Factors associated with admission to the intensive care unit and mortality in patients with COVID-19, Colombia.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has affected millions of people worldwide, and several sociodemographic variables, comorbidities and care variables have been associated with complications and mortality. OBJECTIVE: To identify the factors associated with admission to intensive care units (ICUs) and mortality in patients with COVID-19 from 4 clinics in Colombia. METHODS: This was a follow-up study of a cohort of patients diagnosed with COVID-19 between March and August 2020. Sociodemographic, clinical (Charlson comorbidity index and NEWS 2 score) and pharmacological variables were identified. Multivariate analyses were performed to identify variables associated with the risk of admission to the ICU and death (p<0.05). RESULTS: A total of 780 patients were analyzed, with a median age of 57.0 years; 61.2% were male. On admission, 54.9% were classified as severely ill, 65.3% were diagnosed with acute respiratory distress syndrome, 32.4% were admitted to the ICU, and 26.0% died. The factors associated with a greater likelihood of ICU admission were severe pneumonia (OR: 9.86; 95%CI:5.99-16.23), each 1-point increase in the NEWS 2 score (OR:1.09; 95%CI:1.002-1.19), history of ischemic heart disease (OR:3.24; 95%CI:1.16-9.00), and chronic obstructive pulmonary disease (OR:2.07; 95%CI:1.09-3.90). The risk of dying increased in those older than 65 years (OR:3.08; 95%CI:1.66-5.71), in patients with acute renal failure (OR:6.96; 95%CI:4.41-11.78), admitted to the ICU (OR:6.31; 95%CI:3.63-10.95), and for each 1-point increase in the Charlson comorbidity index (OR:1.16; 95%CI:1.002-1.35). CONCLUSIONS: Factors related to increasing the probability of requiring ICU care or dying in patients with COVID-19 were identified, facilitating the development of anticipatory intervention measures that favor comprehensive care and improve patient prognosis.

The Pharmacology, Efficacy, and Safety of Rivaroxaban in Renally Impaired Patient Populations.

Rivaroxaban is a factor Xa inhibitor oral anticoagulant first approved for use in the United States in 2011. Under the drug class commonly termed direct oral anticoagulants, rivaroxaban is approved for the most indications within its class, 7 indications, which are: (1) reduction of risk of stroke and systemic embolism (SE) in nonvalvular atrial fibrillation, (2) treatment of deep vein thrombosis (DVT), (3) treatment of pulmonary embolism (PE), (4) reduction in the risk of recurrence of DVT and/or PE, (5) prophylaxis of DVT following hip or knee replacement surgery, (6) prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, and (7) reduction of risk of major cardiovascular events in patients with chronic coronary artery disease or peripheral artery disease. Considering the relationship between cardiovascular disease, renal impairment, and the use of oral anticoagulants, the following targeted review was created. This review reports the results of the primary pharmacology, pharmacokinetic modeling, clinical safety and efficacy, and real-world postmarketing effectiveness and safety of rivaroxaban in patients with various degrees of renal impairment. Based on these data, rivaroxaban is a viable option for when anticoagulation is needed in patients who have both cardiovascular disease and renal impairment. However, as with any therapy, the benefits and risks of intervention should be carefully assessed and balanced. Patients treated with rivaroxaban for several of its approved indications should have their kidney function assessed prior to and during continued therapy to ensure consistency with the drug label.

Reducing the Risk of Stroke in Patients with Impaired Renal Function: Nutritional Issues.

Patients with renal failure have extremely high cardiovascular risk; in dialysis patients the risk of stroke is increased approximately 10-fold over that in the general population. Reasons include not only a high prevalence of traditional risk factors such as diabetes, hypertension and dyslipidemia, but also the accumulation of toxic substances that are eliminated by the kidneys, so have very high levels in patients with renal failure. These include plasma total homocysteine, asymmetric dimethylarginine, thiocyanate, and toxic products of the intestinal microbiome (Gut-Derived Uremic Toxins; GDUT), which include trimethylamine N- oxide (TMAO), produced from phosphatidylcholine (largely from egg yolk) and carnitine (largely from red meat). Other GDUT are produced from amino acids, largely from meat consumption. Deficiency of vitamin B12 is very common, raises plasma tHcy, and is easily treated. However, cyanocobalamin is toxic in patients with renal failure. To reduce the risk of stroke in renal failure it is important to limit the intake of meat, avoid egg yolk, and use methylcobalamin instead of cyanocobalamin, in addition to folic acid.

Rivaroxaban and Aspirin in Patients With Symptomatic Lower Extremity Peripheral Artery Disease: A Subanalysis of the COMPASS Randomized Clinical Trial.

Importance: Patients with symptomatic lower extremity peripheral artery disease (LE-PAD) experience an increased risk of major vascular events. There is limited information on what clinical features of symptomatic LE-PAD prognosticate major vascular events and whether patients at high risk have a greater absolute benefit from low-dose rivaroxaban and aspirin. Objective: To quantify the risk of major vascular events and investigate the response to treatment with low-dose rivaroxaban and aspirin among patients with symptomatic LE-PAD based on clinical presentation and comorbidities. Design, Setting, and Participants: This is a subanalysis of a previously reported subgroup of patients with symptomatic LE-PAD who were enrolled in a large, double-blind, placebo-controlled randomized clinical trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]) in 602 centers in 33 countries from March 2013 to January 2020. Data analysis was completed from May 2016 to June 2020. Interventions: A combination of low-dose rivaroxaban and aspirin compared with aspirin alone. Main Outcomes and Measures: Thirty-month incidence risk of myocardial infarction, stroke and cardiovascular death (MACE), major adverse limb events (MALE) including major vascular amputation, and bleeding. Results: The COMPASS trial enrolled 4129 patients with symptomatic LE-PAD (mean [SD] age, 66.8 [8.8] years; 2932 men [71.0%]). The 30-month Kaplan-Meier incidence risk of MACE or MALE, including major amputation, was 22.6% in those with prior amputation (this outcome was observed in 54 patients), 17.6% (n = 15) in those with Fontaine III or IV symptoms, and 11.8% (n = 142) in those with previous peripheral artery revascularization, classifying these features as high-risk limb presentations. The 30-month incidence risk of MACE or MALE, including major amputation, was 14.1% (n = 118) in those with kidney dysfunction, 13.5% (n = 67) in those with heart failure, 13.4% (n = 199) in those with diabetes, and 12.8% (n = 222) in those with polyvascular disease, classifying these features as high-risk comorbidities. Among patients with either high-risk limb presentations or high-risk comorbidities, treatment with rivaroxaban and aspirin compared with aspirin alone was associated with an estimated 4.2% (95% CI, 1.9%-6.2%) absolute risk reduction for MACE or MALE, including major amputation, at 30 months. Although the estimated absolute risk increase of major bleeding was higher with rivaroxaban and aspirin in combination than aspirin alone (2.0% [95% CI, 0.5%-3.9%]) for patients with either high-risk limb presentation or high-risk comorbidity, the estimated absolute risk increase of fatal or critical organ bleeding was low in this high-risk group (0.4% [95% CI, 0.2%-1.8%]), such that the net clinical benefit was estimated to be 3.2% (95% CI, 0.6%-5.3%). Conclusions and Relevance: Patients with LE-PAD with high-risk limb presentations or high-risk comorbidities had a high incidence of major vascular events. For these patients, treatment with rivaroxaban and aspirin in combination compared with aspirin alone led to a large absolute reduction in vascular risk.

Regular Bleeding Risk Assessment Associated with Reduction in Bleeding Outcomes: The mAFA-II Randomized Trial.

BACKGROUND: The mobile atrial fibrillation application (mAFA-II) randomized trial reported that a holistic management strategy supported by mobile health reduced atrial fibrillation-related adverse outcomes. The present study aimed to assess whether regular reassessment of bleeding risk using the Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile international normalized ratio, Elderly, Drugs or alcohol (HAS-BLED) score would improve bleeding outcomes and oral anticoagulant (OAC) uptake. METHODS: Bleeding risk (HAS-BLED score) was monitored prospectively using mAFA, and calculated as 30 days, days 31-60, days 61-180, and days 181-365. Clinical events and OAC changes in relation to the dynamic monitoring were analyzed. RESULTS: We studied 1793 patients with atrial fibrillation (mean, standard deviation, age 64 years, 24 years, 32.5% female). Comparing baseline and 12 months, the proportion of atrial fibrillation patients with HAS-BLED ≥3 decreased (11.8% vs 8.5%, P = .008), with changes in use of concomitant nonsteroidal antiinflammatory drugs/antiplatelets, renal dysfunction, and labile international normalized ratio contributing to the decreased proportions of patients with HAS-BLED ≥3 (P < .05). Among 1077 (60%) patients who had 4 bleeding risk assessments, incident bleeding events decreased significantly from days 1-30 to days 181-365 (1.2% to 0.2%, respectively, P < .001). Total OAC usage increased from 63.4% to 70.2% (Ptrend < .001). Compared with atrial fibrillation patients receiving usual care (n = 1136), bleeding events were significantly lower in atrial fibrillation patients with dynamic monitoring of their bleeding risk (mAFA vs usual care, 2.1%, 4.3%, P = .004). OAC use decreased significantly by 25% among AF patients receiving usual care, when comparing baseline to 12 months (P < .001). CONCLUSION: Dynamic risk monitoring using the HAS-BLED score, together with holistic App-based management using mAFA-II reduced bleeding events, addressed modifiable bleeding risks, and increased uptake of OACs.

Pleiotropic effects of liraglutide treatment on renal risk factors in type 2 diabetes: Individual effects of treatment.

AIMS/HYPOTHESIS: Management of diabetic nephropathy includes reduction of albuminuria, blood pressure and weight. The GLP-1 receptor agonist liraglutide may possess these pleiotropic effects in addition to the glucose lowering effect. We aimed to elucidate the individual liraglutide treatment response by determining if high responders (highest reduction) in each risk factor also had high response in other renal risk factors (cross-dependency). METHODS: Open-label study: 31 type 2 diabetics treated with liraglutide for 7weeks. After 3weeks washout 23 re-started treatment and were followed for 1year. HbA1c, weight, systolic blood pressure (SBP), urinary albumin excretion rate (UAER) and mGFR (51Cr-EDTA) were evaluated. Changes in high (Q4) vs. low responders (Q1-Q3) were compared for each renal risk factor. The effects of treatment/off treatment/re-treatment (off-on/off-on effect) were evaluated to account for random effects. RESULTS: After 7weeks HbA1c was reduced 6(95% CI: 3;9)mmol/mol, weight 2.5(1.8;3.2)kg, SBP 4(-1;9)mmHg, UAER 30(12;44)% and mGFR 11(7;14)ml/min per 1.73m2. mGFR high responders had a significant reduction in weight compared to low responders (4.3 vs. 1.9kg; p=0.002). SBP high responders had a tendency of a higher reduction in UAER compared to low responders (47 vs. 23%, p=0.14). No cross-dependency was observed in any of the other renal risk factors (p≥0.16). Treatment response did not differ after 7weeks and 1year (p≥0.12). CONCLUSIONS/INTERPRETATION: Liraglutide possesses pleiotropic effects on renal risk factors. On patient level, effect on the individual risk factor cannot be anticipated based on response in other risk factors. Response when re-starting treatment did not differ, indicating that our primary findings were not random.

Preexposure Prophylaxis for HIV Prevention in a Large Integrated Health Care System: Adherence, Renal Safety, and Discontinuation.

BACKGROUND: Placebo-controlled and open-label studies have demonstrated the safety and efficacy of daily oral preexposure prophylaxis (PrEP) in preventing HIV infection, but data are limited on real-world PrEP use. METHODS: We conducted a cohort study from July 2012 through June 2015 of Kaiser Permanente Northern California members initiating PrEP. We assessed pharmacy refill adherence and discontinuation, decreases in estimated glomerular filtration rate (eGFR), and sexually transmitted infection (STI)/HIV incidence. RESULTS: Overall, 972 individuals initiated PrEP, accumulating 850 person-years of PrEP use. Mean adherence was 92% overall. Black race/ethnicity [adjusted risk ratio (aRR) 3.0; 95% confidence interval: 1.7 to 5.1, P < 0.001], higher copayments (aRR 2.0; 1.2 to 3.3, P = 0.005), and smoking (aRR 1.6; 1.1 to 2.3, P = 0.025) were associated with <80% adherence. PrEP was discontinued by 219 (22.5%); female sex (aRR 2.6; 1.5 to 4.6, P < 0.001) and drug/alcohol abuse (aRR 1.8; 1.3 to 2.6, P = 0.002) were associated with discontinuation. Among 909 with follow-up creatinine testing, 141 (15.5%) had an eGFR <70 mL·min·1.73 m and 5 (0.6%) stopped PrEP because of low eGFR. Quarterly STI positivity was high and increased over time for rectal chlamydia (P < 0.001) and urethral gonorrhea (P = 0.012). No HIV seroconversions occurred during PrEP use; however, 2 occurred in individuals who discontinued PrEP after losing insurance coverage. CONCLUSIONS: PrEP adherence was high in clinical practice, consistent with the lack of HIV seroconversions during PrEP use. Discontinuation because of renal toxicity was rare. STI screening every 6 months, as recommended by current guidelines, may be inadequate. Strategies are needed to increase PrEP access during gaps in insurance coverage.

Evaluation of Dose-Reduced Direct Oral Anticoagulant Therapy.

BACKGROUND: Compared with vitamin K antagonists, direct-acting oral anticoagulants (DOACs) have fixed dosing, limited drug interactions, and do not require therapeutic drug level monitoring. Dose adjustments are recommended for moderate renal dysfunction, low body weight, and select drug interactions. OBJECTIVES: The aim of our study is to determine if DOAC dose reductions were appropriate based on the manufacturer labeling recommendations for each agent. We also followed patients' treatment outcomes. METHODS: We retrospectively reviewed patients administered a DOAC at a reduced dose between January 2011 and August 2014. The primary outcome was adherence to current manufacturer dose recommendations. The secondary outcome measures were the incidence of thromboembolic events or any bleeding episodes, regardless of severity, while on therapy. RESULTS: Of 224 patients included in the analysis, 43.3% of patients fit criteria for a dose adjustment according to manufacturer recommendations. Only 3 of 28 (10.7%) patients treated with apixaban met 2 out of 3 clinical criteria required for a dose reduction per manufacturer recommendations. Only 54.7% of rivaroxaban-treated patients and 32.2% of dabigatran-treated patients had renal insufficiency requiring a dose reduction. Half of our patient population received aspirin therapy, with 6.3% of patients on triple antithrombotic therapy (dual antiplatelet agents plus an anticoagulant). A past medical history significant for bleeding was prevalent in patients treated with a reduced-dose DOAC (32.1%, 20.4%, and 25.4% of patients in the apixaban-, rivaroxaban-, and dabigatran-treated groups, respectively). Thromboembolic events occurred in 10.7%, 3.6%, and 5.1% of patients in the apixaban, rivaroxaban, and dabigatran groups, respectively. Frequency of bleeding complications, regardless of severity, was 17.9%, 18.2%, and 23.7% of patients in the apixaban, rivaroxaban, and dabigatran groups, respectively. CONCLUSION: We found that dose-adjusted DOAC therapy was often prescribed in a dose that was lower than package insert recommendations.

Selenium, copper, zinc, iron levels and mortality in patients with sepsis and systemic inflammatory response syndrome in Western Black Sea Region, Turkey.

OBJECTIVE: To evaluate the changing levels of selenium, copper, zinc and iron in patients with sepsis and systemic inflammatory response syndrome and their influence on mortality. METHODS: The prospective study was conducted at a tertiary care university hospital in Zonguldak city in the western Black Sea region of Turkey from January 2012 to December 2013, and comprised patients with sepsis and systemic inflammatory response syndrome. Blood samples were taken on 1st, 3rd, 5th and 7th days to measure serum selenium, copper, zinc and iron levels. Patients' demographic data, presence of additional diseases and mortality were recorded. RESULTS: Of the 57 patients, 28(49.1%) were female and 29(50.9%) were male, with an overall mean age of 60.3±19.4 years, mean height of 166.1±11.4cm, mean weight of 76.5±17.5kg. Copper and zinc levels were in the normal range, while selenium and iron levels were lower than the limit values at all measuring periods. There was no significant difference between first and other days in accordance with element levels (p>0.05). Baseline copper levels in patients with malignancy were lower than patients without malignancy (p< 0.05). In hypertensive patients, baseline copper levels were higher and 7th day levels were lower than non-hypertensive (p< 0.05). Baseline selenium levels of those who died were lower than the other patients (p< 0.05). Selenium and iron levels were decreased in patients with sepsis-systemic inflammatory response syndrome and copper levels were lower in patients with malignancy, hypertension and chronic obstructive pulmonary disease (p< 0.05). There was no change in zinc levels of the patients. CONCLUSIONS: Reduced basal selenium levels of patients with sepsis and systemic inflammatory response syndrome were associated with mortality.

Comparison of combination therapy of high-dose oral N-acetylcysteine and intravenous sodium bicarbonate hydration with individual therapies in the reduction of Contrast-induced Nephropathy during Cardiac Catheterisation and Percutaneous Coronary Intervention (CONTRAST): A multi-centre, randomised, controlled trial.

INTRODUCTION: N-acetylcysteine (NAC) and sodium bicarbonate (SOB) therapies may prevent contrast-induced nephropathy (CIN). However, the efficacy of using combination over individual therapies was not established, and there was no large randomised study comparing abbreviated SOB therapy with conventional sustained saline pre-hydration with oral NAC. METHODS: In a multi-centre, open-label, randomised, controlled trial (NCT00497328), we prospectively enrolled 548 patients with at least moderate renal impairment undergoing cardiac catheterisation with or without percutaneous coronary intervention. Patients were randomly assigned to 3 groups: 1) NAC: 154 mEq/L sustained sodium chloride regime (1 mL/kg/h 12 h before, during and 6h after the procedure) with oral NAC at 1.2g bid for 3 days (n=185); 2) SOB: 154 mEq/L abbreviated SOB regime at 3 mL/kg/h 1h before the procedure, and 1 mL/kg/h during and 6h after the procedure (n=182); and 3) COM: combination of abbreviated SOB regime and oral NAC (n=181). The primary end point was incidence of CIN. The secondary end points were rise in serum creatinine, hospitalisation duration, haemodialysis, morbidity and mortality within 30 days. RESULTS: The 3 groups had similar baseline characteristics: age 68 ± 10 years, 76% male, 48% diabetic and baseline glomerular filtration rate (GFR) 47.7 ± 13.0 mL/min. There were 41 (8.8%) patients with GFR<30. The CIN incidences were NAC 6.5%, SOB 12.8% and COM 10.6%. The COM regimen was not superior to either the NAC (relative risk (RR)=1.61, 95% confidence interval (CI): 0.76 to 3.45, p=0.225) or SOB (RR=0.83, 95% CI: 0.44 to 1.56, p=0.593) regimens. The CIN incidence was lower in the NAC group than the SOB group (adjusted odds ratio (OR)=0.40, 95% CI: 0.17 to 0.92; p=0.032). Multivariate analysis showed contrast volume (OR=1.99, 95% CI: 1.33 to 2.96, p<0.001 per 100mL), female (OR=2.47, 95% CI: 1.22 to 5.00, p=0.012) and diabetes (OR=2.03, 95% CI: 1.03 to 3.99, p=0.041) were independent risk predictors. There were no differences in the secondary outcomes among the 3 groups. CONCLUSION: The combination regimen was not superior to individual regimens in preventing CIN in patients with baseline renal impairment. There was a trend suggesting that the 12-hour sustained sodium chloride pre-hydration regimen was more protective than the 1-hour abbreviated SOB regimen.

Renal impairment among postmenopausal women with osteoporosis from a large health plan in Israel.

UNLABELLED: Bisphosphonates are a first-line treatment for osteoporosis but require adequate renal function. We estimated the prevalence of renal impairment among osteoporotic women in Israeli. Approximately 2.3 % of women had renal impairment at a level that makes them inappropriate for bisphosphonate use, demonstrating the need for alternative therapies for osteoporosis treatment. PURPOSE: The purpose of this study is to estimate the prevalence of renal impairment among postmenopausal osteoporotic women within a large Israeli health plan. METHODS: This was a retrospective analysis of Maccabi electronic medical records, including Israeli women aged ≥55 with either an osteoporosis diagnosis or osteoporosis-related fracture between January 1, 2007, and December 31, 2011. The estimated glomerular filtration rate (eGFR), which was calculated from the lowest serum creatinine levels reported during the study period, was used to classify stage 1-5 renal impairment: normal ≥90, mild 60-89, moderate 30-59, severe 15-29, and failure <15 mL/min/1.73 m(2), respectively. Outcomes were distributions of renal impairment across the study population and stratified by age and osteoporosis-defining event. RESULTS: A total of 15,608 patients met all eligibility criteria. Patients with stage 1-5 renal function accounted for 25.2, 54.9, 18.5, 1.2, and 0.3 %, respectively, of all patients. Of osteoporotic patients, 2.3 % had eGFR levels (<35 mL/min/1.73 m(2)) that make them inappropriate for bisphosphonate use. This rate was 1.6 % among patients with an osteoporosis diagnosis and 3.8 % among patients with osteoporosis-related fracture. Within the group of renally impaired patients, older patients were overrepresented. Of the fracture group, patients with hip fractures had a higher prevalence of renal dysfunction (9.3 %) than those having vertebral fractures (3.2 %) or other fractures (2.0 %). CONCLUSIONS: Among postmenopausal women with osteoporosis, 2.3 % had renal impairment which makes them inappropriate for bisphosphonate use in Israel.

Prevalence of vitamin D deficiency in peritoneal dialysis patients.

Peritoneal dialysis (PD) patients have a high risk of developing vitamin D deficiency as 25(OH) vitamin D, the precursor of active vitamin D, is lost during dialysis. This cross-sectional study was conducted to investigate the prevalence of vitamin D deficiency among adult Saudi patients on regular PD The data was collected in the summer of 2010 from patients who were on PD for more than six months at the King Khalid University Hospital, Riyadh. We recorded the demographic and clinical parameters for all patients. Blood samples were taken for serum vitamin D level (25 OH), serum parathyroid hormone (PTH) levels and other necessary biochemical parameters. There were 27 patients (11 males and 16 females) with a mean age of 46 (15-78 ± 21) years. Five patients were on continuous ambulatory PD and 22 patients were using automated PD. The average time on PD was 27.5 (6-84 ± 18.5) months. The mean serum vitamin D 25 (OH) level was 16.1 (4.9-41.5 ± 8.23) nmol/L. Sixteen (59.2%) of the patients had levels below 15 nmol/L, while another eight patients (29.6%) had vitamin D levels between 15 and 25 nmol/L, indicating a marked deficiency. The mean serum calcium was 2.2 (1.7-2.6 ± 0.2) mmol/L and the mean serum phosphorous was 1.48 (0.64-2.22 ± 0.37) mmol/L. Fifteen patients (55.5%) had significant hyperparathyroidism (serum PTH levels above 30 pmol/L). Majority of the PD patients in our center had vitamin D deficiency. The possible reasons include chronic renal failure, dietary restrictions, loss of vitamin D and decreased exposure to sunlight.

Associations among epoetin therapy, inflammation, nutritional status, and mortality in patients on hemodialysis.

OBJECTIVE: Inflammation contributes to hemopoiesis by lowering responses to epoetin (EPO) and to an increase in the mortality of patients on hemodialysis. However, nutritional status might alter associations among inflammation, EPO responsiveness, and the risk of mortality. We assessed the effect of inflammation on mortality according to nutritional status among EPO responses in a cohort of prevalent hemodialysis patients. DESIGN AND METHODS: The observational cohort study analyzed data from the Japanese Dialysis Registry (2005-2006; n = 36,956; mean follow-up 11.5 months). Patients were categorized into tertiles of the EPO responsiveness index (ERI; the weekly weight-adjusted EPO dose [IU/kg/week] divided by hemoglobin [g/dL]) and an EPO-free group. Body mass index (BMI) and C-reactive protein (CRP) levels were measured. RESULTS: Bimodal peaks indicated associations between CRP and BMI in each group. Hazard ratio (HR) curves of CRP for mortality according to BMI in the upper ERI tertile, particularly among those with diabetes mellitus (DM), were reverse J-shaped. However, HR curves in the other groups were increased below a threshold BMI of 21 kg/m(2). These associations were confirmed in propensity score-matched populations. CONCLUSION: Risk of CRP for death is apparently changed by BMI in hemodialysis patients with a lower EPO response, especially in those with DM.

Incident hyperkalemia may be an independent therapeutic target in low ejection fraction heart failure patients: insights from the HEAAL study.

BACKGROUND: Angiotensin receptor antagonists (ARBs) improve outcomes in patients with heart failure (HF) with reduced left ventricular ejection fraction, but may induce hyperkalemia (HK) and/or a worsening of renal function (WRF). METHODS AND RESULTS: The incidence and risk factors of HK and its inter-relationship with WRF, as well as associations with clinical outcome (death or admission for HF i.e. the primary outcome) in 3846 HF patients enrolled in the double blind HEAAL trial (losartan 150 mg/d vs. 50 mg/d) were assessed. Worsening of renal function was defined as a decrease in eGFR >20% from baseline and HK as serum K >5.5 or >5 mmol/L. Higher dose of losartan increased serum potassium. Episodes of HK >5 mmol/L or WRF occurred at least once in about half of the patients. WRF was associated with higher occurrence of HK (HR 1.19 (1.06-1.34)) and vice versa (HR 1.35 (1.19-1.53)), but preceded HK in only about half of the events. High dose losartan improved outcome despite more frequent WRF and HK, both being independently associated with adverse outcomes in multivariate analyses. CONCLUSIONS: HK and WRF are common in HF patients. Both can be predicted from baseline risk factors and are therefore potentially preventable. Although associated with worse outcome, occurrence of any does not hinder the efficacy of high dose losartan. HK was associated with WRF and worse outcomes. Whether therapy targeting specifically HK may maximize the survival benefit derived from renin angiotensin aldosterone inhibitor use should be appropriately tested in future trials.

Incremental prognostic information from kidney function in patients with new onset coronary heart disease.

BACKGROUND: Prognostic factors are usually evaluated by their statistical significance rather than by their clinical utility. Risk reclassification measures the extent to which a novel marker adds useful information to a prognostic model. The extent to which estimated glomerular filtration rate (eGFR) adds information about prognosis among patients with coronary heart disease is uncertain. METHODS: We studied patients in an integrated health care delivery system with newly diagnosed coronary heart disease. We developed a model of the risk of death over 2 years of follow-up and then added eGFR to the model and measured changes in C-index, net reclassification improvement, and integrated discrimination improvement. RESULTS: Almost half of the 31,533 study patients had reduced eGFR (<60 mL/min per 1.73 m(2)). Mortality was significantly higher among patients who had lower levels of eGFR, even after adjustment for baseline characteristics (P < .0001). The addition of eGFR to the prognostic model increased the C-index from 0.837 to 0.843, the net reclassification improvement by 3.2% (P < .0001), and integrated discrimination improvement by 1.3% (P = .007). CONCLUSION: Estimated glomerular filtration rate is an informative prognostic factor among patients with incident coronary heart disease, independent of other clinical characteristics.

Predicting deficiency of vitamin D in renal transplant recipients in northern climates.

BACKGROUND: Renal transplant patients have been shown to have a higher risk of bone disease than the general population. The aim of this study was to examine vitamin D status, a modifiable risk factor in bone disease, in the renal transplant population in a northern climate. METHODS: This retrospective observational study included 331 subjects and analyzed demographic, biochemical, and medication information for associations with vitamin D. RESULTS: Of the study population, 45.3% were vitamin D deficient. The percentage of deficient subjects increases to 76.5% if those receiving supplementation are excluded. The mean daily dose of vitamin D was 1275 IU for sufficient patients. For every 1000 IU of vitamin D daily, the risk of deficiency is decreased by 40.3%. Time from transplantation had a significant positive association (P<0.001) in which every year out of transplantation decreased the risk of deficiency by 9.1%. Body mass index had a significant negative association (P=0.012) with vitamin D in which the risk of deficiency increased by 6% for each kilogram per meter squared. Ethnicity was found to be statistically significant on univariate analysis (P=0.034), with white patients having 9.1% decreased risk of deficiency. CONCLUSION: Despite a high rate of supplementation of vitamin D, close to half of the renal transplant population was still deficient. Those who were receiving over 1000 IU daily were more likely to be vitamin D sufficient. Early supplementation after transplantation along with higher doses for non-white patients or patients with a high body mass index may be warranted for normalization of vitamin D status.

Is serum phosphorus control related to parathyroid hormone control in dialysis patients with secondary hyperparathyroidism?

BACKGROUND: Elevated serum phosphorus (P) levels have been linked to increased morbidity and mortality in dialysis patients with secondary hyperparathyroidism (SHPT) but may be difficult to control if parathyroid hormone (PTH) is persistently elevated. We conducted a post hoc analysis of data from an earlier interventional study (OPTIMA) to explore the relationship between PTH control and serum P. METHODS: The OPTIMA study randomized dialysis patients with intact PTH (iPTH) 300-799 pg/mL to receive conventional care alone (vitamin D and/or phosphate binders [PB]; n=184) or a cinacalcet-based regimen (n=368). For patients randomized to conventional care, investigators were allowed flexibility in using a non-cinacalcet regimen (with no specific criteria for vitamin D analogue dosage) to attain KDOQI™ targets for iPTH, P, Ca and Ca x P. For those assigned to the cinacalcet-based regimen, dosages of cinacalcet, vitamin D sterols, and PB were optimized over the first 16 weeks of the study, using a predefined treatment algorithm. The present analysis examined achievement of serum P targets (≤ 4.5 and ≤ 5.5 mg/dL) in relation to achievement of iPTH ≤ 300 pg/mL during the efficacy assessment phase (EAP; weeks 17-23). RESULTS: Patients who achieved iPTH ≤ 300 pg/mL (or a reduction of ≥ 30% from baseline) were more likely to achieve serum P targets than those who did not, regardless of treatment group. Of those who did achieve iPTH ≤ 300 pg/mL, 43% achieved P ≤ 4.5 mg/dL and 70% achieved P ≤ 5.5 mg/dL, versus 21% and 46% of those who did not achieve iPTH ≤ 300 pg/mL. Doses of PB tended to be higher in patients not achieving serum P targets. Patients receiving cinacalcet were more likely to achieve iPTH ≤ 300 pg/mL than those receiving conventional care (73% vs 23% of patients). Logistic regression analysis identified lower baseline P, no PB use at baseline and cinacalcet treatment to be predictors of achieving P ≤ 4.5 mg/dL during EAP in patients above this threshold at baseline. CONCLUSIONS: This post hoc analysis found that control of serum P in dialysis patients was better when serum PTH levels were lowered effectively, regardless of treatment received. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00110890.

Local versus general anesthesia for transfemoral aortic valve implantation.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) represents a novel option for elderly with severe aortic valve stenosis who are denied surgical aortic valve replacement due to high perioperative risk. While transfemoral TAVI generally is being performed in general anesthesia (GA), TAVI under local anesthesia plus mild sedation (LAPS) might be an effective and safe alternative. METHODS: In a single-centre analysis, we assessed clinical data, preoperative risk scores (STS-Score), echocardiography, periprocedural data and labor costs in 74 patients undergoing transfemoral TAVI under GA (n = 33) and LAPS (n = 41). RESULTS: Patients who underwent TAVI in LAPS presented significantly more often with pulmonary hypertension and impaired renal function, and tended to have a higher STS score and more severe symptoms (higher NYHA class) versus the GA group. There were no significant differences in procedure-related 30-day mortality or complications between groups. The peak systolic and mean central aortic pressure were significantly higher in the LAPS group, while at the same time these patients required significantly less often periprocedural adrenergic support. Intervention time was shorter in the LAPS group due to avoidance of surgical cut-down of the access site. Moreover, total procedure time was significantly shorter and labor costs were lower in the LAPS group. Patients who underwent TAVI in LAPS could be mobilized significantly earlier. CONCLUSION: Our study indicates that TAVI under LAPS is as effective and safe as TAVI under GA. Furthermore, total procedure time, intervention time and labor costs could be reduced by LAPS. Mobilization of patients could be achieved earlier. We therefore consider LAPS to be favorable in patients undergoing transfemoral TAVI.

Parathyroid hormone, vitamin D, renal dysfunction, and cardiovascular disease: dependent or independent risk factors?

BACKGROUND: Vitamin D (Vit D) deficiency has been associated with prevalent and incident cardiovascular (CV) disease, suggesting a role for bioregulators of bone and mineral metabolism in CV health. Vitamin D deficiency leads to secondary hyperparathyroidism, and both primary and secondary hyperparathyroidism are associated with CV pathology. Parathyroid hormone (PTH) is an important regulator of calcium homeostasis, and its impact on CV disease risk is of interest. We tested whether elevated PTH is associated with CV disease and whether risk associations depend on Vit D status and renal function. METHODS: Patients in the Intermountain Healthcare system with concurrent PTH and Vit D as 25-hydroxy-vitamin D (25[OH]D) levels were studied (N = 9,369, age 63 ± 16 years, 36% male). Parathyroid hormone levels were defined as low (<15 pg/mL), normal (15-75 pg/mL), or elevated (>75 pg/mL). Prevalence and incidence of hypertension, diabetes, hyperlipidemia, coronary artery disease/myocardial infarction, heart failure, stroke, and peripheral vascular disease were determined by the International Classification of Diseases, Ninth Revision codes documented in electronic medical records at baseline and, for incident events, during an average of 2.0 ± 1.5 years (maximum 7.5 years) of follow-up. RESULTS: Parathyroid hormone elevation at baseline was noted in 26.1% of the study population. Highly significant differential CV prevalence/incidence rates for most CV risk factors, disease diagnoses, and mortality were noted for PTH >75 pg/mL (by 1.25- to 3-fold). Parathyroid hormone correlated only weakly (r = -0.15) with 25(OH)D and moderately with glomerular filtration rate (r = -0.36). 25(OH)D, standard risk factors, and renal dysfunction variably attenuated PTH risk associations, but risk persisted after full multivariable adjustment. CONCLUSIONS: Elevated PTH is associated with a greater prevalence and incidence of CV risk factors and predicts a greater likelihood of prevalent and incident disease, including mortality. Risk persists when adjusted for 25(OH)D, renal function, and standard risk factors. Parathyroid hormone represents an important new CV risk factor that adds complementary and independent predictive value for CV disease and mortality.

Fenofibrate, homocysteine and renal function.

Fibrates or PPAR alpha agonists, in particular fenofibrate, are known to increase homocysteine levels (Hcy). A 3 to 5 micromol/L increase in Hcy is commonly observed within the first few weeks of fenofibrate treatment; it then persists in plateau when treatment is continued and is reversible upon its cessation. Since its description in 1999, this pharmacological effect attracted a great deal of attention as epidemiological studies in most populations have shown that elevated Hcy levels i.e.Hcy> or =15 micromol/L are associated with an increased risk of cardiovascular events (CVD), venous thromboembolic events (VTE) and possibly cognitive disorders and bone fractures. Chronic kidney disease is also associated with elevated Hcy levels and since fenofibrate increases creatinine levels by about 10-12 micromol/L, a relationship between Hcy and creatinine was postulated. Animal studies have shown that the Hcy increase is PPARalpha dependent but to date animal or human studies have not provided a clear mechanism. In particular, fenofibrate treatment does not change vitamin B levels; however, vitamin B supplements reduce fenofibrate-induced Hcy elevation but not the concomitant cysteine elevation. Similarly, the increase in creatinine with fenofibrate only partially accounted for by a reduction in glomerular filtration rate (GFR) since creatinine production is also increased by 5-10%. In the FIELD study, a placebo-controlled study in 9795 patients with type 2 diabetes, fenofibrate over 5 years reduced non-fatal cardiovascular events and microvascular events such as albuminuria, the need for laser treatment for proliferative retinopathy or maculopathy and amputations but did not reduce fatal events. The increase in Hcy was indeed much larger that what would be explained by creatinine elevation and independent from baseline kidney function. Although baseline Hcy and creatinine levels were associated with subsequent risk of CVD, as suggested by epidemiology, their respective elevation was not. Of interest, after withdrawal of fenofibrate, a potential renoprotective effect was unmasked, as estimated GFR was 5 ml/min/1.73 m2 higher in previous fenofibrate-allocated patients than in previous placebo-allocated patients. There was no suggestion that Hcy elevation was associated with VTE (which were increased by an unknown mechanism) or bone disorders. In conclusion, the discrepancy between the role of baseline Hcy levels in epidemiology and the absence of effect when altering its levels by either decreasing them with vitamin B supplements or increasing them with fenofibrate, suggests that the risk factor(s) behind homocysteine should be found. Nevertheless, other studies are also needed to understand the mechanism and the implications of the moderate homocysteine and creatinine elevations with fenofibrate and other PPARalpha agonists.