Real-world biologics response and super-response in the International Severe Asthma Registry cohort.

BACKGROUND: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma. METHODS: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV1) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. RESULTS: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria. CONCLUSIONS: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria.

Effectiveness of Mepolizumab in Patients with Severe Eosinophilic Asthma with/without Nasal Polyposis: A Real-Life Study.

INTRODUCTION: Asthma is one of the most common chronic diseases and affects around 334 million people worldwide. The estimated prevalence of severe asthma is 3-10% of the asthmatic population. Mepolizumab has demonstrated efficacy in reducing exacerbations, oral corticosteroid use, and improving quality of life, asthma control, and lung function in patients with severe eosinophilic asthma (SEA). Our study aimed to check the response to mepolizumab in a series of severe asthma patients regarding exacerbations, oral corticosteroid use, asthma control, quality of life, and lung function and to compare the response between patients with and without nasal polyps. METHOD: This is a retrospective, multicenter study of RE-ASGRAMUR (Register of Severe Asthma of the Region of Murcia) performed in eight hospitals of the Region of Murcia (Spain) under routine clinical practice conditions. We included patients diagnosed with SEA who completed at least 1 year of treatment with mepolizumab. We analyzed clinical characteristics, drug tolerance, and effectiveness: exacerbations, ACT, miniAQLQ, forced expiratory volume in 1 s (FEV1), and use of oral corticosteroids. We also compared the results between patients with and without nasal polyps. RESULTS: The median of exacerbations before treatment was 3 and decreased to 0 after treatment (mean decrease of 77.4%). The median diary oral prednisone intake was 15 mg before treatment and 5 mg after treatment (mean 56% reduction). We have obtained a significant improvement in other variables: ED visits and hospitalizations, asthma control (ACT), quality of life (miniAQLQ), and lung function (FEV1). Thirty-four out of 70 patients (48.57%) fulfilled the criteria of super-responder, and 17 out of 70 (24.29%) had a complete response. More patients in the group with nasal polyps fulfilled the criteria of super-responder and complete response to mepolizumab. CONCLUSIONS: Mepolizumab is a safe and effective treatment for SEA patients, improving exacerbations, oral corticosteroid intake, asthma control, quality of life, and lung function. In patients with associated nasal polyposis, there is a statistically significant higher proportion of super-responders and complete responders.

"Life-changing": the experience of super-responders to biologics in severe asthma.

BACKGROUND: There is limited information on the patient's perspective of how biologic treatments impact their lives. We conducted a qualitative study to explore the patient's experience of being considered a super-responder from a quality of life perspective. METHODS: Patients with severe asthma identified as super-responders were invited to semi-structured interviews conducted online. Participants could bring a family member/friend to the interview. The interviews explored experiences of biologic treatment, were transcribed and underwent thematic analysis. RESULTS: Twenty-five participants took part in this study. Themes emerged on the impact of biologic treatment for participants and for their friends/family: (i) Words used to describe their often life-changing experiences and (ii) the positive changes noted. Biologic treatment stopped the disruption of family life and social life caused by exacerbations. Improvements in mental health were also noted. Marked individual variations in the way it affected their lives were noted. Most participants noticed improvements 2-3 months after starting their biologic, but some noticed improvement within a few days and others after 6 months. CONCLUSIONS: Super-responders reported profound but heterogeneous improvements following biologic treatment beyond asthma symptoms and exacerbations including important benefits to social and family life. Improvements may be underestimated as social and family benefits are not reliably measured in current studies with implications for health economic evaluations. Not all patients are super-responders, and excellent responses may be lost in group mean data in trials. Individual time course and response patterns need further elucidation to identify who will respond best to biologics.

Risk of ventricular arrhythmia in cardiac resynchronization therapy responders and super-responders: a systematic review and meta-analysis.

AIMS: Response to cardiac resynchronization therapy (CRT) is associated with improved survival, and reduction in heart failure hospitalization, and ventricular arrhythmia (VA) risk. However, the impact of CRT super-response [CRT-SR, increase in left ventricular ejection fraction (LVEF) to ≥ 50%] on VA remains unclear. METHODS AND RESULTS: We undertook a meta-analysis aimed at determining the impact of CRT response and CRT-SR on risk of VA and all-cause mortality. Systematic search of PubMed, EMBASE, and Cochrane databases, identifying all relevant English articles published until 31 December 2019. A total of 34 studies (7605 patients for VA and 5874 patients for all-cause mortality) were retained for the meta-analysis. The pooled cumulative incidence of appropriate implantable cardioverter-defibrillator therapy for VA was significantly lower at 13.0% (4.5% per annum) in CRT-responders, vs. 29.0% (annualized rate of 10.0%) in CRT non-responders, relative risk (RR) 0.47 [95% confidence interval (CI) 0.39-0.56, P < 0.0001]; all-cause mortality 3.5% vs. 9.1% per annum, RR of 0.38 (95% CI 0.30-0.49, P < 0.0001). The pooled incidence of VA was significantly lower in CRT-SR compared with CRT non-super-responders (non-responders + responders) at 0.9% vs. 3.8% per annum, respectively, RR 0.22 (95% CI 0.12-0.40, P < 0.0001); as well as all-cause mortality at 2.0% vs. 4.3%, respectively, RR 0.47 (95% CI 0.33-0.66, P < 0.0001). CONCLUSIONS: Cardiac resynchronization therapy super-responders have low absolute risk of VA and all-cause mortality. However, there remains a non-trivial residual absolute risk of these adverse outcomes in CRT responders. These findings suggest that among CRT responders, there may be a continued clinical benefit of defibrillators.

Cardiac resynchronization therapy (CRT) device replacement considerations: upgrade or downgrade? A complex decision in the current clinical setting.

There are limited data about the management of patients presenting for elective generator replacements in the setting of previously implanted cardiac resynchronization therapy (CRT) devices that are nearing end-of-life. The individual patient's clinical status and concomitant morbidities may evolve so that considerations may include not only replacement of the pulse generator, but also potentially changing the type of device [e.g. downgrading CRT-defibrillator (CRT-D) to CRT-pacemaker (CRT-P) or ICD or upgrading of CRT-P to CRT-D]. Moreover, the clinical evidence for CRT-D/CRT-P implantation may change over time, with ongoing research and availability of new trial data. In this review we discuss the ethical, clinical and financial implications related to CRT generator replacements and the need for additional clinical trials to better understand which patients should undergo CRT device downgrading or upgrading at the time of battery depletion.

An approach to confirmatory testing of subpopulations in clinical trials.

In oncology studies with immunotherapies, populations of "super-responders" (patients in whom the treatment works particularly well) are often suspected to be related to biomarkers. In this paper, we explore various ways of confirmatory statistical hypothesis testing for joint inference on the subpopulation of putative "super-responders" and the full study population. A model-based testing framework is proposed, which allows to define, up-front, the strength of evidence required from both full and subpopulations in terms of clinical efficacy. This framework is based on a two-way analysis of variance (ANOVA) model with an interaction in combination with multiple comparison procedures. The ease of implementation of this model-based approach is emphasized and details are provided for the practitioner who would like to adopt this approach. The discussion is exemplified by a hypothetical trial that uses an immune-marker in oncology to define the subpopulation and tumor growth as the primary endpoint.

Long-term outcome of 'super-responder' patients to cardiac resynchronization therapy.

AIMS: To evaluate the long-term changes of clinical and echocardiographic parameters, the incidence of cardiac events and parameters associated with late cardiac events in 'super-responders' to cardiac resynchronization therapy (CRT) with [CRT defibrillator (CRT-D)] or without defibrillator back-up. METHODS AND RESULTS: In all consecutive patients treated with CRT in two Italian centres (Trieste and Udine) with left ventricular ejection fraction (LVEF) ≤0.35 at implantation (Timp) and LVEF > 0.50 1 and/or 2 years (Tnorm) after implantation, the long-term outcome and the evolution of echocardiographic parameters were assessed; factors associated with a higher risk of cardiac events, defined as hospitalization or death for heart failure (HF), sudden death, or CRT-D appropriate interventions, were also analysed. Among the 259 patients evaluated, 62 (24%) had LVEF ≥ 0.50 at Tnorm (n = 44 with at 1 year, n = 18 at 2 years). During a mean follow-up of 68 ± 30 months, one cardiac death (for HF) and eight cardiovascular events (two hospitalization for HF and six appropriate CRT-D interventions) occurred. At the last echo evaluation (Tfup) performed 51 ± 26 months after Timp, LVEF was <0.50 in five patients (>0.45 in four of them). At univariable analysis, only LV end-systolic volume evaluated at Tfup was associated with a higher risk of cardiac events during follow-up. CONCLUSION: In 'super-responders' to CRT long-term outcome is excellent. However, cardiac events, mainly CRT-D appropriate interventions, can occur despite the persistence of LVEF > 0.50. Early identification of these patients is still an unsolved issue.

Comparison between super-responders and non-super-responders in psoriasis under adalimumab treatment: a real-life cohort study on the effectiveness and drug survival over one-year.

BACKGROUND: Data on the characteristics and treatment outcomes of super-responders and non-super-responders in psoriasis under adalimumab treatment are limited. METHODS: A retrospective analysis from psoriatic patients treated with adalimumab was compared to characterize super-responders vs non-super-responders' groups, identify factors associated with super response, and assess treatment outcomes after switching. RESULTS: 15 out of 70 (21.4%) patients were categorized as super-responder. The proportion of patients achieving a PASI 100 response was significantly higher in super-responders than non-super-responders at weeks 12, 24, and 52. Female sex and Charlson Co-morbidity Index were significantly associated with super-responders. A high level of high-density lipoprotein was independently associated with PASI 90 response at weeks 24 and 52. Additionally, nearly 35%-43% of non-super-responders switching to interleukin-17A (IL-17A) inhibitors may achieve a PASI 100 response at week 12. In contrast, all super-responders switching to IL-17A inhibitors achieved a PASI 100 response at week 4. CONCLUSIONS: Super-responders treated with adalimumab have a higher rate of being female and fewer comorbidities. And super-responders have better PASI responses than non-super-responders, whether the patients were treated with adalimumab or switched to IL-17A inhibitors.

Comparison of Long-term Response and Remission to Omalizumab and Anti-IL-5/IL-5R Using Different Criteria in a Real-life Cohort of Severe Asthma Patients.

BACKGROUND: Evaluation of biologic therapy response is vital to monitor its effectiveness. Authors have proposed various response criteria including good responder, super-responder, non-responder, and clinical remission. OBJECTIVES: To ascertain the prevalence of response and clinical remission after long-term treatment (>6 months) of anti-IgE and anti-IL-5/IL-5Rα biologics, compare these results with existing criteria, and identify predictors for non-responders and clinical remission. METHODS: A multicenter, real-life study involving severe asthma patients in Spain. Various outcomes were assessed to gauge response and clinical remission against established criteria. RESULTS: The study included 429 patients, 209 (48.7%) omalizumab, 112 (26.1%) mepolizumab, 19 (4.4%) reslizumab and 89 (20.7%) benralizumab, with a mean treatment duration of 55.3±38.8 months. In the final year of treatment, 218 (50.8%) were super-responders, 173 (40.3%) responders, 38 (8.9%) non-responders, and clinical remission in 116 (27%), without differences among biologics. The short-term non-responders (<6 months) were 25/545 (4.6%). Substantial variations in response and clinical remission were observed when applying different published criteria. Predictors of non-response included higher BMI (OR:1.14; 95% CI:1.06-1.23; p<0.001), admissions at ICU (2.69; 1.30-5.56; p=0.01), high count of SAE (1.21; 1.03-1.42; p=0.02) before biologic treatment. High FEV1% (0.96; 0.95-0.98; p<0.001), a high ACT score (0.93; 0.88-0.99; p=0.01) before biologic treatment or NSAID-ERD (0.52; 0.29-0.91; p=0.02) showed strong associations with achieving clinical remission. CONCLUSION: A substantial proportion of severe asthma patients treated long-term with omalizumab or anti-IL5/IL-5Rα achieved a good response. Differences in response criteria highlight the need for harmonization in defining response and clinical remission in biologic therapy to enable meaningful cross-study comparisons.

Normalization of left ventricular ejection fraction after cardiac resynchronization therapy also normalizes survival.

BACKGROUND: Earlier studies in patients with reduced left ventricular ejection fraction (LVEF) ≤35% and prolonged QRS showed better survival outcomes with cardiac resynchronization therapy (CRT). Some patients respond dramatically to CRT by improving their LVEF to the normal range and are considered "super-responders." Our aim was to determine whether super-responders survival increases to levels comparable to the general population. We compared the survival of super-responders to the general population matched for age and sex. METHODS: Of 909 patients with CRT device implantation between September 1998 and July 2008, 814 patients had pre- and post-CRT echocardiogram. A total of 95 patients with LVEF ≥ 50% following CRT were classified as super-responders. For 92 super-responders, who had U.S. Social Security numbers, an age- and sex-matched example was selected from the Social Security Life Tables. An expected survival plot of the matched population was then compared to the actual survival of super-responders. RESULTS: Super-responders had comparable survival to the age-sex matched general population (P = 0.53), and Kaplan-Meier survival analysis in 92 patients showed that super-responders with CRT pacemakers had similar survival to those with CRT implantable cardioverter defibrillators (P = 0.77). Super-responders were more likely to be females (54% vs 25%, P < 0.001) and less likely to have significant coronary artery disease (62% vs 42%, P < 0.001). CONCLUSIONS: Normalization of LVEF by CRT improves survival to levels comparable to the general population. This observation favors the concept that some CRT candidates have a cardiomyopathy likely generated by the conduction abnormality that is reversible through biventricular pacing.

Super-Responders to Biologic Treatment in Type 2-High Severe Asthma: Passing Fad or a Meaningful Phenotype?

Defining super-response to biologic treatment is a major concern in severe asthma. Although many definitions have been proposed, there is still a gap between the clinical perception of the super-response and a standardized classification. The current definition of super-response mainly relies on several clinical features, while many aspects of severe asthma inflammation and lung function are still poorly considered. Furthermore, many criteria of severe asthma super-response overlap with those of the clinical remission, leaving room for possible misclassifications. In this context, identifying the correct trajectory linking these 2 aspects of type 2-high severe asthma could help clinicians to understand which factors can predict a greater response to biologic therapies. In this paper, we review various aspects of super-response assessment, proposing some new criteria for its definition as well as new perspectives on its relationship with severe asthma clinical remission.

Considering Diastolic Dyssynchrony as a Predictor of Favorable Response in LV-Only Fusion Pacing Cardiac Resynchronization Therapy.

Background: CRT improves systolic and diastolic function, increasing cardiac output. Aim of the study: to assess the outcome of LV diastolic dyssynchrony in a population of fusion pacing CRT. Methods: Diastolic dyssynchrony was measured by offline speckle-tracking-derived TDI timing assessment of the simultaneity of E″ and A″ basal septal and lateral walls. New parameters introduced: E″ and, respectively, A″ time (E″T/A″T) as the time difference between E″ (respectively, A″) peak septal and lateral wall. Patients were divided into super-responders (SR), responders (R), and non-responders (NR). Results: Baseline characteristics: 62 pts (62 ± 11 y.o.) with idiopathic DCM, EF 27 ± 5.2%; 29% type III diastolic dysfunction (DD), 63% type II, 8% type I. Average follow-up 45 ± 19 months: LVEF 37 ± 7.9%, 34%SR, 61%R, 5%NR. The E″T decreased from 90 ± 20 ms to 25 ± 10 ms in SR with significant LV reverse remodeling (LV end-diastolic volume 193.7 ± 81 vs. 243.2 ± 82 mL at baseline, p < 0.0028) and lower LV filling pressures (E/E' 13.2 ± 4.6 vs. 11.4 ± 4.5, p = 0.0295). DD profile improved in 65% of R with a reduction in E/E' ratio (21 ± 9 vs. 14 ± 4 ms, p < 0.0001). Significant cut-off value calculated by ROC curve for LV diastolic dyssynchrony is E″T > 80 ms and A″T > 30 msec. Conclusions: The study identifies the cut-off values of diastolic dyssynchrony parameters as predictors of favorable outcomes in responders and super-responder patients with fusion CRT pacing. These findings may have important implications in patient selection and follow-up.

Long-Term Efficacy and Safety Among Patients With Severe Eosinophilic Asthma Treated With Mepolizumab and Its Effect on Small Airways.

BACKGROUND: The major problem at the Cleveland Allergy and Asthma Center was the need for additional therapy for severe eosinophilic asthma patients who were steroid-dependent or required frequent bursts of prednisone. OBJECTIVES: The objectives of this study were to determine the efficacy of monthly mepolizumab (MP) injections up to 6½ years using Asthma Control Quesitonnaire-7 (ACQ-7), forced expiratory volume in 1 second (FEV1), forced expiratory flow at 25% to 75% (FEF25%-75%) overall and among super-responders, and to understand whether FEF25%-75% is an effective parameter to evaluate MP efficacy. METHODS: We reviewed the charts of 67 patients with severe eosinophilic asthma and compared the results between 47 super-responders and the rest of the cohort regarding ACQ-6, ACQ-7, eosinophils, FEV1, and FEF25%-75%. The groups of super-responders and all other patients were described with respect to initial and current values of the study end points using medians and 25th and 75th percentiles. Changes from the initial to the current values in the study end points were measured using percent changes. The Wilcoxon signed rank test was used within each group to test the null hypothesis of 0 median percent change. RESULTS: After 6½ years, there were no significant changes in FEV1. The FEF25%-75%, had a significant median percent increase of 40% among the super-responders (P < .001), which was substantially higher (P = .026) than the median percent increase of 13.8% observed among all other patients. CONCLUSIONS: The use of MP up to 6½ years was safe and effective, with significant changes to ACQ-7 and FEF25%-75% associated with MP treatment, but not the FEV1. A higher magnitude of changes was observed among super-responders than the rest of the cohort. Changes in FEF25%-75% were more meaningful than changes in FEV1 in evaluating pulmonary function responsiveness of severe eosinophilic asthma to MP.

Nonischemic Super-Responders in Fusion CRT Pacing with Normal Atrioventricular Conduction.

Background: Fusion CRT pacing (FCRT) is noninferior to biventricular pacing, according to the current data. The aim of this study is to assess the response to FCRT and to identify predictors of super-responders (SRs) in a nonischemic population with normal AV conduction. Methods: LV-only CRT patients (pts) with a right atrium/left ventricle pacing system implanted in two CRT centers in Romania were included. Device interrogation, exercise tests, echocardiography, and individualized drug optimization were performed every 6 months during close follow-up. SRs pts were defined as those with left ventricular end-systolic volume (LVESV) improvement ≥30% and stable ejection fraction (LVEF) ≥45%. Results: A total of 25 out of 83 pts (31%) were SRs, with nonischemic LBBB low EF cardiomyopathy (50 male, 62 ± 9 y.o.) initially included. Mean follow-up was 5 years ± 27 months. Patients were divided in two groups: SRs and non-SRs (52 responders/6 hypo-responders). Two predictors were found in the SRs group: a higher baseline LVEF (SRs 29 ± 5% vs. non-SRs 26 ± 5%, p = 0.02) and a lower pulmonary arterial systolic pressure (SRs 38 ± 11 mm Hg vs. non-SRs 50 ± 15 mmHg, p = 0.003). Baseline severe mitral regurgitation was found in 11% of SRs vs. 64% in the non-SRs group. Conclusions: SRs in the selected NICM-FCRT group are significative high. Higher baseline LVEF and mild pulmonary arterial hypertension were independently associated with super-response.

Evaluation of super-responders to cardiac resynchronization therapy in the presence of left bundle branch block and absence of scar in the posterolateral wall of the left ventricle.

Patients with heart failure (HF) undergoing cardiac resynchronization therapy (CRT) who exhibit above-expected improvement are known as super-responders. We assessed the rate of super-responders in a population with left bundle branch block (LBBB) > 150 ms in the absence of scar tissue in the left ventricular posterolateral wall as well as prognostic variables. In this prospective observational cohort study (n=20) an electrocardiogram (ECG) was performed pre- and post-CRT. The classic and Strauss LBBB criteria were adopted (> 150 ms). The percent (%) reduction of the QRS was calculated after implantation. All patients responded to the Minnesota Living with Heart Failure questionnaire and underwent an echocardiogram to measure left ventricular ejection function (LVEF), left atrium (LA) diameter, left ventricular end-systolic volume (LVEDV), left ventricular end-diastolic volume (LVESV), and left ventricular end-diastolic diameter (LVEDD) pre- and 6 months post-CRT. Cardiac magnetic resonance imaging (MRI) measured the presence of scar tissue in the posterolateral LV wall and the total scar burden (% LV mass). Fisher's exact test and the Mann-Whitney test were performed to evaluate possible prognostic variables. The mean age was 58.20±8.79 years old, 60% female, with a mean LVEF of 28.15±5.10%, ECG with LBBB mean QRS of 162.15±7.86 ms, LBBB > 150 ms with Strauss standard in 90% of cases, and 90% with non-ischemic cardiomyopathy. Twelve cases (60%) of super-responders (reduction > 30% LVESV after 6 months) were observed. Super-responders did not present a difference in response in sex (12 vs 8 P=0.67), age (58.67 vs 57.7 P=087), Minnesota quality of life (55.50 vs 67.70 P=0.2), % initial QRS reduction (21.16 vs 18.69 P=0.21), LVEF (29.25 vs 26.5 P=0.38), LVEDD (66.33 vs 67.67 P=0.83), LVEDV (211.16 vs 228.53 P=0.75), LVESV (145.83 vs 167.00 P=0.75), or LA diameter (41.58 vs 43.63 P=0.45). The presence of LBBB > 150 ms, using the Strauss standard (90%) and the absence of scar in the posterolateral wall may account for these positive results. Super-responders benefit the most from CRT, and the results of this study can contribute to a better selection of CRT candidates.

Incidence and predictors of super-response to cardiac resynchronization therapy.

OBJECTIVES: Cardiac resynchronization therapy (CRT) has significantly improved management of patients with heart failure with reduced ejection fraction (HFrEF). A significant number of patients have a dramatic response and have been termed "super-responders". The characteristics of this subset of patients in Indian and Asian population have not been well studied. In this study, we sought to assess the prevalence and clinical characteristics of this cohort of patients. METHODS: This was a retrospective study involving patients undergoing CRT. Changes in ejection fraction and LVESV at the end of one year of follow-up following device implantation were assessed, and patients were stratified into non-responders, responders, and super-responders. Responders had a 15-29% decrease in LVESV while super-responders had a >30% decrease in LVESV. RESULTS: Of the 74 patients who had undergone CRT-P/CRT-D implantation, 16 patients did not have echocardiograms at the end of one year of follow-up and were excluded from the analysis. Thus, 58 patients were enrolled for analysis. We identified 16 patients (27.6%) to be super-responders, 26 patients (44.8%) to be responders, and 16 patients (27.6%) to be non-responders. Factors associated with a super-response were a diagnosis of dilated cardiomyopathy as against ischemic cardiomyopathy (93.7% vs 6.3%; p - 0.01), prior right ventricular (RV) apical pacing (25% vs 2.4%; p - 0.02) and absence of a prior history of myocardial infarction (MI) (0% vs 33.3%; p - 0.02). CONCLUSION: In our study, 27.6% of patients were super-responders, and a diagnosis of dilated cardiomyopathy, absence of a prior history of MI and prior RV apical pacing predicted a super-response to CRT.

A comprehensive review of exceptional responders to anticancer drugs in the biomedical literature.

IMPORTANCE: There is broad interest in patients who have exceptional responses to cancer drugs and only one prior systematic review of published case reports. OBJECTIVE: To systematically summarise case reports of patients who have had a super response to a cancer drug and determine patterns and completeness of documentation. DESIGN, SETTING AND PARTICIPANTS: This is a systematic search of biomedical literature and hand searches of seven prominent oncology journals. All cases were adults with cancer in the metastatic or unresectable setting and who were classified as having a remarkable response to a drug therapy were included. Our study was conducted between January 2017 and April 2017. MAIN OUTCOMES AND MEASURES: We extracted patient and tumour characteristics, characteristics surrounding the exceptional response and pertinent oncologic history. Additionally, we noted authors' financial conflicts of interest, if given. RESULTS: We found 180 cases of exceptional response. The most common malignancy was breast cancer (28/180), and the most common class of drug therapy used was targeted therapies (161/274). The median year of publication was 2015. Depth of response included 33% (61/180) complete response, 55% (100/180) partial response and 7.7% (14/180) stable disease. The median length of response to the drug was 14 months. Fifty-nine percent (107/180) reported a driver mutation, and only 52% (56/107) reported two or more correlative studies. Only 14% (26/180) reported a denominator or total number treated to observe this response. Of cases that reported duration of response to a previous drug given in the unresectable setting, 49% demonstrated a progression-free survival ratio of exceptional response to prior line of 1.3 or greater (Von Hoff ratio). CONCLUSIONS AND RELEVANCE: Our survey found that exceptional responders tended to have solid organ malignancies and most received targeted therapies. Many of our cases of exceptional responders were missing important information about the response and key oncologic history. Standardised criteria should be used to maximise usefulness of these case reports in the future.

Predictors of super-response to cardiac resynchronization therapy: the significance of heart failure medication, pre-implant left ventricular geometry and high percentage of biventricular pacing.

BACKGROUND: Super-responders (SRs) are defined as patients who show crucial cardiac function improvement after cardiac resynchronization therapy (CRT). The purpose of this study is to identify and validate predictors of SRs after CRT. METHODS: This study enrolled 201 patients who underwent CRT during the period from 2010 to 2014. Clinical and echocardiographic evaluations were conducted before CRT and 6 months after. Patients with a decrease in New York Heart Association (NYHA) functional class ≥ 1, a decrease in left ventricular end-systolic volume (LVESV) ≥ 15%, and a final left ventricular ejection fraction (LVEF) ≥ 45% were classified as SRs. RESULTS: 29% of the 201 patients who underwent CRT were identified as SRs. At baseline, SRs had significantly smaller left atrial diameter (LAD), LVESV, left ventricular end-diastolic volume (LVEDV) and higher LVEF than the non-super-responders (non-SRs). The percentage of patients using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) was higher in SRs than non-SRs. Most SRs had Biventricular (BiV) pacing percentage greater than 98% six months after CRT. In the multivariate logistic regression analysis, the independent predictors of SRs were lower LVEDV [odd ratios (OR): 0.93; confidence intervals (CI): 0.90-0.97], use of ACEI/ARB (OR: 0.33; CI: 0.13-0.82) and BiV pacing percentage greater than 98% (OR: 0.29; CI: 0.16-0.87). CONCLUSION: Patients with a better compliance of ACEI/ARB and a less ectatic ventricular geometry before CRT tends to have a greater probability of becoming SRs. Higher percentage of BiV pacing is essential for becoming SRs.

Ventricular arrhythmias in super-responders to cardiac resynchronization therapy.

INTRODUCTION AND OBJECTIVES: Cardiac resynchronization therapy is associated with improved quality of life and reduced morbidity and mortality in patients with severe ventricular dysfunction and wide QRS. However, its role in the reduction of ventricular arrhythmias is more controversial. METHODS: We compared the incidence of ventricular arrhythmias in patients who were undergoing cardiac resynchronization therapy with an implantable cardioverter-defibrillator in terms of the degree of echocardiographic response to resynchronization. Patients were classified in 3 subgroups;super-responders, responders, and nonresponders. RESULTS: We included 196 patients who were followed up for a median 30.1 months [interquartile range, 18.0-55.1 months]. We recorded the presence of ventricular arrhythmias in 37 patients (18.8%); 3 patients (5.9%) in the super-responder group had ventricular arrhythmias vs 14 (22.2%) among the responders and 20 (24.4%) in the group of nonresponders (P = .025). In multivariate analysis, the only independent predictors of the appearance of ventricular arrhythmias were secondary-prevention device implantation (odds ratio = 4.04; 95% confidence interval, 1.52-10.75; P=.005), absence of echocardiographic super-response (odds ratio=3.81; 95% confidence interval, 1.04-13.93; P=043), QRS >160 ms (odds ratio=2.39; 95% confidence interval, 1.00-1.35; P=.049) and treatment with amiodarone (odds ratio=2.47; 95% confidence interval, 1.03-5.91; P=.041). CONCLUSIONS: The patients classified as super-responders to cardiac resynchronization therapy had a significant reduction in incidence of ventricular arrhythmias by comparison with the other patients. Despite this, arrhythmic episodes do not completely disappear in this subgroup.