Composite Of Serious Adverse Events Research Articles

Low-Dose Methotrexate and Serious Adverse Events Among Older Adults With Chronic Kidney Disease

Low-dose methotrexate is used to treat rheumatoid arthritis and psoriasis. Due to its kidney elimination, better evidence is needed to inform its safety in adults with chronic kidney disease (CKD). To compare the 90-day risk of serious adverse events among adults with CKD who started low-dose methotrexate vs those who started hydroxychloroquine and to compare the risk of serious adverse events among adults with CKD starting 2 distinct doses of methotrexate vs those starting hydroxychloroquine. This retrospective, population-based, new-user cohort study was conducted in Ontario, Canada (2008-2021) using linked administrative health care data. Adults aged 66 years or older with CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 but not receiving dialysis) who started low-dose methotrexate (n = 2309) were matched 1:1 with those who started hydroxychloroquine. Low-dose methotrexate (5-35 mg/wk) vs hydroxychloroquine (200-400 mg/d). The primary outcome was a composite of serious adverse events: a hospital visit with myelosuppression, sepsis, pneumotoxic effects, or hepatotoxic effects within 90 days of starting the study drug. Prespecified subgroup analyses were conducted by eGFR category. Propensity score matching was used to balance comparison groups on indicators of baseline health. Risk ratios (RRs) were obtained using modified Poisson regression, and risk differences (RDs) using binomial regression. In a propensity score-matched cohort of 4618 adults with CKD (3192 [69%] women; median [IQR] age, 76 [71-82] years), the primary outcome was higher in patients who started low-dose methotrexate vs those who started hydroxychloroquine (82 of 2309 [3.55%] vs 40 of 2309 [1.73%]; RR, 2.05 (95% CI, 1.42-2.96); RD, 1.82% [95% CI, 0.91%-2.73%]). In subgroup analysis, the risks increased progressively at lower eGFR (eg, eGFR <45 mL/min/1.73 m2: RR, 2.79 [95% CI, 1.51-5.13]). In the secondary comparison with hydroxychloroquine, methotrexate users at 15 to 35 mg/wk had a higher risk of the primary outcome. In this cohort of 4618 older patients with CKD, the 90-day risk of serious adverse events was higher among those who started low-dose methotrexate than those who started hydroxychloroquine. If verified, these risks should be balanced against the benefits of low-dose methotrexate use.

Safety and Effectiveness of As-Needed Formoterol in Asthma Patients Taking Inhaled Corticosteroid (ICS)-Formoterol or ICS-Salmeterol Maintenance Therapy.

As-needed low-dose inhaled corticosteroid (ICS)-formoterol reliever is recommended in patients with asthma prescribed maintenance ICS-formoterol. Clinicians often ask whether ICS-formoterol reliever can be used with other maintenance ICS-long-acting β2-agonists. To evaluate the safety and effectiveness of as-needed formoterol in patients taking maintenance ICS-formoterol or ICS-salmeterol from the RELIEF study. RELIEF (SD-037-0699) was a 6-month, open-label study that randomized 18,124 patients with asthma to as-needed formoterol 4.5 μg or salbutamol 200 μg on top of maintenance therapy. This post hoc analysis included patients on maintenance ICS-formoterol or ICS-salmeterol (n= 5436). The primary safety outcome was a composite of serious adverse events (SAEs) and/or adverse events leading to discontinuation (DAEs); the primary effectiveness outcome was time-to-first exacerbation. For both maintenance groups and both relievers, similar numbers of patients had ≥1 SAE and/or DAE. In patients taking maintenance ICS-salmeterol, but not ICS-formoterol, significantly more non-asthma-related and nonserious DAEs occurred with as-needed formoterol versus as-needed salbutamol (P= .0066 and P= .0034, respectively). In patients taking maintenance ICS-formoterol, there was a significantly lower risk in time-to-first exacerbation with as-needed formoterol versus as-needed salbutamol (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.70, 0.95; P= .007). In patients taking ICS-salmeterol maintenance, time-to-first exacerbation was not significantly different between treatment arms (HR: 0.95, 95% CI: 0.84, 1.06; P= .35). As-needed formoterol significantly reduced exacerbation risk compared with as-needed salbutamol when added to maintenance ICS-formoterol, but not to maintenance ICS-salmeterol. More DAEs were seen with ICS-salmeterol maintenance therapy plus as-needed formoterol. Further research is needed to assess whether this is relevant to as-needed combination ICS-formoterol.

PFO closure for the prevention of cerebrovascular events in high-risk individuals: an updated and across-the-board meta-analysis

Abstract Introduction Patent foramen ovale (PFO) closure has emerged as a secondary prevention option in patients with PFO and cerebrovascular events. Despite its seemingly established efficacy, its associated long-term outcomes – including safety – remain unclear. Purpose To ascertain the extent to which PFO percutaneous closure is able to improve long-term clinical outcomes in patients with cryptogenic vascular events. Methods We systematically searched MEDLINE, Embase and Cochrane CENTRAL for randomized controlled trials (RCTs) and observational studies comparing PFO percutaneous closure with antithrombotic therapy, in what concerns recurrent cerebrovascular and serious adverse events, as well as mortality. A composite of stroke and transient ischemic attack (TIA) was the primary endpoint. Data related to RCTs, patients with high-risk PFO features, subjected to PFO closure with the most represented device and with antiplatelet therapy as control were further investigated separately. Study-specific odds ratios (ORs) were pooled using traditional meta-analytic techniques, under a random- (DerSimonian-Laird method) or a fixed-effects (Mantel-Haenszel method) model. Results Literature search yielded 2145 references, of which 26 – 8 regarding RCTs – were included. Patients undergoing PFO closure reached 4304, whereas 4180 were treated with antithrombotic therapy. PFO closure was significantly associated with lower stroke/TIA recurrence (OR 0.35 [0.24–0.53], I2=58%). Moreover, such reduction met statistical significance for both stroke (OR 0.34 [0.21–0.54], I2=29%) and TIA (OR 0.53 [0.34–0.82], I2=39%), individually. Subgroup analyses focusing only on RCTs and on studies featuring the most represented device confirmed these trends, while the effects were even more pronounced in patients with high-risk PFO characteristics and in those controlled with antiplatelet therapy. On the other hand, PFO closure was not associated with neither lower all-cause (OR 0.76 [0.46–1.27], I2=0%) nor lower cardiovascular mortality (OR 0.92 [0.37–2.29], I2=0%). Moreover, neither a composite of serious adverse events (SAEs) (OR 1.10 [0.94–1.29], I2=0%) nor major bleeding episodes (OR 0.75 [0.40–1.38], I2=23%) differed significantly between groups. However, PFO closure was associated with increased odds of procedure- or device-related complications (OR 12.94 [5.56–30.13], I2=0%) and atrial fibrillation or flutter (OR 3.35 [1.78–6.30], I2=30%). Conclusion In patients with history of cryptogenic vascular events, when compared with medical management, PFO percutaneous closure is indeed associated with a reduction in the odds of recurrent stroke and TIA. However, mortality seems not to be impacted by this apparently enhanced effect. While general SAEs and major bleeding are comparable between both approaches, PFO closure may bring upon procedure- or device-related complications and increase the odds of atrial fibrillation or flutter. Funding Acknowledgement Type of funding sources: None.

Primary health insurance and cardiovascular outcomes in the systolic blood pressure intervention trial

Abstract Background The Systolic Blood Pressure Intervention Trial (SPRINT) found that intensive versus standard blood pressure (BP) control reduced cardiovascular (CV) morbidity and mortality in high-risk patients. Although antihypertensive therapies were provided at no cost to trial participants, patients were covered by various entities. Insurance coverage provides a unique dimension of risk assessment and may provide additional prognostic information in this setting. Purpose To assess the risks of incident CV events and safety events in a high CV risk population according to type of health insurance, and to assess if insurance type interacted with the effect of intensive versus standard BP control. Methods SPRINT was a randomized, controlled trial conducted across 102 US sites of 9,361 high-risk adults ≥50 years, without diabetes, and with a systolic BP 130–180 mmHg at screening. Study participants were randomized to intensive (target systolic BP &amp;lt;120mmHg) or standard BP control (target systolic BP &amp;lt;140mmHg) and followed for median 3.2 years (range 0–4.8 years). The primary efficacy endpoint was the composite of acute coronary syndromes, stroke, heart failure, or CV death. The primary safety endpoint was the composite of serious adverse events. The risk of efficacy and safety events according to type of health insurance, including the effect of intensive BP control in each subgroup, was evaluated using multivariable Cox proportional-hazards regression with interaction analyses. Private/other insurance type served as the reference group. Results Of 9361 participants, 3980 (42.5%) were covered by private/other insurance, 1483 (15.8%) by a Veterans Affairs (VA) health plan, 2691 (28.8%) by Medicare, 207 (2.2%) by Medicaid, and 1000 (10.7%) were uninsured. Insurance coverage distribution was well-balanced between the two study arms (P&amp;gt;0.05). Compared with patients who had private/other insurance, the risk of the primary endpoint was significantly higher among Medicaid beneficiaries (adj. hazard ratio [HR], 1.81, 95% confidence interval [CI], 1.09–3.00; P=0.02). The risk of death was similarly highest among Medicaid patients (adj. HR, 2.08, 95% CI, 1.08–4.02; P=0.03) and was also significantly higher among VA patients (adj. HR, 1.49, 95% CI, 1.11–2.99; P=0.008) (Figure). Serious adverse events were more common in the VA population (HR, 1.12, 95% CI, 1.01–1.23; P=0.03). Insurance type did not modify the efficacy and safety of intensive BP control (P&amp;gt;0.05 for all interactions). Conclusions In SPRINT, Medicaid beneficiaries were at significantly greater risk for experiencing a primary CV event. Medicaid patients and VA patients both had higher mortality than those covered by private/other insurance. The risks and benefits of intensive BP control were not affected by insurance type. Funding Acknowledgement Type of funding sources: None. Risk of death and health insurace type

Greater event rates in high-risk patients with a history of heart disease: from the Systolic Blood Pressure Intervention Trial (SPRINT)

Abstract Background The Systolic Blood Pressure Intervention Trial (SPRINT) found that intensive versus standard blood pressure (BP) control reduced cardiovascular (CV) morbidity and mortality in patients at high CV risk. Effects were consistent among patients with and without prevalent CV disease. However, it is unknown whether the benefits and risks of intensive BP control are affected by the specific type of heart disease. Purpose To assess the risks of incident CV events and safety events in patients with individual types of heart disease, and to assess if the presence of heart disease modified the effect of intensive versus standard BP control. Methods SPRINT was a randomized, controlled trial comprising 9,361 individuals ≥50 years of age at high CV risk, without diabetes, and with a systolic BP 130–180 mmHg. Participants were randomized to intensive or standard BP control. The primary efficacy endpoint was the composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from CV causes. The primary safety endpoint was the composite of serious adverse events. We assessed event risk in patients with self-reported heart disease versus those without and further assessed the safety and efficacy of intensive BP control, including relevant interactions, in these individuals, using multivariable Cox proportional-hazards regression. Results Of 9361 participants, 326 (3.5%) reported a history of congestive heart failure, 760 (8.1%) of myocardial infarction, 1206 (12.9%) of angina, and 1830 (19.6%) of atrial fibrillation, atrial flutter, or irregular heartbeat. The prevalence of these conditions did not significantly differ between patients randomized to intensive versus standard BP control (P&amp;gt;0.05 for all). At median 3.2 years (range 0–4.8 years), congestive heart failure (adjusted hazard ratio [aHR], 1.94, 95% confidence interval [CI], 1.45–2.61; P&amp;lt;0.001), myocardial infarction (aHR, 1.73, 95% CI, 1.33–2.25; P&amp;lt;0.001), angina (aHR, 1.41, 95% CI, 1.09–1.84; P=0.01), and atrial fibrillation, atrial flutter, or irregular heartbeat (aHR, 1.36, 95% CI, 1.12–1.64; P=0.002) were all independently associated with the primary endpoint (Figure). All conditions except prior myocardial infarction were also associated with composite serious adverse events (P=0.24 for myocardial infarction, P&amp;lt;0.05 for all others). A history of angina modified the efficacy of intensive versus standard BP control, i.e., patients without angina appeared to benefit from intensive BP control (aHR, 0.66, 95% CI, 0.54–0.80; P&amp;lt;0.001) while those with angina did not (aHR, 1.04, 95% CI, 0.76–1.44; P=0.80) (P=0.02 for interaction). No significant interactions were detected for the primary safety endpoint. Conclusions In SPRINT, a history of any type of heart disease was associated with a greater risk for both efficacy and safety events. Patients with angina did not appear to derive benefit from intensive BP control. Funding Acknowledgement Type of funding sources: None. Figure 1

B-PO05-073 THE FASTR-AF TRIAL: ASSESSING THE DIAMOND TIP TEMPERATURE-CONTROLLED RADIOFREQUENCY ABLATION CATHETER TO TREAT PATIENTS WITH ATRIAL FIBRILLATION

Catheter ablation (CA) technology evolves as practitioners look to improve treatment options for atrial fibrillation (AF). A novel diamond tip, irrigated, radiofrequency (RF) ablation system accurately measures tip-tissue temperature in real-time and modulates power to maintain a target therapeutic tissue temperature. Recently, the DiamondTemp Ablation (DTA) system demonstrated strong outcomes against a contact force-sensing RF ablation system in a paroxysmal AF (PAF) population. However, no data pertaining to persistent AF (PsAF) has been reported in literature. This study sought to characterize the performance of the DTA system for the treatment of patients with drug-refractory PAF and PsAF with the second-generation RF DTA generator. DIAMOND FASTR-AF (NCT03626649) was a prospective, single-arm, multicenter European trial. Primary effectiveness endpoint was freedom from atrial arrhythmia recurrence following a 90-day blanking period through 12 months. Primary safety endpoint was a composite of serious adverse events. In total, 60 subjects (34 PAF and 26 PsAF) underwent CA with the DTA system at three centers. Patient demographics were consistent with contemporary AF studies (male 71.7%, age 63.9 ± 10.2 yrs, AF history 3.1 ± 3.9 yrs, LA size 4.4 ± 0.8 cm). The PAF cohort showed marked procedural efficiencies, as compared to PsAF, in total procedure time (76.9 ± 21.7 min vs 108.9 ± 33.6 min, p<0.001, respectively), total RF time (10.4 ± 3.5 min vs 20.4 ± 8.0 min, p<0.001), and number of RF applications (62.1 ± 25.3 vs 109.5 ± 45.5, p<0.001). Pulmonary vein isolation only was performed in 82% of PAF and 23% of PsAF subjects. Additional left-sided lesions were performed in 69% of PsAF subjects (vs 6% of PAF subjects). Safety event rate in the PAF and PsAF groups were 5.9% (2/34) and 11.5% (3/26), respectively. Freedom from recurrence was observed in 67.6% (23/34) of PAF and 61.5% (16/26) of PsAF subjects. The DiamondTemp Ablation system demonstrated long-term safety and effectiveness through 12 months post-ablation for patients with PAF or PsAF. Procedures were demonstrated to be highly efficient, with shorter time and fewer applications seen in PAF procedures.

Comparison of CryoMaze With Cut-and-Sew Maze Concomitant With Mitral Valve Surgery: A Randomized Noninferiority Trial

In this trial, we sought to evaluate the efficacy and safety of the addition of the Maze performed by cryoablation (CryoMaze) to the mitral valve surgeries. The trial is a randomized, single-center trial to determine whether CryoMaze was noninferior to cut-and-sew maze procedure (CSM) in patients with persistent or long-standing persistent atrial fibrillation (AF), with a 15% margin to establish noninferiority. The primary endpoint was freedom from AF off antiarrhythmic drugs (AADs) at 12 months. Secondary endpoints included freedom from AF off AADs at 3 and 6 months, and a composite of serious adverse events. Two hundred patients were randomized to either CryoMaze (n = 100) or CSM (n = 100). Freedom from AF was achieved in 85 % (95% confidence interval, 0.76-0.91) in the CryoMaze group and 88% (95% confidence interval, 0.80-0.94) in the CSM group, showing that CryoMaze was noninferior to CSM at 12 months (P value for noninferiority = 0.0065). There was no significant difference in serious adverse effects (n = 12 in CryoMaze; n = 17 in CSM; P = 0.315). Perioperative bleeding and the length of surgery, ICU stay, postoperative hospital stay; and the need for temporary pacing decreased significantly in the CryoMaze group. CryoMaze was noninferior to CSM for efficacy and safety for patients with persistent or long-standing persistent AF undergoing mitral valve surgeries. CryoMaze significantly decreased bleeding, the length of surgery, ICU and hospital stay, as well the need for temporary pacing. (Chinese Clinical Trial Register number, ChiCTR-IOR-16008112.).

Intensive versus standard blood pressure control and vascular procedures: insights from the Systolic Blood Pressure Intervention Trial

Abstract Background The Systolic Blood Pressure Intervention Trial (SPRINT) found that intensive versus standard blood pressure control reduced cardiovascular (CV) morbidity and mortality. Previous studies have shown that control of blood pressure reduces the risk of stroke and is one of the most modifiable risk factors for carotid artery disease. On the other hand, data on effect of blood pressure control on peripheral artery disease are more diverse. In addition, it is unknown whether intensive blood pressure control affects the risk of vascular procedures. Purpose To assess the relationship between intensive blood pressure control and incident vascular procedures. Methods SPRINT was a randomized, controlled trial comprising 9,361 individuals ≥50 years of age at high CV risk but without diabetes who had a systolic BP (SBP) 130–180 mmHg. Patients were randomized to intensive (target SBP &amp;lt;120mmHg) or standard antihypertensive treatment (target SBP &amp;lt;140mmHg). The primary efficacy endpoint was the composite of acute coronary syndromes, stroke, heart failure, or death from CV causes. The primary safety endpoint was the composite of serious adverse events. We examined the risk of composite and individual vascular procedures with intensive versus standard blood pressure control. We further examined subgroup heterogeneity using interaction analyses. Results During a median follow-up time of 3.3 years (range 0–5.5 years), a total of 174 (1.9%) composite vascular procedures were recorded. Intensive blood pressure control did not significantly reduce the risk of composite vascular procedures (intensive blood pressure control, 76 (1.6%) versus standard blood pressure control, 98 (2.1%), hazard ratio 0.76, 95% confidence interval, 0.57 to 1.03; P=0.08) (Figure 1). Similarly, the risks of the individual endpoints of carotid angioplasty, carotid endarterectomy, peripheral angioplasty or thrombolysis, lower extremity amputation for ischemia and gangrene, surgical or vascular procedure for abdominal aortic aneurysm, surgical or vascular procedure for thoracic aortic aneurysm, and surgical or vascular procedure for other problems were not significantly affected (P≥0.05 for all). Intensive blood pressure control reduced the risk of peripheral vascular surgery (intensive blood pressure control, 7 (0.2%) versus standard blood pressure control, 21 (0.5%), hazard ratio 0.33, 95% confidence interval, 0.14 to 0.77; P=0.01), though this was based on a small number of events. The safety and efficacy of intensive BP lowering was not modified by chronic kidney disease, age, sex, race, previous cardiovascular disease, or baseline systolic blood pressure tertile (P≥0.05 for all). Conclusions In SPRINT, intensive versus standard blood pressure control did not reduce the risk of composite incident vascular procedures. Figure 1. Vascular procedures Funding Acknowledgement Type of funding source: None

Management of sodium-glucose cotransporter 2 inhibitors during the perioperative period: A retrospective comparative study.

Current guidelines recommend withholding sodium-glucose cotransporter 2 inhibitors perioperatively due to concerns of euglycaemic diabetic ketoacidosis. However, such guidelines are largely based on case reports and small case series, many extrapolated from non-surgical patients. The aim was to investigate whether withholding sodium-glucose cotransporter 2 inhibitors as per current perioperative guidelines was associated with a reduction in serious adverse events, including euglycaemic diabetic ketoacidosis. Instances of perioperative management of sodium-glucose cotransporter 2 inhibitors, over a four-year period were classified into two categories: those where sodium-glucose cotransporter 2 inhibitors were withheld as per guidelines and those where sodium-glucose cotransporter 2 inhibitors were administered in the perioperative period. The primary outcome was 'total major perioperative complications': a composite of serious adverse events including euglycaemic diabetic ketoacidosis, diabetic ketoacidosis, acute kidney injury, urosepsis and death. Eighty-two instances in 64 patients were included. Withholding sodium-glucose cotransporter 2 inhibitors was associated with an increased incidence of total major perioperative complications and poorer glycaemic control postoperatively. Multivariable logistic regression analysis revealed that withholding sodium-glucose cotransporter 2 inhibitors perioperatively (OR = 13.15; 95% CI = 1.8-138.9) and preoperative urea (OR 1.85 (95% CI = 1.17-3.43) were independently associated with an increase in total major postoperative complications. Withholding sodium-glucose cotransporter 2 inhibitors as per current guidelines was associated with an increase in postoperative complications and reduced glycaemic control.

3036Identifying low-risk patients eligible for early discharge after ST-segment elevation myocardial infarction

Abstract Introduction Early discharge after ST-segment elevation myocardial infarction (STEMI) should be considered in low-risk patients after successful percutaneous coronary intervention (PCI) to reduce healthcare costs and improve resource utilization. The Zwolle criteria is recommended by current guidelines for the identification of low-risk patients but a new score, the FASTEST score, has recently demonstrated to add prognostic value over Zwolle score in small and unicentric studies. Purpose Assess if FASTEST score could better identify low-risk patients compared to Zwolle in a contemporary nationwide cohort of patients with STEMI who underwent primary PCI and complete revascularization. Methods Multicentric observational study of consecutive patients with ACS recorded in the Portuguese Registry of Acute Coronary Syndromes (ProACS) between October 2010 and January 2019. Patients who underwent primary PCI and received complete revascularization were included, and those with missing data for score calculation were excluded. The FASTEST score awards 1 point for each: femoral access, age&gt;65, LVEF&lt;50, TIMI&lt;3; creatinine &gt;1.5 mg/dl; stenosis of the left main coronary artery; and Killip≥2. The Zwolle score was calculated for comparison. The rate of hospital mortality and a composite of serious adverse events (heart failure, cardiogenic shock, re-infarction, mechanical complication, ventricular arrhythmia and major hemorrhage) was compared between low-risk patients as classified by FASTEST (score=0) or Zwolle (score≤3). One-year mortality and cardiovascular rehospitalization was compared between the two groups. Results We included 3322 patients (77.4% male, mean age 62±13 years, 49.5% with anterior STEMI). The FASTEST score identified 855 (25.8%) and Zwolle 2353 (70.7%) low-risk patients. Discrimination by AUC for hospital mortality was 0.92 (95% CI 0.91–0.93) for FASTEST score, significantly higher than Zwolle (0.83 (95% CI 0.82–0.84), p&lt;0.001 for comparison) (Fig.1). Overall hospital mortality was 2.8%. 1 patient died in low-risk FASTEST compared to 24 (1%) in low-risk Zwolle (p=0.01). Low-risk Zwolle patients were more likely to suffer serious hospital adverse events compared with FASTEST score low-risk (19.5% vs 8.5%, p&lt;0.001). At one-year, 1384 patients had follow-up data. Mortality was significantly lower in low-risk FASTEST than Zwolle (1.5% vs 4.6%, p&lt;0.001) and a tendency for less cardiovascular rehospitalization was also noted (5.4% vs 7.5%, p=0.08). Figure 1. ROC-AUC for hospital mortality Conclusion Approximately one in every four patients were classified as low-risk according to FASTEST score, in contrast with 70% for Zwolle score. Low-risk FASTEST score patients exhibited significantly less hospital mortality (1 patient), hospital serious adverse events and 1-year mortality compared with low-risk Zwolle patients. FASTEST score demonstrated better discriminatory capacity for hospital mortality than Zwolle score and its use for risk stratification should be preferred.

P57262018 ESC/ESH guideline-recommended age categories and intensive blood pressure management in high-risk adults: insights from SPRINT

Abstract Background The 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines for arterial hypertension propose different intensities of blood pressure (BP) lowering in patients &lt;65 years, 65–79 years, and ≥80 years of age. However, it is unclear whether intensive BP management is well-tolerated and modifies risk uniformly across this age spectrum. Purpose To assess the relationship between age, treatment response to intensive BP lowering, and cardiovascular (CV) outcomes. Methods SPRINT was a randomized, controlled trial in which 9,361 individuals ≥50 years of age, at high CV risk but without diabetes who had a systolic BP (SBP) 130–180 mmHg, were randomized to intensive (target SBP &lt;120mmHg) or standard antihypertensive treatment (target SBP &lt;140mmHg). The primary efficacy endpoint was the composite of acute coronary syndromes, stroke, heart failure, or death from CV causes. The primary safety endpoint was the composite of serious adverse events (SAE). We examined the prognostic implications of age, using Cox proportional-hazards regression models adjusted for demographic, clinical, and laboratory variables. Whether a linear association was present between age and clinical endpoints was evaluated using restricted cubic splines. We further explored the effects of intensive BP lowering across the age spectrum using interaction analyses. Results Age was noted for all individuals, and 3,805 (41%), 4,390 (47%), and 1,166 (12%) were &lt;65 years, 65–79 years, and ≥80 years, respectively. Mean age was similar between the two study groups (intensive group 67.9 years vs. standard group 67.9 years; P=0.94). Median follow-up was 3.3 years (range 0–4.8), with 562 primary efficacy events (6%) and 3,529 primary safety events (38%) recorded during the study period. Age was linearly associated with the risk of stroke (test for overall trend, P&lt;0.001) and non-linearly associated with the risk of primary efficacy events, death from CV causes, death from any cause, heart failure, and SAE (test for non-linearity, P&lt;0.05; test for overall trend, P&lt;0.001). Age remained significantly associated with all tested endpoints after multivariable adjustment (P&lt;0.001). Furthermore, the risk of primary events increased over guideline-recommended age-categories (65–79 years vs. &lt;65 years; adj. HR 1.65, 95% CI 1.34–2.04; P&lt;0.001 and ≥80 years vs. 65–79 years; adj. HR 1.92, 95% CI 1.54–2.40; P&lt;0.001), as did the risk of SAE (P&lt;0.001). The safety and efficacy of intensive BP lowering was not modified by age whether tested continuously or categorically (P&gt;0.05). The Figure shows similar treatment effects (hazard ratios) across the spectrum of age. P-values are for the interaction between age and treatment effect for each endpoint. Figure 1 Conclusions In SPRINT, higher age was associated with a greater risk of both CV events and SAE. However, intensive BP lowering appeared to be associated with similar risks and benefits across the age spectrum.

4877Renal function and intensive blood pressure lowering in high-risk adults without diabetes: insights from the Systolic Blood Pressure Intervention Trial (SPRINT)

Abstract Background The Systolic Blood Pressure Intervention Trial (SPRINT) found that intensive blood pressure (BP) lowering reduced the rates of cardiovascular events and mortality but increased the risk of certain adverse events, in patients with and without chronic kidney disease at baseline. However, it is unclear whether intensive BP management is well-tolerated and modifies risk uniformly across the entire spectrum of renal function. Purpose To assess the relationship between renal function, treatment response to intensive BP lowering, and cardiovascular (CV) outcomes. Methods SPRINT was a randomized, controlled trial in which 9,361 individuals ≥50 years of age, at high CV risk but without diabetes who had a systolic BP (SBP) 130–180 mmHg, were randomized to intensive (target SBP &lt;120mmHg) or standard antihypertensive treatment (target SBP &lt;140mmHg). The primary efficacy endpoint was the composite of acute coronary syndromes, stroke, acute decompensated heart failure, or death from CV causes. The primary safety endpoint was the composite of serious adverse events (SAE). Renal function was assessed using the estimated glomerular filtration rate (GFR), calculated with the Modification of Diet in Renal Disease equation. We first assessed whether a linear association was present between eGFR and clinical endpoints using restricted cubic splines. We then examined the prognostic implications of eGFR, unadjusted and adjusted for demographic, clinical, and laboratory variables. We further explored the effects of intensive BP lowering across the eGFR spectrum. Results Baseline eGFR was available for 9,324 (&gt;99%) individuals. Mean eGFR was similar between the two groups (intensive group 71.8 ml/min/1.73m2 vs. standard group 71.7 ml/min/1.73m2; P=0.92). Median follow-up was 3.3 years (range 0–4.8), with 561 primary efficacy events (6%) and 3,522 SAE (38%) recorded during the study period. Baseline eGFR was non-linearly associated with the risk of the primary efficacy endpoint, death from CV causes, death from any cause, acute decompensated heart failure, SAE, electrolyte abnormality, and acute kidney injury (test for non-linearity, P&lt;0.05; test for overall trend, P&lt;0.001) and remained significantly associated with all tested endpoints upon multivariable adjustment (P&lt;0.05). Baseline eGFR significantly modified the effects of intensive BP lowering on the primary efficacy endpoint (P=0.02), acute decompensated heart failure (P=0.01), SAE (P=0.01), and acute kidney injury (P=0.04). The Figure shows treatment effects (hazard ratios) across the spectrum of eGFR for these four endpoints. P-values are for the interaction between eGFR and treatment effect. Significant interactions were not detected for other endpoints. Figure 1 Conclusions In SPRINT, lower eGFR was associated with a greater risk of both CV events and SAE. Patients with higher eGFR appeared to derive more benefit from intensive BP lowering while the relationship with safety events was complex.

Clinical Consequences of Cardiomyopathy in Children With Biliary Atresia Requiring Liver Transplantation.

Cirrhotic cardiomyopathy (CCM), a comorbidity of end-stage cirrhotic liver disease, remains uncharacterized in children, largely because of a lack of an established pediatric definition. The aim of this retrospective cohort analysis is to derive objective two-dimensional echocardiographic (2DE) criteria to define CCM associated with biliary atresia (BA), or BA-CCM, and correlate presence of BA-CCM with liver transplant (LT) outcomes in this population. Using receiver operating characteristic (ROC) curve analysis, optimal cut-off values for left ventricular (LV) geometrical parameters that were highly sensitive and specific for the primary outcomes: A composite of serious adverse events (CSAE) and peritransplant death were determined. These results were used to propose a working definition for BA-CCM: (1) LV mass index (LVMI) ≥95 g/m2.7 or (2) relative wall thickness of LV ≥0.42. Applying these criteria, BA-CCM was found in 34 of 69 (49%) patients with BA listed for LT and was associated with increased multiorgan dysfunction, mechanical and vasopressor support, and longer intensive care unit (ICU) and hospital stays. BA-CCM was present in all 4 waitlist deaths, 7 posttransplant deaths, and 20 patients with a CSAE (P < 0.01). On multivariable regression analysis, BA-CCM remained independently associated with both death and a CSAE (P < 0.01). Utilizing ROC analysis, LVMI was found to be a stronger predictor for adverse outcomes compared with current well-established markers, including Pediatric End-Stage Liver Disease (PELD) score. Conclusion: BA-CCM is highly sensitive and specific for morbidity and mortality in children with BA listed for LT. 2DE screening for BA-CCM may provide pertinent clinical information for prioritization and optimal peritransplant management of these children.

381: Comparison of neonatal morbidity and mortality in twin pregnancies born at moderately preterm, late preterm, and term gestation

ObjectiveTo describe and compare neonatal outcomes in twin pregnancies following moderately preterm (MPTB), late preterm (LPTB) and term birth.Study DesignSecondary analysis of a multi-center, RCT of multiple gestations was performed. LPTB was defined as delivery between 34 0/7 to 36 6/7 weeks and MPTB between 32 0/7 to 33 6/7 weeks. Primary outcome was a composite of serious adverse events defined as one of the following: neonatal death, RDS, early-onset culture proven sepsis, stage 2 or 3 NEC, BPD, grade 3 or 4 IVH, PVL, pneumonia or severe ROP. Secondary outcomes included rate of TTN and mechanincal ventilation (MV). Statistical analysis included Cochran-Armitage trend test. The earliest time of delivery, death or mobidity of either of the fetuses was used in the analysis.ResultsAmong 552 twin pregnancies, the MPTB rate was 14.6%, LPTB 49.9% and term birth rate 35.5%. The rate of the primary outcome was different between groups: 30.0% for MPTB, 12.8% for LPTB, 0.5% for term; p< 0.001. Most of the differences in neonatal outcomes were respiratory morbidities as illustrated in the table. There were no cases of severe ROP, grade 3 or 4 IVH or PVL and only one case of BPD, Stage 2 or 3 NEC, seizures and neonatal death within the preterm groups. There were no differences between groups in rate of pneumonia.Tabled 1MPTB (n=80)LPTB (n=275)Term(n=197)P-valueRDS28.8%11.7%0%<.0001TTN38.8%20.8%6.7%<.0001MV26.3%6.2%1.0%<.0001Sepsis5.0%2.2%0%.004 Open table in a new tab ConclusionTwin pregnancies born moderately and late preterm encounter higher rates of neonatal respiratory morbidities compared to twins born at term. ObjectiveTo describe and compare neonatal outcomes in twin pregnancies following moderately preterm (MPTB), late preterm (LPTB) and term birth. To describe and compare neonatal outcomes in twin pregnancies following moderately preterm (MPTB), late preterm (LPTB) and term birth. Study DesignSecondary analysis of a multi-center, RCT of multiple gestations was performed. LPTB was defined as delivery between 34 0/7 to 36 6/7 weeks and MPTB between 32 0/7 to 33 6/7 weeks. Primary outcome was a composite of serious adverse events defined as one of the following: neonatal death, RDS, early-onset culture proven sepsis, stage 2 or 3 NEC, BPD, grade 3 or 4 IVH, PVL, pneumonia or severe ROP. Secondary outcomes included rate of TTN and mechanincal ventilation (MV). Statistical analysis included Cochran-Armitage trend test. The earliest time of delivery, death or mobidity of either of the fetuses was used in the analysis. Secondary analysis of a multi-center, RCT of multiple gestations was performed. LPTB was defined as delivery between 34 0/7 to 36 6/7 weeks and MPTB between 32 0/7 to 33 6/7 weeks. Primary outcome was a composite of serious adverse events defined as one of the following: neonatal death, RDS, early-onset culture proven sepsis, stage 2 or 3 NEC, BPD, grade 3 or 4 IVH, PVL, pneumonia or severe ROP. Secondary outcomes included rate of TTN and mechanincal ventilation (MV). Statistical analysis included Cochran-Armitage trend test. The earliest time of delivery, death or mobidity of either of the fetuses was used in the analysis. ResultsAmong 552 twin pregnancies, the MPTB rate was 14.6%, LPTB 49.9% and term birth rate 35.5%. The rate of the primary outcome was different between groups: 30.0% for MPTB, 12.8% for LPTB, 0.5% for term; p< 0.001. Most of the differences in neonatal outcomes were respiratory morbidities as illustrated in the table. There were no cases of severe ROP, grade 3 or 4 IVH or PVL and only one case of BPD, Stage 2 or 3 NEC, seizures and neonatal death within the preterm groups. There were no differences between groups in rate of pneumonia.Tabled 1MPTB (n=80)LPTB (n=275)Term(n=197)P-valueRDS28.8%11.7%0%<.0001TTN38.8%20.8%6.7%<.0001MV26.3%6.2%1.0%<.0001Sepsis5.0%2.2%0%.004 Open table in a new tab Among 552 twin pregnancies, the MPTB rate was 14.6%, LPTB 49.9% and term birth rate 35.5%. The rate of the primary outcome was different between groups: 30.0% for MPTB, 12.8% for LPTB, 0.5% for term; p< 0.001. Most of the differences in neonatal outcomes were respiratory morbidities as illustrated in the table. There were no cases of severe ROP, grade 3 or 4 IVH or PVL and only one case of BPD, Stage 2 or 3 NEC, seizures and neonatal death within the preterm groups. There were no differences between groups in rate of pneumonia. ConclusionTwin pregnancies born moderately and late preterm encounter higher rates of neonatal respiratory morbidities compared to twins born at term. Twin pregnancies born moderately and late preterm encounter higher rates of neonatal respiratory morbidities compared to twins born at term.