Optimization of pharmacotherapies for ambulatory patients with heart failure and reduced ejection fraction is associated with improved outcomes.

BACKGROUND: In heart failure, specific target doses for each drug are recommended, but some patients receive suboptimal dosing, others are undertreated or remain chronically in a titration phase, despite having no apparent contraindication or intolerance. We assessed the association of different levels of adherence to guidelines with outcomes in patients with heart failure and reduced ejection fraction (HFrEF). METHODS: Medical records of patients with HFrEF followed at our heart failure (HF) clinic for at least 6 months (n = 511) were reviewed and patients categorized as: 1) optimized (25.4%); 2) in-titration (29.0%); 3) undertreated (32.7%); and 4) intolerant/contraindicated (12.9%). Risk of mortality or HF events (hospitalization, emergency visit or ambulatory administration of intravenous diuretics) within one year was assessed using Cox regression models and Kaplan-Meier curves. RESULTS: Compared to optimized patients, those intolerant (HR: 4.60 [95%CI: 2.23-9.48]; p < 0.0001) had the highest risk of outcomes, followed by those undertreated (3.45 [1.78-6.67]; p = 0.0002) and in-titration (1.99 [0.97-4.06]; p = 0.0588). Overall predictors of outcomes included loop diuretics' use (4.54 [2.39-8.60]), undertreatment (2.38 [1.22-4.67]), intolerance/ contraindication to triple therapy (3.08 [1.47-6.42]), peripheral vascular disease (2.13 [1.29-3.50]) and NYHA class III-IV (1.89 [1.25-2.85]); all p < 0.05. CONCLUSION: Level of adherence to guidelines is associated with outcomes, with intolerant/contraindicated patients having the worst prognosis and those undertreated and in-titration at intermediate risk compared to those optimized. Up-titration of therapy should be attempted whenever possible, considering patients' limitations, to potentially improve outcomes.

Care Gaps in Adherence to Heart Failure Guidelines: Clinical Inertia or Physiological Limitations?

OBJECTIVES: This study evaluated the impact of clinical and physiological factors limiting treatment optimization toward recommended medical therapy in heart failure (HF). BACKGROUND: Although guidelines aim to assist physicians in prescribing evidence-based therapies and to improve outcomes of patients with HF and reduced ejection fraction (HFrEF), gaps in clinical care persist. METHODS: Medical records of all patients with HFrEF followed for at least 6 months at the authors' HF clinic (n = 511) allowed for drug optimization and were reviewed regarding the prescription rates of recommended pharmacological agents and devices (implantable cardioverter-defibrillator [ICD] or cardiac resynchronization therapy [CRT]). Then, an algorithm integrating clinical (New York Heart Association [NYHA] functional class, heart rate, blood pressure and biologic parameters (creatinine, serum potassium) based on the inclusion/exclusion criteria of landmark trials guiding these recommendations) was applied for each agent and device to identify potential explanations for treatment gaps. RESULTS: Gross prescription rates were high for beta-blockers (98.6%), mineralocorticoid receptor antagonist (MRA) (93.4%), vasodilators (90.3%), ICDs (75.1%), and CRT (82.1%) among those eligible, except for ivabradine (46.3%, n = 41). However, achievement of target physiological doses was lower (beta-blockers, 67.5%; MRA, 58.9%; and vasodilators, 63.4%), and one-fifth of patient dosages were still being up-titrated. Suboptimal doses were associated with older age (odds ratio [OR]: 1.221; p < 0.0001) and history of stroke or transient ischemic attack (TIA) (no vs. yes, OR: 0.264; p = 0.0336). CONCLUSIONS: Gaps in adherence to guidelines exist in specialized HF setting and are mostly explained by limiting physiological factors rather than inertia. Older age and history of stroke/TIA, potential markers of frailty, are associated with suboptimal doses of guideline-directed medical therapy, suggesting that an individualized rather than a "one-size-fits-all" approach may be required.

"Hook effect" in calcitonin immunoradiometric assay in patients with metastatic medullary thyroid carcinoma: case report and review of the literature.

CONTEXT: Calcitonin is a well-established tumor marker for medullary thyroid carcinoma (MTC). Because surgery is the only effective treatment for patients with MTC, the postoperative level of serum calcitonin will dictate whether residual disease was left behind and whether reintervention is necessary. RESULTS: We describe here the case of a 41-yr-old man with metastatic MTC. Despite extensive disease in the neck as well as metastatic lesions in the liver, his serum calcitonin, measured with a commercial one-step immunoradiometric assay, was only minimally elevated (244 ng/liter). After serial dilutions, a nonlinear relationship became evident, suggesting the presence of a "hook effect." Treatment of the serum with heterophilic blocking reagent revealed no change. Calcitonin was then measured with a different immunoradiometric assay and revealed a much higher level. Similar discrepancies were found in different samples from various patients when analyzed with different calcitonin immunoassays. CONCLUSION: To our knowledge, this is the first reported case of a phenomenon such as the hook effect in a calcitonin immunoradiometric assay in patients with MTC. Being aware of this phenomenon is important, because a low calcitonin result could give false reassurance to both the patient and the clinician and could dramatically change the prognosis of the patient.

When is bioavailable testosterone a redundant test in the diagnosis of hypogonadism in men?

OBJECTIVES: Total testosterone (TT) is frequently prescribed with an SHBG and/or free or bioavailable testosterone measurement. Our objective was to identify a TT range for which subsequent SHBG measurement/calculation adds no additional clinical information. DESIGN AND METHODS: Study data were composed of 3955 sets of TT, SHBG and calculated bioavailable testosterone (cBAT) results from unscreened ambulatory male subjects, aged 18-99. RESULTS: 90% of mismatches between TT and cBAT were observed with TT levels between 6.5 and 13.0 nmol/L, with only slight age variation and no important change with albumin level. SHBG measurement restricted to male patients with TT between 6.5 and 13.0 nmol/L should enable reagent cost savings of over 55%. CONCLUSION: We suggest that a TT level below 6.5 nmol/L or above 13.0 nmol/L provides sufficient useful information for ruling out hypogonadism in ambulatory adult males. This strategy of BAT testing should lead to significant time and cost savings.

Comparison of two methods to assess variability of platelet response to anti-platelet therapies in patients with acute coronary syndrome undergoing angioplasty.

The study investigated the clinical usefulness of a new method to evaluate platelet activation and the variability of platelet response to anti-platelet therapy in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Platelet activation was assessed in parallel by a new method for platelet density measurements (MPC, Mean Platelet Component Concentration), on the automated ADVIA 120 Hematology System and by the classic measurement of P-selectin (CD62P) expression, on a fluorescence flow cytometer. Patients received a loading dose of clopidogrel (300 mg; n = 29) or a bolus of abciximab (0.25 mg/kg; n = 15). Blood samples were collected before (baseline) and at different times after PTCA and antiplatelet drugs administration. Our data showed a close inverse correlation between the change in MPC and the CD62P fluorescence surface marker expression (r = -0.776, P<0.0001). Individual platelet activation determinations in patients receiving either clopidogrel or abciximab showed a variation in platelet activation as assayed by MPC and CD62P expression. Patients were characterized as having either high platelet activity upon admission and positive response to treatment or no detectable platelet activation before or after treatment. This study demonstrates the heterogeneity of platelet activation states in ACS patients undergoing coronary angioplasty. The present work also illustrates the potential use of the MPC parameter, generated on an automated hematology system, to define high risk patients and to monitor the variability of platelet response to anti-platelet therapies.

Analytical and clinical evaluation of the Bayer ADVIA Centaur automated B-type natriuretic peptide assay in patients with heart failure: a multisite study.

BACKGROUND: B-Type natriuretic peptide (BNP) is released from the left ventricle of the heart into the circulation in response to ventricular stretching and volume overload. Increased BNP concentrations are associated with heart failure (HF). METHODS: We evaluated the analytical and clinical performance of the Bayer ADVIA Centaur BNP assay. Studies included precision, analytical correlation (against the Shionogi ShionoRIA and Biosite Triage BNP assays), BNP results for blood collected in plastic tubes containing EDTA vs other collection tubes, high-dose hook effect, detection limits, and interferences. The clinical performance was tested on 2243 blood samples collected from 983 apparently healthy individuals, 538 patients with chronic disease but without HF (renal insufficiency, chronic obstructive pulmonary disease, diabetes, and hypertension), and 722 patients with HF (New York Heart Association classes I-IV). RESULTS: The ADVIA Centaur assay had total imprecision (CV) of 3.4%, 2.9%, and 2.4% at BNP concentrations of 48, 461, and 1768 ng/L, respectively. The Passing-Bablok correlations to the ShionoRIA and Triage were as follows: ADVIA Centaur = 1.11(ShionoRIA) - 1.19 ng/L (r = 0.98); ADVIA Centaur = 0.78(Triage) + 5.89 ng/L (r = 0.92), respectively. Of the different blood collection tubes, only EDTA plastic tubes (with and without the barrier gel) were acceptable. The lower detection limit was 0.5 ng/L, and there were no interferences from common analytes, other neuropeptides, or unusual antibodies. BNP exhibited different reference intervals according to age and gender. BNP concentrations increased progressively as the severity of HF increased. CONCLUSIONS: The ADVIA Centaur is the first commercially available BNP assay for use on an automated immunochemistry platform. This assay has good analytical and clinical performance characteristics for diagnosing HF.

Assessment of platelet activation in several different anticoagulants by the Advia 120 Hematology System, fluorescence flow cytometry, and electron microscopy.

In vivo platelet activation results are often confounded by activation induced in vitro during the preparative procedures. We measured ex vivo (basal) and in vitro (thrombin-induced) platelet activation in sodium citrate, ethylenediaminetetraacetic acid (EDTA), and Citrate Theophylline Dipyridamole Adenosine (CTAD) whole blood specimens. Determinations were made by measurements of platelet density (mean platelet component: MPC concentration) on the Advia 120 Hematology System. The MPC has been previously shown to correlate with a fluorescence flow cytometric method, also determined in this study, using the surface expression of CD62P. Moreover, platelet shape and structure changes in EDTA and CTAD anticoagulated whole blood specimens were characterized by transmission electron microscopy (TEM). Observations made using the Advia 120 Hematology System platelet density parameter, MPC, in the absence of thrombin were 25.7 +/- 0.9 g/dl, 27.9 +/- 0.9 g/dl and 24.8 +/- 1.2 g/dl in sodium citrate, EDTA and CTAD whole blood specimens, respectively. Addition of thrombin induced a significant change in platelet MPC for sodium citrate (21.9 +/- 1.9 g/dl; p<0.0001) and EDTA (23.2 +/- 0.9 g/dl; p<0.0001) whole blood specimens. In contrast, thrombin had no effect on MPC measured in whole blood taken into CTAD tubes. In vitro fluorescence flow cytometric platelet activation experiments measuring the percentage of platelets expressing anti-CD62P showed increase in sodium citrate specimens from 9.2 +/- 7.0 to 55.5 +/- 23.1 % (p<0.0001) and in EDTA specimens from 1.9 +/- 1.7 to 64.6 +/- 12.4 % (p<0.0001) after addition of thrombin. However, in blood taken into CTAD tubes, there was no significant change. Studies on platelets isolated from whole blood in CTAD showed activation by thrombin indicating that platelets in CTAD, while protected in its presence remained functional upon its removal. When observed by TEM over time, platelets in EDTA appear more activated and contain fewer granules than platelets in CTAD. We conclude that CTAD demonstrates in vitro platelet activation inhibition and may be useful in stabilizing ex vivo platelet activation. The novel platelet activation parameter, MPC, measured by an automated routine hematology system, using customized proprietary software, may be used in conjunction with CTAD, a stabilizing anticoagulant, to measure the ex vivo platelet activation state in whole blood specimens. TEM studies verify shape modifications and simultaneous retention of intracellular granules at early post-venipuncture time periods in CTAD specimens.

Addition of protected and unprotected fish oil to diets for dairy cows. I. Effects on the yield, composition and taste of milk.

Thirty Holstein cows in mid-lactation (158+/-20 DIM) were given a total mixed ration based on grass silage, maize silage and rolled barley. After a preliminary period of 1 week, this diet was supplemented with nothing (control), unprotected fish oil (3.7% of dry matter, DM), or two levels of glutaraldehyde-protected microcapsules of fish oil (1.5% and 3.0% of DM, respectively). Unprotected and protected supplements contained, respectively, 74% and 58% of DM as lipids. Cows given the unprotected supplement reduced their feed intake by > 25%. Consequently, these cows lost body weight and produced less milk. DM intake, body weight, and milk yield were unaffected by protected fish oil. Fish oil reduced both milk fat and protein percentages, and decreased the proportion of short-chain fatty acids, stearic, and oleic acids in milk fat. Milk trans C18:1 fatty acids increased in cows given both unprotected and protected fish oil. Milk fat content of very-long-chain n3 polyunsaturated fatty acids, including C20:5 and C22:6, increased with fish oil in the diet. Accordingly, the peroxide index increased and a taste panel was able to detect unusual taste in milk from cows consuming the higher level of protected fish oil and disliked the milk from cows given unprotected fish oil. In conclusion, when lactating cows consumed fish oil, milk concentration of long-chain n3 fatty acids increased and mammary de novo synthesis of fatty acids decreased, but milk yield and milk protein content were reduced, and the milk was more susceptible to oxidation and its taste was adversely affected.

Addition of fish oil to diets for dairy cows. II. Effects on milk fat and gene expression of mammary lipogenic enzymes.

Sixteen Holstein cows in mid-lactation were used to determine whether alterations of mammary fatty acid metabolism are responsible for the milk fat depression associated with consumption of fish oil. Cows were given a total mixed ration with no added fish oil (control), unprotected fish oil (3.7 % of dry matter), or glutaraldehyde-protected microcapsules of fish oil (1.5% or 3.0% of dry matter) for 4 weeks. Milk samples were taken once a week and a mammary biopsy was taken from a rear quarter at the end of the treatment period. Milk fat content was lower in cows given unprotected fish oil (26.0 g/kg), 1.5% protected fish oil (24.6 g/kg) and 3% protected fish oil (20.4 g/kg) than in cows fed the control diet (36.0 g/kg). This was mainly due to a decrease in the synthesis of short-chain fatty acids. Consumption of protected fish oil decreased the abundance of lipogenic enzymes mRNA in the mammary gland. Acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase mRNAs for cows given 3% protected fish oil averaged only 30%, 25% and 25% of control values, respectively. Dietary addition of unprotected fish oil slightly decreased mRNA abundance of these enzymes but markedly reduced the amount of lipoprotein lipase mRNA. Milk fat content was significantly correlated with gene expression of acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase but not lipoprotein lipase. These results suggest that fish oil reduces milk fat percentage by inhibiting gene expression of mammary lipogenic enzymes.