Khan, Safi U.

Abstract Aims To compare early de-escalation of dual antiplatelet therapy (DAPT) (1–3 months) to monotherapy with either P2Y12 inhibitor or aspirin vs. 12 months DAPT after percutaneous coronary intervention (PCI) with drug-eluting stent (DES). Methods and results Electronic databases of Medline, Embase, and Cochrane library were searched through February 2020 to identify randomized controlled trials. A Bayesian network meta-analysis was conducted with random effects model. The main endpoints of interest were cardiovascular mortality and total bleeding events. Among seven trials (35 821 patients), 52.6% patients were presented with acute coronary syndrome. A total of 3359 patients and 14 530 patients were de-escalated to aspirin and P2Y12 inhibitor monotherapy, respectively. At a median follow-up of 12 months, compared with 12 months of DAPT, there was no significant difference in cardiovascular mortality between 1-month DAPT followed by P2Y12 inhibitor monotherapy [hazard ratio (HR) 0.84 (95% credible interval 0.29–2.43)], 3 months of DAPT followed by P2Y12 inhibitor monotherapy [HR 0.74 (0.39–1.46)], or 3 months of DAPT [HR 1.00 (0.54–1.86)] followed by aspirin monotherapy. Except for de-escalation of DAPT to aspirin monotherapy after 3 months [HR 0.75 (0.43–1.20)], de-escalation to P2Y12 inhibitor monotherapy after 1 month [HR 0.28 (0.10–0.83)], or 3 months [HR 0.57 (0.33–0.98)] were associated with significant decrease in total bleeding events. There were no significant differences in terms of ischaemic endpoints among different DAPT strategies. Conclusion Early de-escalation of DAPT (1–3 months) to monotherapy with a P2Y12 inhibitor instead of aspirin might be a safer and equally effective approach compared with 12 months of DAPT in patients with PCI and DES.

e19503 Background: The risk of venous thromboembolic events (VTE) despite mandatory thromboprophylaxis (TPx) in patients with multiple myeloma (MM) receiving contemporary lenalidomide (Len)-based regimens is not well-defined. Methods: Medline, Embase, and CENTRAL databases were queried to identify phase 1-3 clinical trials of Len-based regimens with mandatory TPx published until April 2018. Random effects meta-analysis was performed using CMAv3 software to obtain crude, and per 100 patient-cycle incidence rate (IR). Prespecified subgroup analyses were performed to obtain IR for VTE by (1) line of treatment (newly diagnosed [ND], relapsed/refractory [RR] and maintenance [Mx] phase) and (2) different Len-based regimens. Results: We screened 1069 citations and analyzed data from 43 trials with 8696 patients, including 17 in ND, 23 in RR and 3 in Mx phase. 12 out of 43 were Phase 3 randomized controlled trials. The overall incidence of VTE in 8696 patients was 4.6% (95% CI, 3.7-5.8%), with 1.0 event (95% CI, 0.7-1.4%) per 100 patient cycles. In patients with NDMM (n = 3295), 193 (5.9%) experienced VTE with a pooled IR of 0.9 (95% CI, 0.3-2.3) per 100 patient-cycle. Among RRMM patients (n = 3981), 251 (6.3%) experienced VTE with a pooled IR of 1.0 (95% CI, 0.4-2.3) per 100 patient-cycle. The incidence of VTE was highest with the following triplet regimens: Rd + Proteasome inhibitor (PIs) and Rd + Anthracycline (Ac) [+/- Vincristine], with the latter having a high risk of VTE regardless of the treatment phase (table). With Len Mx (n = 1420), 38 (2.7%) patients had VTE, with a pooled IR of 0.2 (95% CI, 0-2.1) per 100 patient-cycle. Conclusions: Patients with MM undergoing treatment with Len-based regimens remain at risk of VTE despite current TPx strategies. The estimates of VTE IR provided by this analysis can guide clinicians in assessing treatment-related risk of VTE in this setting. [Table: see text]

Background Thromboprophylaxis is routinely used with lenalidomide‐based regimens in multiple myeloma because of a substantial risk of venous thromboembolism (VTE). However, little is known about the incidence of VTE with contemporary lenalidomide‐based regimens. The objective of the current study was to estimate the incidence of VTE despite thromboprophylaxis with currently used lenalidomide‐based regimens in patients with myeloma. Methods The Ovid MEDLINE, Embase, and Cochrane databases were queried from study inception to January 2019 for keywords to cover the following concepts: “lenalidomide,” “venous thromboembolism,” and “multiple myeloma.” Phase 1, 2, and 3 clinical trials evaluating lenalidomide‐based regimens with thromboprophylaxis were included. The pooled incidence rate of VTE was estimated using a random‐effects model. Results The search generated 1372 citations, with 51 clinical trials and 9069 patients included for analysis. The most common thromboprophylaxis agents were aspirin, low‐molecular‐weight heparin or warfarin, administered either per risk‐stratification or at investigators' discretion. The pooled incidence of VTE in trials of patients who had newly diagnosed and relapsed/refractory myeloma was 6.2% (95% CI, 5.4%‐7.1%) over median treatment durations ranging from 2 to 34 cycles, which translated into 1.2 VTE events per 100 patient‐cycles (95% CI, 0.9‐1.7 VTE events per 100 patient‐cycles). Among contemporary regimens, the risk of VTE was low with combined lenalidomide and low‐dose dexamethasone (0.2 [95% CI, 0.1‐0.6] events/100 patient‐cycles) and lenalidomide maintenance (0.0 [95% CI, 0.0‐0.7] events per 100 patient‐cycles). VTE risk was higher with combined lenalidomide and low‐dose dexamethasone plus proteasome inhibitors (1.3 [95% CI, 0.7‐2.3] events per 100 patient‐cycles). Conclusions Despite adequate thromboprophylaxis, lenalidomide‐based regimens have a substantial risk of VTE in controlled clinical trial settings. Further studies are needed on new thromboprophylaxis strategies with regimens that have a high VTE risk.

Background: Efficacy of an intervention is commonly evaluated using P values, in addition to effect size measures such as absolute risk reduction, relative risk reduction, and numbers needed to treat. However, these measures are not always intuitive to clinicians. The fragility index (FI) is a more intuitive number that can facilitate interpretation but can only be used with binary outcomes. FI is the minimum number of patients who must be moved from the nonevent group to the event group to turn a significant result nonsignificant. In this retrospective analysis, we assessed the robustness of cardiovascular randomized controlled trials (RCTs), which report a positive (statistically significant) primary outcome by using the FI. Methods and Results: We searched Medline from 2007 to 2017 to identify cardiovascular RCTs published in 6 high impact journals ( The Lancet , New England Journal of Medicine , Journal of the American Medical Association , Circulation , Journal of the American College of Cardiology and European Heart Journal ). Only RCTs with sample sizes >500 and a 2-by-2 factorial design or dichotomous primary outcomes were selected. FI was calculated using a defined approach. Among the cohort of 123 RCTs that met inclusion criteria, median FI was 13 (interquartile range, 5–26). In 28 trials (22.8%), FI ranged between 1 and 4. In 37 trials (30.1%), number of patients lost to follow-up was higher than the FI. Pharmaceutical interventions had higher FI compared with other interventions, FI=19 (7–52; P =0.002). Median FI varied according to subspecialty (electrophysiology=2; heart failure=11; interventional cardiology=8; P =0.020) and multiregional RCTs had higher FI=22 (12–53.25; P =0.023). FI did not differ based on risk of bias indicators, funding, or publication year. Conclusions: Considerable variations in FI were observed among cardiovascular trials, suggesting the need for careful interpretation of results, particularly when number of patients lost to follow-up exceeds FI.

AbstractBackgroundHypertrophic cardiomyopathy (HCM) accounts for significant morbidity and mortality worldwide. Arrhythmias are considered the main cause of mortality, however, there is paucity of data relating to trends of arrhythmia and associated outcomes in HCM patients.MethodsNationwide Inpatient Sample from 2003 to 2014 was analyzed. HCM related hospitalizations were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9‐CM) code 425.1 and 425.11 in all diagnosis fields.ResultsOverall, there was an increase in number of hospitalizations related to arrhythmias among HCM patients from 7784 in 2003 to 8380 in 2014 (relative increase 10.5%, P < 0.001). The increase was most significant in patients ≥ 80 years and those with higher comorbidity burden. Atrial fibrillation (AF) was the most frequently occurring arrhythmia however atrial flutter (AFL) witnessed the highest rise during the study period. In general, there was a down trend in mortality with the greatest reduction occurring in patients with ventricular fibrillation/flutter (VF/VFL). The mean length of stay was higher if patients had arrhythmia, which led to increased cost of care from $16105 in 2003 to $19310 in 2014 (relative increase 22.9%, P < 0.001).ConclusionThere is overall decline in HCM related hospitalizations but rise in hospitalization among HCM patients with arrhythmias. HCM with arrhythmia accounts for significant inpatient mortality coupled with prolonged hospital stay and increased cost of care. However, there is an encouraging downtrend in the mortality most likely because of improved clinical practice, cardiac screening and primary and secondary prevention strategies.

Background: In the busy world of cardiovascular medicine, abstracts may be the only part of a publication that clinicians read. Therefore, it is critical for abstracts to accurately reflect article content. The extended CONSORT (Consolidated Standards of Reporting Trials) Statement for Abstracts was developed to ensure high abstract quality. However, it is unknown how often adherence to CONSORT guidelines occurs among cardiovascular journals. Methods and Results: We searched MEDLINE for randomized controlled trials published in 3 major cardiovascular journals ( Circulation, Journal of the American College of Cardiology , and European Heart Journal ) from 2011 to 2017. Post hoc, interim, and cost-effective analyses of randomized controlled trials were excluded. Two independent investigators extracted the data using a prespecified data collection form and a third investigator adjudicated the data. The primary outcome was frequency of subcategory adherence to CONSORT guidelines. A total of 478 abstracts were included in the analysis. Approximately half of the abstracts (53%; 255/478; 95% CI, 49%–57%) identified the article as randomized in the title. All abstracts detailed the interventions for both study groups (100%) and 81% (95% CI, 78%–85%) reported trial registration. Methodological quality reporting was relatively low: 9% (45/478; 95% CI, 6%–12%) described participant eligibility criteria with settings for data collection, 43% (204/478; 95% CI, 39%–47%) reported details of blinding, and <1% (4/478; 95% CI, 0%–2%) reported allocation concealment. Approximately 60% (301/478; 95% CI, 59%–67%) of the included abstracts provided primary outcome results while 55% (262/478; 95% CI, 51%–60%) reported harms or adverse effects. Conclusions: There is a high prevalence of nonadherence to CONSORT guidelines among leading cardiovascular journals. Efforts by editors, authors, and reviewers should be made to increase adherence and promote transparent and unbiased presentation of study results.

Background: Poly (ADP-ribose) polymerases (PARPs) are a highly conserved family of enzymes whose main function is to preserve genomic integrity following DNA damage. PARP inhibitors (PARPi) are increasingly used in cancers with deficiencies in homologous recombination. Clinical trials in breast and ovarian cancers have led to several FDA approvals in recent years, and their use in clinical practice is continuing to rise. It is thus necessary to assess their adverse event (AE) profile. Method: Literature search was performed using Ovid MEDLINE, EMBASE, CENTRAL, and Scopus (inception through October 26, 2018). Eligible studies were phase 3, randomized, controlled trials that compared single agent PARPi to placebo or standard treatment. Number of patients treated and AEs reported were recorded. Observed incidence of AE was reported with 95% CI. Heterogeneity was evaluated using Cochran Q statistic and I2 statistics quantified the proportion of heterogeneity not due to chance. Results: Databases revealed 869 references. Of these, 6 were eligible: 2 in breast cancer (OlympiAD, EMBRACA) and 4 in ovarian cancer (NOVA, ARIEL3, SOLO1, SOLO2). PARPi included niraparib (NOVA), olaparib (OlympiAD, SOLO1, SOLO2), rucaparib (ARIEL3), and talazoparib (EMBRACA). Of 1,685 patients who received PARPi, incidence of any AE, regardless of grade, was 98.5% (95% CI, 97.2–99.2%). Common AEs were: nausea (incidence rate, 68.9% and 95% CI, 58.7%–77.5%), fatigue (56.3%, 45.3%–66.8%), anemia (46.3%, 37.2%–55.8%), vomiting (33.7%, 29.5%–38.3%), neutropenia (24.7%, 15.3%–37.4%), headache (23.9%, 19.9%–28.4%), and reduced appetite (21.7%, 19.3%–24.3%). Myeloid neoplasms were rare (1.2%, 0.7%–1.9%). Incidence of grade 3 or higher AE was 44.3% (30.2%–59.5%) and often related to myelosuppression, specifically anemia (24.7%, 15.3%–37.4%), neutropenia (10.7%, 6.6%–16.9%), and thrombocytopenia (5.0%, 1.7%–14.0%). Incidence of serious AE was 24.3% (19.4%–29.9%); dose interruption occurred in 53.3% (41.2%–65.0%) and dose reduction occurred in 39.2% (23.6%–57.4%). 10% (7.4%–13.6%) of patients discontinued therapy due to AE. Death due to AE was rare; less than 1% (0.4%, 0.2%–0.8%) in all trials. Conclusion: Myelosuppression and gastrointestinal toxicities were the most commonly reported AE in 6 randomized phase 3 trials of PARPi for breast and ovarian cancers. Therapy was rarely discontinued due to AE. It remains to be seen whether these results will be reflected in clinical practice.

263 Background: In non-metastatic CRPC with short PSA doubling time, APA or ENZA with ADT have shown to slow development of metastasis. We performed an indirect comparison of APA and ENZA clinical effectiveness (efficacy and side effects) using network meta-analysis. Methods: A search of Medline, Embase, Cochrane Library, and Cochrane Central Register of Controlled Trials was performed to identify relevant RCTs. Collected data included hazard ratio (HR) and confidence interval (CI) for primary outcome of median time to metastasis free survival (MFS) and secondary outcomes of median time to overall survival (OS), PSA progression, initiation of cytotoxic therapy and number of adverse events (AE) in each study arm. Risk for bias was assessed using the Cochrane Collaboration’s tool. We used a fixed effects model using Bayesian approach to generate pooled estimates. Results: Two randomized trials (n=2608) were analyzed. SPARTAN trial compared APA plus ADT to ADT alone and PROSPER compared ENZA plus ADT to ADT alone. Risk of bias was low. There were no statistically significant differences between APA and ENZA in MFS, OS, median time to PSA progression and initiation of cytotoxic therapy. The MFS endpoint hazard ratio (HR) was 0.97 (95% CI 0.73-1.28) for comparing the two drugs. APA had fewer reports of hypertension (HR 0.54, 95% CI 0.31–0.91) compared to enzalutamide. However, no significant differences were observed in other AEs including grade 3 or higher AE, serious AE, AE leading to death or trial discontinuation. Common AEs (nausea, diarrhea, fall, dizziness, arthralgia, weight loss) and AEs of special interests (mental impairment disorders, seizures) were also comparable between APA and ENZA. Conclusions: In non-metastatic CRPC with short PSA doubling time, APA and ENZA showed similar time to metastasis free survival. APA was associated with lower incidence of hypertension than ENZA; otherwise, side effect profile was similar. Given similar efficacy and risk profile demonstrated in this study, clinical decision making should depend on other factors such as cost and availability.