed by a 2 week dose titration period and two treatment evaluation periods of 2 weeks each. Both diltiazem and placebo were associated with a significant reduction in weekly frequency of angina from the baseline rate. Intergroup comparison disclosed a significantly greater reduction for the patients receiving diltiazem than for those receiving placebo. A similar reduction was noted for nitroglycerin consumption. Total exercise duration at week 10 was statistically greater in patients treated with diltiazem. Diltiazem was well tolerated. No abnormalities in hematologic profiles or in routine serum chemistry values were observed; electrocardiographic P-R and QRS intervals were unaffected. Adverse effects that could have been related to drug administration were reported in 11 patients who received diltiazem and in 12 patients who received placebo. Of the 17 episodes in the diltiazem group only 3 were considered significant and drug-related, and only one of these resulted in discontinuation of the drug.

Twenty-nine patients symptomatic despite beta-blocker therapy were entered into a randomized, double-blind, placebo-controlled, crossover trial of lidoflazine added to propranolol. After clinically documented beta blockade was achieved, patients were randomized to either propranolol plus placebo (P) or propranolol plus lidoflazine (L). Patients initially receiving lidoflazine (group with treatment sequence LP) showed improvement in exercise tolerance from propranolol alone (7.2 to 9.3 minutes, p less than 0.05). Those randomized initially to propranolol plus placebo (group with treatment sequence PL) had unchanged exercise tolerance (7.3 minutes). After 4 months, patients were crossed over to the alternative form of therapy. Patients (group PL) now receiving lidoflazine in addition to propranolol increased their exercise duration (7.8 minutes), but not, significantly. However, patients switched to propranolol plus placebo (group LP) continued to sustain their improved exercise capacity, showing a "carryover" effect. Symptomatic improvement was manifested by a statistically significant reduction in both anginal attack rate and nitroglycerin consumption. The therapeutic efficacy of combined therapy was associated with further blunting of the heart rate response to exercise achieved by beta blockade alone. The combination of agents was well tolerated.

Twenty-four patients with stable angina were evaluated in a 14 week crossover trial. A single-blind placebo period (baseline 1) was followed by two double-blind periods evaluating maximum tolerated doses of diltiazem (up to 360 mg daily) vs placebo. Over the next 1 to 4 weeks, propranolol was started and increased until clinically documented beta-blockade was achieved (baseline 2). The final phase consisted of a pair of evaluation periods comparing propranolol plus the maximum tolerated dose of diltiazem to propranolol and placebo. The daily rate of angina attack was 1.6 during baseline, was unchanged during placebo therapy, but fell during treatment with diltiazem to 0.6 (p less than .005). With the addition of diltiazem to propranolol, the angina rate was improved (0.3) compared with that with either propranolol alone (0.6) or propranolol and placebo (0.5) (p less than .01). Total exercise duration during baseline 1 was 360 sec and increased to 497 sec with diltiazem, 481 sec with propranolol, and 527 sec with the combination of diltiazem and propranolol. Two patients with reduced ejection fractions developed congestive heart failure with propranolol. The combination of diltiazem and propranolol similarly resulted in congestive heart failure in one patient who had tolerated both drugs alone.

Two dimensional echocardiography is just beginning to be used to characterize cardiac damage in patients with acute myocardial infarction. The two dimensional approach allows for a more comprehensive evaluation of cardiac anatomy and is able to detect with high sensitivity changes in regional wall motion that previously were sometimes missed or only found with difficulty using M mode echocardiography. Two dimensional echocardiography appears to offer a basis for quantifying the extent of myocardial damage in acute myocardial infarction and thus may permit objective assessment of therapeutic modalities and prognosis. In addition, the technique facilitates recognition of specific complications in acute myocardial infarction. In particular, the technique offers te ability to distinguish true from false ventricular aneurysm, postinfarction ventricular septal defect from papillary muscle dysfunction and rupture, and right ventricular infarction from cardiac tamponade.

When heparin is injected intravenously, it can induce an immediate release of platelet factor 4 PF4), probably from the non-platelet pool of endothelial cells. We evaluated this release in a group of normal subjects and patients with cardiovascular disorders or thrombocytosis after an intravenous injection of a bolus of 5,000 I.U. of a commercial mucous heparin. The mean level in normals was 102 +/- 32 (range 50-160) ng/ml and no correlation was found before and after heparin injection between PF4 and heparin level, body weight or platelet count. Only three cardiovascular patients had an elevated level of PF4 released by heparin (HR-PF4) that could be the expression of an increased platelet turnover, whereas all the patients with thrombocytosis had an extremely elevated level of HR-PF4. These patients have much more PF4 available for the binding sites of endothelial cells since only a small percentage of potential binding sites are normally occupied "in vivo". Although no correlation could be found between platelet count and HR-PF4 in subjects with a normal platelet count or in patients with thrombocytosis there was a positive correlation, however, when all the cases were considered together. The other proteins with heparin affinity, B-thromboglobulin, antithrombin III and fibronectin were not influenced by a bolus of heparin and did not correlate in normals as well in patients with HR-PF4.

Diseases that cause symptoms incompletely relieved by available modes of treatment stimulate search for new therapies. Chronic disease processes, in which interventions are palliative rather than curative provide a particular challenge in determining the value of therapeutic intervention. Management of patients with angina pectoris is an example of this challenge.

The direct-current magnetocardiogram, which shows the T-Q (baseline) shift, is used to clarify the cause of S-T depression induced by stress testing in the human heart. Measurements are made of the amount of baseline shift associated with the S-T depression. Results are presented of a well-documented patient, with typical coronary artery disease, undergoing a two-step exercise test. Before exercise, there was no S-T or baseline shift. During exercise, the S-T segment became depressed and the baseline segment was simultaneously elevated, at about 70% of the S-T amplitude. After termination of exercise, the baseline elevation disappeared somewhat more rapidly than the S-T depression. These results were consistent in repeated tests of this patient. Because the baseline shift is a reflection of an injury current, these results confirm the belief that exercise-induced S-T depression is mostly due to an injury current which is interrupted during the S-T interval. The baseline shift seen here is the first non-invasive measurement of an injury current in the human heart, and its presence and time-course generally agree with measurements in the animal heart. This work also confirms that the direct-current magnetocardiogram, although not practical for clinical purposes, is useful as a research tool.