Complementary and Alternative Medicines in the Management of Heart Failure: A Scientific Statement From the American Heart Association.

Complementary and alternative medicines (CAM) are commonly used across the world by diverse populations and ethnicities but remain largely unregulated. Although many CAM agents are purported to be efficacious and safe by the public, clinical evidence supporting the use of CAM in heart failure remains limited and controversial. Furthermore, health care professionals rarely inquire or document use of CAM as part of the medical record, and patients infrequently disclose their use without further prompting. The goal of this scientific statement is to summarize published efficacy and safety data for CAM and adjunctive interventional wellness approaches in heart failure. Furthermore, other important considerations such as adverse effects and drug interactions that could influence the safety of patients with heart failure are reviewed and discussed.

Erroneous electrocardiographic interpretations and its clinical implications.

INTRODUCTION: The advancement of artificial intelligence (AI) has aided clinicians in the interpretation of electrocardiograms (ECGs) serving as an essential tool to provide rapid triage and care. However, in some cases, AI can misinterpret an ECG and may mislead the interpreting physician. Therefore, we aimed to describe the rate of ECG misinterpretation and its potential clinical impact in patient's management. METHODS: We performed a retrospective descriptive analysis of misinterpreted ECGs and its clinical impact from May 28, 2020 to May 9, 2021. An electrophysiologist screened ECGs with confirmed diagnosis of atrial fibrillation (AF), sinus tachycardia (ST), sinus bradycardia (SB), intraventricular conduction delay (IVCD), and premature atrial contraction (PAC) that were performed in the emergency department. We then classified the misinterpreted ECGs as wrongly diagnosed AF, ST, SB, IVCD, or PAC into the correct diagnosis and reviewed the misinterpreted ECGs and medical records to evaluate inappropriate use of antiarrhythmic drugs (AAD), beta-blockers (BB), calcium channel blockers (CCB), anticoagulation, or resource utilization of cardiology and/or electrophysiology (EP) consultation. RESULTS: A total of 4969 ECGs were screened with diagnoses of AF (2282), IVCD (296), PAC (972), SB (895), and ST (638). Among these, 101 ECGs (2.0%) were misinterpreted. Wrongly diagnosed AF (58.4%) was the most common followed by wrongly diagnosed PAC (14.9%), wrongly diagnosed ST (12.9%), wrongly diagnosed IVCD (7.9%), and wrongly diagnosed SB (6.0%). Patients with misinterpreted ECGs were aged 76.6 ± 11.6 years with male (52.5%) predominance and hypertension being the most prevalent (83.2%) comorbid condition. The misinterpretation of ECGs led to the inappropriate use of BB (19.8%), CCB (5.0%), AAD therapy (7.9%), anticoagulation (6.9%) in patients with wrongly diagnosed AF, as well as inappropriate resource utilization including cardiology (41.6%) and EP (8.9%) consultations. CONCLUSIONS: Misinterpretation of ECGs may lead to inappropriate medical therapies and increased resource utilization. Therefore, it is essential to encourage physicians to carefully examine AI interpreted ECG's, especially those interpreted as having AF.

PCSK9 inhibitors safely and effectively lower LDL after heart transplantation: a systematic review and meta-analysis.

Coronary allograft vasculopathy (CAV) continues to afflict a high number of heart transplant (HT) recipients, and elevated LDL is a key risk factor. Many patients cannot tolerate statin medications after HT; however, data for alternative agents remains scarce. To address this key evidence gap, we evaluated the safety and efficacy of the PCSK9i after HT through systematic review and meta-analysis. We searched Medline, Cochrane Central, and Scopus from the earliest date through July 15th, 2021. Citations were included if they were a report of PCSK9i use in adults after HT and reported an outcome of interest. Outcomes included change in LDL cholesterol from baseline, incidence of adverse events, and evidence of CAV. Changes from baseline and outcome incidences were pooled using contemporary random-effects model methodologies. A total of six studies including 97 patients were included. Over a mean follow-up of 13 months (range 3-21), PCSK9i use lowered LDL by 82.61 mg/dL (95% CI - 119.15 to - 46.07; I2 = 82%) from baseline. Serious adverse drug reactions were rarely reported, and none was attributable to the PCSK9i therapy. Four studies reported stable calcineurin inhibitor levels during PCSK9i initiation. One study reported outcomes in 33 patients with serial coronary angiography and intravascular ultrasound, and PCSK9i were associated with stable coronary plaque thickness and lumen area. One study reported on immunologic safety, showing no DSA development within 1 month of therapy. Preliminary data suggest that long-term PCSK9i therapy is safe, significantly lowers LDL, and may attenuate CAV after HT. Additional study on larger cohorts is warranted to confirm these findings.

Cardiac donors with renal impairment: Usage and outcomes after heart transplant.

INTRODUCTION: Utilization of hearts from donors with significant renal dysfunction and the impact of donor renal function on outcomes following heart transplant (HT) is unknown. We sought to investigate the trends, characteristics and outcomes associated with these donor hearts and the impact of donor renal function on survival and graft failure in adult HT recipients. METHODS: We reviewed the Scientific Registry of Transplant Recipients (SRTR) and summarized trends, characteristics and outcomes of hearts from adult donors by renal impairment. Single-organ HTs were evaluated and stratified by donors with estimated glomerular filtration rate (eGFRs) < and ≥30 ml/min. We constructed Cox proportional hazards regression models to compare time-to-mortality over 30-day, 1-, 3-, and 5-year time-horizons between groups, and the association of donor eGFR group with graft failure. RESULTS: A total of 162,586 adults were evaluated for cardiac donation, of which, 22,780 (14%) had an eGFR ≤ 30 ml/min. Donors with an eGFR ≤ 30 ml/min increased over time, from 7.2% (358/4966) in 2000 to a high of 19.5% (2283/11,728) in 2020. Such donors were significantly more likely discarded (not offered (7.9% vs. 9.8%, p < .001) or accepted (62.6% vs. 72.2%, p < .001), and less likely to be transplanted (18.0 % vs. 29.5%; p < .001). Of 41,044 HT recipients, 3906 (9.5%) had hearts from such donors. Primary graft failure was similar between groups (OR 1.20, 95% CI .91-1.58; p = .1) while adjusted mortality was lower for recipients from donors with eGFR ≤ 30 ml/min. CONCLUSIONS: More than two-third of hearts from donors with renal dysfunction are discarded. Recipients from donors with renal dysfunction sustained lower mortality post HT during the study period. Increased evaluation and utilization of donors with renal dysfunction has the potential to expand the critically low donor pool.

Restoration of forest resilience to fire from old trees is possible across a large Colorado dry-forest landscape by 2060, but only under the Paris 1.5℃ goal.

Fire-prone dry forests often face increasing fires from climate change with low resistance and resilience due to logging of large, old fire-resistant trees. Their restoration across large landscapes is constrained by limited mature trees, physical settings, and protection. Active restoration has been costly and shown limited effectiveness, but lower cost passive restoration is less studied. I used GIS and machine learning to see whether passive restoration of old trees could overcome constraints in time, by 2060, across 667,000 ha of montane forests in the San Juan Mountains, Colorado, where temperatures are increasing faster than the global average. Random Forest models of physical locations of reconstructed historical old growth (OG) and relatively frequent fire (RFF) show historical OG with RFF was favored between 6.1 and 7.9℃ annual mean temperatures. Random Forest models projected that similar temperature-suitable locations were moved into the current middle montane ca 2015, and would be extended to just below the upper limit of the montane if the Paris 1.5℃ goal is reached, but beyond if not. US Forest Service common stand exam data, which covered ~15% of the study area and included 26,149 tree ages, show the highest potential for restoring resistance and resilience from old trees is a ≥120-year age class. This class could become a ≥160-year age class, which meets old-growth age criteria, over 81% of the area by ca 2060, nearly fully restoring historical old-growth levels. Half this age class is already protected, and much of the remainder could be retained using evidence-based diameter caps. Datasets thus are sufficient to show that passive restoration of old-tree resistance and resilience to fire is feasible by ca 2060 across a large montane landscape, although contingent on global success in achieving the Paris 1.5℃ goal. Passive restoration may be viable elsewhere.

Assessment of spontaneous breathing during pressure controlled ventilation with superimposed spontaneous breathing using respiratory flow signal analysis.

Integrating spontaneous breathing into mechanical ventilation (MV) can speed up liberation from it and reduce its invasiveness. On the other hand, inadequate and asynchronous spontaneous breathing has the potential to aggravate lung injury. During use of airway-pressure-release-ventilation (APRV), the assisted breaths are difficult to measure. We developed an algorithm to differentiate the breaths in a setting of lung injury in spontaneously breathing ewes. We hypothesized that differentiation of breaths into spontaneous, mechanical and assisted is feasible using a specially developed for this purpose algorithm. Ventilation parameters were recorded by software that integrated ventilator output variables. The flow signal, measured by the EVITA® XL (Lübeck, Germany), was measured every 2 ms by a custom Java-based computerized algorithm (Breath-Sep). By integrating the flow signal, tidal volume (VT) of each breath was calculated. By using the flow curve the algorithm separated the different breaths and numbered them for each time point. Breaths were separated into mechanical, assisted and spontaneous. Bland Altman analysis was used to compare parameters. Comparing the values calculated by Breath-Sep with the data from the EVITA® using Bland-Altman analyses showed a mean bias of - 2.85% and 95% limits of agreement from - 25.76 to 20.06% for MVtotal. For respiratory rate (RR) RRset a bias of 0.84% with a SD of 1.21% and 95% limits of agreement from - 1.53 to 3.21% were found. In the cluster analysis of the 25th highest breaths of each group RRtotal was higher using the EVITA®. In the mechanical subgroup the values for RRspont and MVspont the EVITA® showed higher values compared to Breath-Sep. We developed a computerized method for respiratory flow-curve based differentiation of breathing cycle components during mechanical ventilation with superimposed spontaneous breathing. Further studies in humans and optimizing of this technique is necessary to allow for real-time use at the bedside.

Myth Busters: Dietary Supplements and COVID-19.

News and social media platforms have implicated dietary supplements in the treatment and prevention of coronavirus disease 2019 (COVID-19). During this pandemic when information quickly evolves in the presence of contradicting messages and misinformation, the role of the pharmacist is essential. Here, we review theoretical mechanisms and evidence related to efficacy and safety of select supplements in the setting of COVID-19, including vitamin C, vitamin D, zinc, elderberry, and silver. Evidence evaluating these supplements in COVID-19 patients is lacking, and providers and patients should not rely on dietary supplements to prevent or treat COVID-19. Rather, reference to evidence-based guidelines should guide treatment decisions.

Comparative Effectiveness of Analgesics to Reduce Acute Pain in the Prehospital Setting.

Objectives: The objectives of this study were to assess comparative effectiveness and harms of opioid and nonopioid analgesics for the treatment of moderate to severe acute pain in the prehospital setting. Methods: We searched MEDLINE®, Embase®, and Cochrane Central from the earliest date through May 9, 2019. Two investigators screened abstracts, reviewed full-text files, abstracted data, and assessed study level risk of bias. We performed meta-analyses when appropriate. Conclusions were made with consideration of established clinically important differences and we graded each conclusion's strength of evidence (SOE). Results: We included 52 randomized controlled trials and 13 observational studies. Due to the absence or insufficiency of prehospital evidence we based conclusions for initial analgesia on indirect evidence from the emergency department setting. As initial analgesics, there is no evidence of a clinically important difference in the change of pain scores with opioids vs. ketamine administered primarily intravenously (IV) (low SOE), IV acetaminophen (APAP) (low SOE), or nonsteroidal anti-inflammatory drugs (NSAIDs) administered primarily IV (moderate SOE). The combined use of an opioid and ketamine, administered primarily IV, may reduce pain more than an opioid alone at 15 and 30 minutes (low SOE). Opioids may cause fewer adverse events than ketamine (low SOE) when primarily administered intranasally. Opioids cause less dizziness than ketamine (low SOE) but may increase the risk of respiratory depression compared with ketamine (low SOE), primarily administered IV. Opioids cause more dizziness (moderate SOE) and may cause more adverse events than APAP (low SOE), both administered IV, but there is no evidence of a clinically important difference in hypotension (low SOE). Opioids may cause more adverse events and more drowsiness than NSAIDs (low SOE), both administered primarily IV. Conclusions: As initial analgesia, opioids are no different than ketamine, APAP, and NSAIDs in reducing acute pain in the prehospital setting. Opioids may cause fewer total side effects than ketamine, but more than APAP or NSAIDs. Combining an opioid and ketamine may reduce acute pain more than an opioid alone but comparative harms are uncertain. When initial morphine is inadequate, giving ketamine may provide greater and quicker acute pain relief than giving additional morphine, although comparative harms are uncertain. Due to indirectness, strength of evidence is generally low, and future research in the prehospital setting is needed.

Effectiveness and safety of rivaroxaban and warfarin for prevention of major adverse cardiovascular or limb events in patients with non-valvular atrial fibrillation and type 2 diabetes.

AIMS: To assess the effectiveness and safety of rivaroxaban versus warfarin for the prevention of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with type 2 diabetes (T2D) and non-valvular atrial fibrillation (NVAF). MATERIALS AND METHODS: Using MarketScan data from January 2012 to December 2017, we identified oral anticoagulant-naïve patients with NVAF and comorbid T2D and ≥12 months of insurance coverage prior to rivaroxaban or warfarin initiation. Differences in baseline covariates between cohorts were adjusted for using inverse probability of treatment weights based on propensity scores (absolute standardized differences <0.1 achieved for all covariates after adjustment). Patients were followed until a MACE, MALE or major bleeding event, oral anticoagulant discontinuation/switch, insurance disenrolment or end of data availability. Hazard ratios (HRs) and 95% confidence intervals (CIs) comparing the cohorts were calculated using Cox regression. RESULTS: We identified 10 700 rivaroxaban users (24.1% received a reduced dose) and 13 946 warfarin users. The median (25%, 75% range) age was 70 (62, 79) years, CHA2DS2-VASc score was 4 (3, 5) and duration of available follow-up was 1.4 (0.6, 2.7) years. Eleven percent of patients had peripheral artery disease, 5.1% had coronary artery disease, and 5.1% had a prior MALE, at baseline. Rivaroxaban was associated with a 25% (95% CI 4-41) reduced risk of MACE and a 63% (95% CI 35-79) reduced risk of MALE compared to warfarin. Major bleeding risk did not significantly differ between cohorts (HR 0.95). CONCLUSIONS: Among patients with NVAF and T2D treated in routine practice, rivaroxaban was associated with lower risks of both MACE and MALE versus warfarin, with no significant difference in major bleeding.

Vasopressin therapy in cardiac surgery.

BACKGROUND: Arginine vasopressin (AVP) is a naturally occurring peptide with diverse effects mediated through selective V1 and V2 receptors. About 10% of patients undergoing cardiopulmonary bypass develop postoperative vasodilatory shock requiring high-dose catecholamines. We sought to examine the role of AVP therapy in cardiac surgery. METHODS: A search of Medline was conducted through September 2018 using key words and medical subject headings (MeSH) relating to AVP, copeptin, and cardiac surgery. A systematic review was performed on articles as they pertained to AVP for use as a vasopressor after cardiovascular surgery complicated by vasodilatory shock. RESULTS: A relative or absolute deficiency of Arginine vasopressin is associated with vasodilatory shock after cardiopulmonary bypass. Physiologic replacement with exogenous Arginine vasopressin results in significant increases in systemic vascular resistance and mean arterial pressure with decreased requirements of catecholamines. At doses of <0.1 U/min Arginine vasopressin is safe with very few adverse effects. CONCLUSION: Post-cardiopulmonary bypass vasodilatory shock is largely due to a relative deficiency of Arginine vasopressin. Exogenous administration of low-dose Arginine vasopressin alone or in combination with traditional catecholamines is a safe and effective way to manage this type of vasodilatory shock.

Cardiovascular Effects of Incretin-Based Therapies.

The incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, are important new classes of therapy for type 2 diabetes mellitus (T2DM). These agents prolong the action of the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), by inhibiting their breakdown. The incretin hormones improve glycemic control in T2DM by increasing insulin secretion and suppressing glucagon levels. The cardiovascular (CV) effects of the incretin-based therapies have been of substantial interest since 2008, when the US Food and Drug Administration began to require that all new therapies for diabetes undergo rigorous assessment of CV safety through large-scale CV outcome trials. This article reviews the most recent CV outcome trials of the DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) as evidence that the incretin-based therapies have acceptable CV safety profiles for patients with T2DM. The studies differ with regard to patient population, trial duration, and heart failure outcomes but show similar findings for CV death, nonfatal myocardial infarction, and stroke, as well as hospitalization for unstable angina.

Effectiveness and Safety of Rivaroxaban in Patients With Cancer-Associated Venous Thrombosis.

Background: Although not designated as guideline-recommended first-line anticoagulation therapy, patients are receiving rivaroxaban for the treatment and secondary prevention of cancer-associated venous thrombosis (CAT). We sought to estimate the cumulative incidence of recurrent venous thromboembolism (VTE), major bleeding, and mortality/hospice care in patients with CAT treated with outpatient rivaroxaban in routine practice. Methods: Using US MarketScan claims data from January 2012 through June 2015, we identified adults with active cancer (using SEER program coding) who had ≥1 primary hospitalization or emergency department discharge diagnosis code for VTE (index event) and received rivaroxaban as their first outpatient anticoagulant within 30 days of the index VTE. Patients were required to have ≥180 days of continuous medical/prescription benefits prior to the index VTE. Patients with a previous claim for VTE, atrial fibrillation, or valvular disease or receiving anticoagulation during the baseline period were excluded. We estimated the cumulative incidence with 95% CIs of recurrent VTE, major bleeding, and mortality or need for hospice care at 180 days, assuming competing risks. Results: A total of 949 patients with active cancer were initiated on rivaroxaban following their index VTE. Time from active cancer diagnosis to index CAT was ≤90 days for 27% of patients, 91 to 180 days for 19%, and >180 days for 54%. The mean [SD] age of patients was 62.5 [12.8] years, 43.6% had pulmonary embolism, and metastatic disease was present in 42.6%. During follow-up, there were 37 cases of recurrent VTE, 22 cases of major bleeding (17 gastrointestinal, 3 intracranial, 1 genitourinary, and 1 other bleed), and 105 deaths/hospice claims. The cumulative incidence estimate was 4.0% (95% CI, 2.8%-5.4%) for recurrent VTE, 2.7% (95% CI, 1.7%-4.0%) for major bleeding, and 11.3% (95% CI, 9.2%-13.6%) for mortality/hospice care. Conclusions: Event rates observed in this rivaroxaban-treated cohort were overall consistent with previous studies of patients with rivaroxaban- and warfarin-managed CAT.

Effect of intensive blood pressure control in patients with type 2 diabetes mellitus over 9 years of follow-up: A subgroup analysis of high-risk ACCORDION trial participants.

Although guidelines recommend strict blood pressure (BP) control in patients with type 2 diabetes mellitus (T2DM) and elevated cardiovascular risk, the long-term effects of this approach are unknown. We investigated the effect of intensive BP control on clinical outcomes in patients with T2DM over 9 years of follow-up. We included Action to Control Cardiovascular Risk in Diabetes - Blood Pressure participants in the standard glucose control arm who had established cardiovascular disease, chronic kidney disease, were ≥75 years of age or who had a 10-year coronary heart risk ≥15%. Participants were randomized to either intensive (systolic BP < 120 mm Hg) or standard (systolic BP < 140 mm Hg) BP control for an average of 5 years. Observational follow-up occurred for an average of 4 years thereafter. After an average total follow-up of 9 years, intensive BP control reduced the composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke by 25% (hazard ratio, 0.75; 95% confidence interval, 0.60-0.95; P = .02). The overall benefit was driven by a reduction in nonfatal myocardial infarction (P = .01). In this post-hoc analysis, the benefits of a fixed-duration intensive BP control intervention in patients with T2DM persisted throughout 9 years of follow-up.

Land surveys show regional variability of historical fire regimes and dry forest structure of the western United States.

An understanding of how historical fire and structure in dry forests (ponderosa pine, dry mixed conifer) varied across the western United States remains incomplete. Yet, fire strongly affects ecosystem services, and forest restoration programs are underway. We used General Land Office survey reconstructions from the late 1800s across 11 landscapes covering ~1.9 million ha in four states to analyze spatial variation in fire regimes and forest structure. We first synthesized the state of validation of our methods using 20 modern validations, 53 historical cross-validations, and corroborating evidence. These show our method creates accurate reconstructions with low errors. One independent modern test reported high error, but did not replicate our method and made many calculation errors. Using reconstructed parameters of historical fire regimes and forest structure from our validated methods, forests were found to be non-uniform across the 11 landscapes, but grouped together in three geographical areas. Each had a mixture of fire severities, but dominated by low-severity fire and low median tree density in Arizona, mixed-severity fire and intermediate to high median tree density in Oregon-California, and high-severity fire and intermediate median tree density in Colorado. Programs to restore fire and forest structure could benefit from regional frameworks, rather than one size fits all.

Meta-Analysis of Time in Therapeutic Range in Continuous-Flow Left Ventricular Assist Device Patients Receiving Warfarin.

Continuous-flow left ventricular assist devices (CF-LVADs) prolong survival in advanced heart failure patients. Anticoagulation control is critical in CF-LVAD patients due to increased thromboembolic and bleeding risk. We assessed the quality of INR control in CF-LVAD patients measured by time in therapeutic range (TTR). We performed a systematic literature search of MEDLINE and SCOPUS through July 2017 to identify studies evaluating TTR in anticoagulated adult CF-LVAD patients. Data on key characteristics and the TTR end point were then extracted from each study by two investigators using a standardized tool. Using a Hartung-Knapp random effects model, a weighted mean TTR estimate with accompanying 95% confidence interval (CI) was calculated. Statistical heterogeneity was estimated using the I2 statistic. Five published studies were included. All studies were single-center, retrospective investigations that calculated TTR using the Rosendaal method. Sample sizes ranged from 11 to 115 patients (total of 270 patients) with durations of follow-up ranging from 9 to 76 person-years. On meta-analysis, CF-LVAD patients had a weighted mean TTR of 46.6% (95% CI: 36.0-57.3%, I2 = 94%). This suggests that warfarin is difficult to manage in CF-LVAD patients, which may contribute to high rates of bleeding and thromboembolic complications.

Electrocardiographic effects of hawthorn (Crataegus oxyacantha) in healthy volunteers: A randomized controlled trial.

The objective of this study was to evaluate the electrocardiographic effects of hawthorn in healthy adult volunteers. It was double-blind cross-over trial randomized 20 healthy adult volunteers to receive either a single oral 160-mg dose of hawthorn or matching placebo. Triplicate 12-lead electrocardiograms were taken before treatment and at 1-, 2-, 4-, and 6-hr post-dose. Following at least a 7-day washout period, participants were crossed over to the opposing treatment arm and had the measurements repeated. The primary endpoint was the change in corrected (Fridericia) QT intervals (QTc I) at 4 and 6 hr. Maximum post-dose QTc I and changes in PR and QRS intervals were measured. No significant differences in 4- or 6-hr QTc I were seen between hawthorn and placebo. Maximum post-dose QTc I in the hawthorn and placebo groups were similar (346 ± 35 vs 346 ± 40 ms; p = .979). No significant adverse events were seen. In conclusion, a single dose of oral hawthorn had no effect on electrocardiographic parameters in healthy volunteers.

Association of Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists With Asthma Control in Patients With Uncontrolled, Persistent Asthma: A Systematic Review and Meta-analysis.

Importance: Long-acting muscarinic antagonists (LAMAs) are a potential adjunct therapy to inhaled corticosteroids in the management of persistent asthma. Objective: To conduct a systematic review and meta-analysis of the effects associated with LAMA vs placebo or vs other controllers as an add-on therapy to inhaled corticosteroids and the use of a LAMA as add-on therapy to inhaled corticosteroids and long-acting ß-agonists (LABAs; hereafter referred to as triple therapy) vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma. Data Sources: MEDLINE, EMBASE, Cochrane databases, and clinical trial registries (earliest date through November 28, 2017). Study Selection: Two reviewers selected randomized clinical trials or observational studies evaluating a LAMA vs placebo or vs another controller as an add-on therapy to inhaled corticosteroids or triple therapy vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma reporting on an outcome of interest. Data Extraction and Synthesis: Meta-analyses using a random-effects model was conducted to calculate risk ratios (RRs), risk differences (RDs), and mean differences (MDs) with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength-of-evidence grading were completed by 2 independent reviewers. Main Outcomes and Measures: Asthma exacerbations. Results: Of 1326 records identified, 15 randomized clinical trials (N = 7122 patients) were included. Most trials assessed adding LAMA vs placebo or LAMA vs LABA to inhaled corticosteroids. Adding LAMA vs placebo to inhaled corticosteroids was associated with a significantly reduced risk of exacerbation requiring systemic corticosteroids (RR, 0.67 [95% CI, 0.48 to 0.92]; RD, -0.02 [95% CI, -0.04 to 0.00]). Compared with adding LABA, adding LAMA to inhaled corticosteroids was not associated with significant improvements in exacerbation risk (RR, 0.87 [95% CI, 0.53 to 1.42]; RD, 0.00 [95% CI, -0.02 to 0.02]), or any other outcomes of interest. Triple therapy was not significantly associated with improved exacerbation risk vs inhaled corticosteroids and LABA (RR, 0.84 [95% CI, 0.57 to 1.22]; RD, -0.01 [95% CI, -0.08 to 0.07]). Conclusions and Relevance: In this systematic review and meta-analysis, the use of LAMA compared with placebo as add-on therapy to inhaled corticosteroids was associated with a lower risk of asthma exacerbations; however, the association of LAMA with benefit may not be greater than that with LABA. Triple therapy was not associated with a lower risk of exacerbations.

Association of Inhaled Corticosteroids and Long-Acting ß-Agonists as Controller and Quick Relief Therapy With Exacerbations and Symptom Control in Persistent Asthma: A Systematic Review and Meta-analysis.

Importance: Combined use of inhaled corticosteroids and long-acting ß-agonists (LABAs) as the controller and the quick relief therapy termed single maintenance and reliever therapy (SMART) is a potential therapeutic regimen for the management of persistent asthma. Objective: To conduct a systematic review and meta-analysis of the effects of SMART in patients with persistent asthma. Data Sources and Study Selection: The databases of MEDLINE via OVID, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews were searched from database inception through August 2016 and updated through November 28, 2017. Two reviewers selected randomized clinical trials or observational studies evaluating SMART vs inhaled corticosteroids with or without a LABA used as the controller therapy and short-acting ß-agonists as the relief therapy for patients aged 5 years or older with persistent asthma and reporting on an outcome of interest. Data Extraction and Synthesis: Meta-analyses were conducted using a random-effects model to calculate risk ratios (RRs), risk differences (RDs), and mean differences with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength of evidence grading were completed by 2 independent reviewers. Main Outcomes and Measures: Asthma exacerbations. Results: The analyses included 16 randomized clinical trials (N = 22 748 patients), 15 of which evaluated SMART as a combination therapy with budesonide and formoterol in a dry-powder inhaler. Among patients aged 12 years or older (n = 22 524; mean age, 42 years; 14 634 [65%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.68 [95% CI, 0.58 to 0.80]; RD, -6.4% [95% CI, -10.2% to -2.6%]) and a higher dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.77 [95% CI, 0.60 to 0.98]; RD, -2.8% [95% CI, -5.2% to -0.3%]). Similar results were seen when SMART was compared with inhaled corticosteroids alone as the controller therapy. Among patients aged 4 to 11 years (n = 341; median age, 8 [range, 4-11] years; 69 [31%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with a higher dose of inhaled corticosteroids as the controller therapy (RR, 0.55 [95% CI, 0.32 to 0.94]; RD, -12.0% [95% CI, -22.5% to -1.5%]) or the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.38 [95% CI, 0.23 to 0.63]; RD, -23.2% [95% CI, -33.6% to -12.1%]). Conclusions and Relevance: In this meta-analysis of patients with persistent asthma, the use of single maintenance and reliever therapy compared with inhaled corticosteroids as the controller therapy (with or without a long-acting ß-agonist) and short-acting ß-agonists as the relief therapy was associated with a lower risk of asthma exacerbations. Evidence for patients aged 4 to 11 years was limited.