Antiplatelet Trialists Research Articles

Ninety-Day Stroke Recurrence in Minor Stroke: Systematic Review and Meta-Analysis of Trials and Observational Studies.

Risk of recurrence after minor ischemic stroke is usually reported with transient ischemic attack. No previous meta-analysis has focused on minor ischemic stroke alone. The objective was to evaluate the pooled proportion of 90-day stroke recurrence for minor ischemic stroke, defined as a National Institutes of Health Stroke Scale severity score of ≤5. Published papers found on PubMed from 2000 to January 12, 2021, reference lists of relevant articles, and experts in the field were involved in identifying relevant studies. Randomized controlled trials and observational studies describing minor stroke cohort with reported 90-day stroke recurrence were selected by 2 independent reviewers. Altogether 14 of 432 (3.2%) studies met inclusion criteria. Multilevel random-effects meta-analysis was performed. A total of 6 randomized controlled trials and 8 observational studies totaling 45 462 patients were included. The pooled 90-day stroke recurrence was 8.6% (95% CI, 6.5-10.7), reducing by 0.60% (95% CI, 0.09-1.1;P=0.02) with each subsequent year of publication. Recurrence was lowest in dual antiplatelet trial arms (6.3%, 95% CI, 4.5-8.0) when compared with non-dual antiplatelet trial arms (7.2%, 95% CI, 4.7-9.6) and observational studies 10.6% (95% CI, 7.0-14.2). Age, hypertension, diabetes, ischemic heart disease, or known atrial fibrillation had no significant association with outcome. Defining minor stroke with a lower National Institutes of Health Stroke Scale threshold made no difference - score ≤3: 8.6% (95% CI, 6.0-11.1), score ≤4: 8.4% (95% CI, 6.1-10.6), as did excluding studies with n<500%-7.3% (95% CI, 5.5-9.0). The risk of recurrence after minor ischemic stroke is declining over time but remains important.

COVID-19 and the Cardiovascular System: Requiem for a Medical Minotaur.

COVID-19 and the Cardiovascular System: Requiem for a Medical Minotaur.

Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy

Anti-vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown. To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported. Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53; range, 0 [worst] to 100 [best]) without CI-DME. Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss. Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years. Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P < .001). The mean (SD) change in visual acuity from baseline to 4 years was -2.7 (6.5) letters with aflibercept and -2.4 (5.8) letters with sham (adjusted mean difference, -0.5 letters [97.5% CI, -2.3 to 1.3]; P = .52). Antiplatelet Trialists' Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants. Among patients with NPDR but without CI-DME at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME. ClinicalTrials.gov Identifier: NCT02634333.

Safety and Outcomes of Intravitreal Aflibercept in Diabetic Macular Edema - A Systematic Review.

Recent evidence on the role of vascular endothelial growth factor (VEGF) in the pathogenesis of ischemia and microvascular hyperpermeability leading to macular edema has brought anti-VEGF intravitreal therapy into the limelight. We performed a systematic literature review focusing on the outcomes and safety of the intravitreal use of aflibercept in diabetic macular edema. The studies documented cases with at least three consecutive intravitreal injections of aflibercept (IVA) repeated monthly with a follow-up period of at least one year. The outcomes were evaluated in terms of reported functional and anatomical improvement of the macula, as reflected by changes in visual acuity and macular thickness measured by Optical Coherence Tomography (OCT). In addition, for safety assessment, all reported local and general adverse effects were analyzed. All studies showed an overall significant anatomical and functional improvement. In patients with the 5 IVA monthly at the beginning of the therapy, the visual gain at 52 weeks varied widely between 5 and 18.9 EDRS letters, with a mean value of 9.48 letters. The higher gain was obtained in treatment naïve patients, with worse VA and increased CST at baseline. The lower gain was obtained in patients previously treated with anti- VEGF. Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events were not statistically different between the aflibercept group and the laser group. Intravitreal aflibercept therapy provides significant improvement in visual acuity and a good safety profile. Randomized studies are needed to document the optimal frequency of intravitreal injections for optimal treatment.

Cardiovascular safety of celecoxib in rheumatoid arthritis and osteoarthritis patients: A systematic review and meta-analysis.

To assess the cardiovascular safety of celecoxib compared to non-selective non-steroid anti-inflammatory drugs or placebo. We included randomized controlled trials of oral celecoxib compared with a non-selective NSAID or placebo in rheumatoid arthritis and osteoarthritis patients. We conducted searches in EMBASE, Cochrane CENTRAL, MEDLINE, China National Knowledge Infrastructure, VIP, Wanfang, and Chinese Biomedical Literature Database. Study selection and data extraction were done by two authors independently. The risk of bias was assessed using Cochrane's risk-of-bias Tool for Randomized Trials. The effect size was presented as a risk ratio with their 95% confidence interval. Until July 22nd, 2021, our search identified 6279 records from which, after exclusions, 21 trials were included in the meta-analysis. The overall pooled risk ratio for Antiplatelet Trialists Collaboration cardiovascular events for celecoxib compared with any non-selective non-steroid anti-inflammatory drugs was 0.89 (95% confidence interval: 0.80-1.00). The pooled risk ratio for all-cause mortality for celecoxib compared with non-selective non-steroid anti-inflammatory drugs was 0.81 (95% confidence interval: 0.66-0.98). The cardiovascular mortality rate of celecoxib was lower than non-selective non-steroid anti-inflammatory drugs (risk ratio: 0.75, 95% confidence interval: 0.57-0.99). There was no significant difference between celecoxib and non-selective non-steroid anti-inflammatory drugs or placebo in the risk of other cardiovascular events. Celecoxib is relatively safe in rheumatoid arthritis and osteoarthritis patients, independent of dose or duration. But it remains uncertain whether this would remain the same in patients treated with aspirin and patients with established cardiovascular diseases.

Sex-based outcomes in contemporary antiplatelet therapy trials

Balancing ischaemic and bleeding risks in high-risk populations undergoing percutaneous coronary interventions has become an everyday dilemma for clinicians. It is particularly difficult to make decisions concerning combinations and duration...

Strengthening the interpretability of clinical trial results by assessing the effect of informative censoring on the primary estimand in PRECISION.

The ICH E9(R1) addendum states that the strategy to account for intercurrent events should be included when defining an estimand, the treatment effect to be estimated based on the study objective. The estimator used to assess the treatment effect needs to be aligned with the estimand that accounted for intercurrent events. Regardless of the strategy, missing data resulting from patient premature withdrawal could undermine the robustness of the study results. Informative censoring due to dropouts in an events-based study is one such example. Sensitivity analyses using imputation methods are useful to examine the uncertainty due to informative censoring and address the robustness and strength of the study results. We assessed the effect of premature patient withdrawal in the PRECISION study, a randomized non-inferiority clinical trial of patients with chronic arthritic pain that compared the cardiovascular safety of three nonsteroidal anti-inflammatory drugs-based treatment policies or paradigms. The protocol-defined use of concomitant or rescue medications was permitted since changes in pain medications due to insufficient analgesia were expected in patients in this long-term study. Anticipating that premature study discontinuations could potentially lead to informative censoring, a supplementary analysis was pre-specified in which censored outcomes due to the premature study discontinuation were imputed based on adverse events that were clinically associated with the primary endpoint (cardiovascular outcome based on the Antiplatelet Trialists Collaboration composite endpoint). Furthermore, tipping point analyses were conducted to test the robustness of the primary analysis results by assuming data censored not at random. The level of increase at which the primary study conclusion would change was estimated. For the analysis of time to first primary endpoint event through 30 months, 4065 out of the 24,081 enrolled patients were lost to follow-up, withdrew consent, or were no longer willing to participate in the study. These withdrawals occurred gradually and resulted in a cumulative total of 5893 censored patient-years of observation (10.2%). The rate of discontinuation and the baseline characteristics of the discontinued patients were similar across the three treatment groups. The non-inferiority conclusion from the primary analysis was confirmed in the supplementary analysis incorporating relevant adverse events. Furthermore, tipping point analyses demonstrated that in order to lose non-inferiority in the primary analysis, the risk of primary endpoint events during the censored observation time would have to increase by more than 2.7-fold in the celecoxib group while remaining constant in the other nonsteroidal anti-inflammatory drugs groups, demonstrating that the scenarios where the study results are invalid appear not plausible. Supplementary and sensitivity analyses presented to address informative censoring in PRECISION helped to further interpret and strengthen the study results.

Meta-Analysis of Intraocular Bleeding With Dual Antiplatelet Therapy Using P2Y12 Inhibitors Prasugrel or Ticagrelor

Intraocular bleeding is a devastating clinical event due to its potentially blinding nature. It is not known if determine if dual antiplatelet therapy using aspirin and potent P2Y12 inhibitors increases this risk. We searched MEDLINE and ClinicalTrials.gov for randomized controlled trials that were phase III, randomly assigned patients to dual antiplatelet therapy with either aspirin and a potent P2Y12 inhibitor or aspirin and clopidogrel, had follow-up of 6 months, and at least 200 patients. Corresponding authors were contacted for intraocular bleeding data. Inverse-variance, weighted, fixed-effects meta-analysis was undertaken, with random-effects meta-analysis performed as a sensitivity analysis. Four trials enrolling 42,850 patients were included. The median follow-up ranged from 12 to 14 months. There was overall low risk of bias. Pooled analysis demonstrated no statistically significant increase in the risk of intraocular bleeding with dual antiplatelet therapy using potent P2Y12 inhibitors compared with clopidogrel (risk ratio 0.89, 95% confidence interval 0.58 to 1.36). There was no significant heterogeneity observed across trials (I2 statistic 0%, p = 0.98). The use of random-effects meta-analysis did not change the effect estimate or confidence intervals, and the results appeared similar when stratified by potent P2Y12 inhibitor (p = 0.97). In conclusion, this collaborative meta-analysis of dual antiplatelet trials does not suggest that the risk of intraocular bleeding is increased with the use of potent P2Y12 inhibitors compared with clopidogrel. Our results suggest that these potent P2Y12 inhibitors may continue to be used cautiously where indicated as part of dual antiplatelet therapy, even in those at high risk of spontaneous intraocular bleeding.

Replication of the TRITON-TIMI Antiplatelet Trial in Healthcare Claims Data

Replication of the TRITON-TIMI Antiplatelet Trial in Healthcare Claims Data

Replication of the PLATO Antiplatelet Trial in Healthcare Claims Data

Replication of the PLATO Antiplatelet Trial in Healthcare Claims Data

Intravitreal Combined Aflibercept + Anti–Platelet-Derived Growth Factor Receptor β for Neovascular Age-Related Macular Degeneration: Results of the Phase 2 CAPELLA Trial

To compare the efficacy and safety of intravitreal aflibercept+ anti-platelet-derived growth factor receptor β (PDGFRβ) combination with intravitreal aflibercept injection (IAI) monotherapy in patients with treatment-naïve neovascular age-related macular degeneration (nAMD). Phase 2, randomized, double-masked study. A total of 505 patients (eyes) with nAMD. Patients were randomized 1:2:2 to low-dose combination intravitreal anti-PDGFRβ 1 mg and aflibercept 2 mg (LD combo), high-dose combination intravitreal anti-PDGFRβ 3 mg and aflibercept 2 mg (HD combo), or IAI alone every 4 weeks through week 12. At week 12, patients in the HD combo and IAI groups were re-randomized to continue as assigned or switch to HD combo → IAI or IAI → HD combo and dosed every 4 weeks through week 28. During weeks 28 to 52, patients received treatment as needed per prespecified criteria. This report presents efficacy through week 28 and safety through week52. Mean best-corrected visual acuity (BCVA) change from baseline at week 12(primary end point). At week 12, mean BCVA gains from baseline were 5.8, 5.8, and 7.5 letters with LD combo, HD combo, and IAI, respectively (P= 0.21 for LD combo and P= 0.10 for HD combo vs. IAI). The corresponding proportions of eyes that gained ≥15 letters were 12%, 19%, and 22%, respectively. Mean reductions in central retinal thickness from baseline were 126.1, 127.1, and 126.9 μm, respectively. Proportions of eyes with complete resolution of fluid from baseline were 35%, 24%, and 42%, respectively. Vision and anatomic outcomes at week 28 were consistent with the week 12 results. Through week 52, the incidence of intraocular inflammation was 1.0%, 7.5%, 2.1%, 2.1%, and 0%, respectively. The incidence of Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events was 1.9%, 0.9%, 1.1%, 2.1%, and 1.9%, respectively. Intravitreal aflibercept+ anti-PDGFRβ did not improve BCVA over IAI alone. Anatomic outcomesevaluating complete fluid resolution favored IAI. Adverse events were consistent with the reported IAIsafety profile, except for a higher frequency of intraocular inflammation in the HD combo group.

Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity

Intravitreous injections of antivascular endothelial growth factor agents are effective for treating diabetic macular edema (DME) involving the center of the macula (center-involved DME [CI-DME]) with visual acuity impairment (20/32 or worse). The best approach to treating patients with CI-DME and good visual acuity (20/25 or better) is unknown. To compare vision loss at 2 years among eyes initially managed with aflibercept, laser photocoagulation, or observation. Randomized clinical trial conducted at 91 US and Canadian sites among 702 adults with type 1 or type 2 diabetes. Participants had 1 study eye with CI-DME and visual acuity of 20/25 or better. The first participant was randomized on November 8, 2013, and the final date of follow-up was September 11, 2018. Eyes were randomly assigned to 2.0 mg of intravitreous aflibercept (n = 226) as frequently as every 4 weeks, focal/grid laser photocoagulation (n = 240), or observation (n = 236). Aflibercept was required for eyes in the laser photocoagulation or observation groups that had decreased visual acuity from baseline by at least 10 letters (≥ 2 lines on an eye chart) at any visit or by 5 to 9 letters (1-2 lines) at 2 consecutive visits. The primary outcome was at least a 5-letter visual acuity decrease from baseline at 2 years. Antiplatelet Trialists' Collaboration adverse events (defined as myocardial infarction, stroke, or vascular or unknown death) were reported. Among 702 randomized participants (mean age, 59 years; 38% female [n=264]), 625 of 681 (92% excluding deaths) completed the 2-year visit. For eyes with visual acuity that decreased from baseline, aflibercept was initiated in 25% (60/240) and 34% (80/236) in the laser photocoagulation and observation groups, respectively. At 2 years, the percentage of eyes with at least a 5-letter visual acuity decrease was 16% (33/205), 17% (36/212), and 19% (39/208) in the aflibercept, laser photocoagulation, and observation groups, respectively (aflibercept vs laser photocoagulation risk difference, -2% [95% CI, -9% to 5%]; relative risk, 0.88 [95% CI, 0.57-1.35; P = .79]; aflibercept vs observation risk difference, -3% [95% CI, -11% to 4%]; relative risk, 0.83 [95% CI, 0.55-1.27; P = .79]; laser photocoagulation vs observation risk difference, -1% [95% CI, -9% to 6%]; relative risk, 0.95 [95% CI, 0.64-1.41; P = .79]). Antiplatelet Trialists' Collaboration vascular events occurred in 15 (7%), 13 (5%), and 8 (3%) participants in the aflibercept, laser photocoagulation, and observation groups. Among eyes with CI-DME and good visual acuity, there was no significant difference in vision loss at 2 years whether eyes were initially managed with aflibercept or with laser photocoagulation or observation and given aflibercept only if visual acuity worsened. Observation without treatment unless visual acuity worsens may be a reasonable strategy for CI-DME. ClinicalTrials.gov Identifier: NCT01909791.

Randomized Trial of Treat and Extend Ranibizumab With and Without Navigated Laser Versus Monthly Dosing for Diabetic Macular Edema: TREX-DME 2-Year Outcomes

To prospectively evaluate a treat and extend algorithm of ranibizumab with and without navigated laser to monthly dosing for center-involving diabetic macular edema. This was a multicenter, randomized, clinical trial. One hundred fifty eyes were randomized into 3 cohorts: monthly (n= 30), treat and extend without laser photocoagulation (TREX; n= 60), and treat and extend with angiography-guided laser photocoagulation (GILA; n= 60). Monthly cohort eyes received ranibizumab 0.3mg every 4weeks. TREX and GILA cohort eyes received 4monthly injections of ranibizumab 0.3mg followed by a treat and extend dosing strategy. GILA cohort eyes also received navigated focal laser at month 1 and again every 3months as needed. The primary outcomes included the mean change in best-corrected visual acuity and central retinal thickness and the number of injections from baseline to 2 years. At 2 years, mean best-corrected visual acuity and central retinal thickness improved by 7.5, 9.6, and 9.0 letters (P= .75) and 139, 140, and 175μm (P= .09), in the monthly, TREX, and GILA cohorts, respectively. The mean number of injections was significantly reduced in both the TREX (18.9) and GILA (17.5) cohorts compared with the monthly cohort (24.7, P < .001). Between the TREX and GILA cohorts, there was no significant difference in the mean treatment interval, mean maximal treatment interval, or percentage of eyes extended to 12weeks. The total 2-year incidence of Anti-Platelet Trialists' Collaboration events was 6.7%. The treat and extend algorithm of ranibizumab in the TREX-DME trial resulted in significantly fewer injections and yielded visual and anatomic gains comparable to monthly dosing at 2 years.

Abstract 37: Secondary Stroke Prevention With Aspirin and Clopidogrel in CYP2C19 *17 Carriers Increases Risk of Major Non-CNS Bleeding

Combination aspirin and clopidogrel reduces risk of recurrent ischemic stroke, but was also associated with risk of non-central nervous system (CNS) major bleeding in the Platelet-Oriented Inhibition in New TIA or minor stroke clinical trial. The loss-of-function CYP2C19*2 allele potentially reduces clopidogrel efficacy, while the gain-of-function CYP2C19*17 allele may increase bleeding risk. The clinical application of these alleles is unclear. SNP genotyping of CYP2C19*2 and CYP2C19*17 are available in the Secondary Prevention of Small Subcortical Strokes clinical trial, a 2x2 factorial study in patients with lacunar infarcts where one arm tested the efficacy of secondary stroke prevention with aspirin plus clopidogrel versus aspirin alone. We hypothesized that patients carrying CYP2C19*2 would have more clopidogrel failure events (defined as a composite of ischemic stroke, transient ischemic attack, and cognitive decline), while patients carrying at least one CYP2C19*17 allele, would have more major bleeding, including sub-analysis of CNS and non-CNS major bleeding. The associations of CYP2C19*2 with treatment failure and CYP2C19*17 with major bleeding were assessed through logistic regression, adjusting for age, gender, race, and excluding CYP2C19*2/*17 carriers. The mean age of the cohort (n=522) was 62 (62% male). There were no significant differences in treatment failure events between *2 carriers and *2 non-carriers (Odds ratio (OR) [95% confidence interval (CI)] = 1.60 [0.66-3.87], p-value=0.29), adjusting for *17. Patients with a *17 allele had a significantly higher odds of a non-CNS hemorrhage (OR [95% CI] =2.50 [1.03-6.09], p-value=0.043), and a trend for significance after adjusting for *2, p-value=0.06. Only two CNS hemorrhages occurred in the total cohort; both occurred in normal CYP2C19 metabolizers. Although limited by sample size, the study suggests that CYP2C19 carrier status may contribute to non-CNS major bleeding risks seen in dual antiplatelet therapy secondary stroke prevention trials. Further studies are needed to confirm whether the presence of CYP2C19*17 or absence of *2 increases the risk of bleeding complications, which could have implications for treatment decisions in a precision medicine approach.

Tegaserod Cardiovascular Safety Analysis: Importance of a Methodologic Approach to Drug Safety Analysis

Introduction: In 2007, tegaserod was voluntarily withdrawn from the market due to an imbalance in cardiovascular adverse events (CVAEs; including myocardial infarction, stroke, unstable angina, and transient ischemic attacks) reported by investigators among subjects in 29 placebo-controlled, doubleblind trials across many gastrointestinal indications. In these trials, 11,614 subjects received tegaserod and 7031 received placebo. Initial analysis before complete primary source documents were available, identified 13 CVAEs in the tegaserod group and 1 in the placebo group. We report on the finalized independent blinded second adjudicated analysis performed by the Duke Clinical Research Institute (DCRI) after obtaining full source documentation for adjudication of CV events. Methods: The blinded adjudication by the DCRI of the CVAEs had the unique advantage compared to the previous reviews of using rigorous search methodologies to identify potential CVAEs, broadened potential definitions, and access to all available source materials for the identified potential cases. It used FDA-requested Antiplatelet Trialists’ Collaboration (APTC) classifications (vascular death or non-fatal heart attack or stroke), which are similar to the major adverse cardiovascular events (MACE) classification (CV death, non-fatal MI or stroke). In addition, an exploratory post hoc analysis of females with ≤1 CV risk factor (hypertension, smoking, diabetes, hyperlipidemia, obesity, and age ≥55 years), was performed to evaluate CVAEs in a low cardiovascular risk population. Results: Overall CVAEs (7 events in the tegaserod cohort and 1 in the placebo group, P=NS) and using APTC/MACE definitions (4 vs 0, respectively, P=NS) were adjudicated (Table 1). In the post hoc analysis excluding participants with >1 CV risk factor, there were 7804 participants in the tegaserod group and 4687 in the placebo group; there was only 1 CV event in the tegaserod group and none when APTC/MACE standards were applied. Conclusion: Since 2007, 2 epidemiologic studies have been published that include data from >54,000 patients who received tegaserod (Loughlin, et al. J Cardiovasc Pharmacol Ther.2010;15:151-157; Anderson, et al. J Cardiovasc Pharmacol Ther. 2009;1:170-175). Each failed to identify an increased risk for CV events. Based on a thorough analysis of the tegaserod clinical trial database using rigorous definitions and access to source documents and epidemiologic data, tegaserod appears to have a low risk of CV events.462 Figure 1. Results from Duke Adjudication and Post Hoc Low Cardiovascular Risk Population Analysis

Systemic Safety in Ranibizumab-Treated Patients with Neovascular Age-Related Macular Degeneration: A Patient-Level Pooled Analysis

This study evaluated the cardiovascular/cerebrovascular safety profile of ranibizumab 0.5 mg versus sham ± verteporfin in patients with neovascular age-related macular degeneration (nAMD). In addition, comparisons of ranibizumab 0.3 mg with sham and ranibizumab 0.5 mg to 0.3 mg were performed. Intravitreal anti-vascular endothelial growth factor (VEGF) agents carry potential increased systemic risks, including cardiovascular or cerebrovascular events. Pooled safety analyses allow better interpretation of safety outcomes seen in individual clinical trials, especially for less common events. To our knowledge, this is the largest patient-level pooled analysis of patients with nAMD treated with ranibizumab. Patient-level pooled analysis of data from 7 Genentech- and Novartis-sponsored phase II, III, and IV studies in nAMD that were completed by December 31, 2013. Pairwise comparisons (primary comparison: ranibizumab 0.5 mg [globally approved dose for nAMD] vs. sham or verteporfin) were performed using Cox proportional hazard regression (hazard ratios [HRs], 95% confidence intervals [CIs]) and rates per 100 patient-years. Standardized Medical Dictionary for Regulatory Activities queries (SMQs) and extended searches were used to identify relevant safety endpoints, including arterial thromboembolic events (ATEs), myocardial infarction (MI), stroke or transient ischemic attack (TIA), stroke (excluding TIA), vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). The HRs (95% CIs) for the primary comparison of ranibizumab 0.5 mg (n=480) versus sham or verteporfin (n=462) were 1.16 (0.72-1.88) for ATE, 1.33 (0.59-2.97) for MI, 1.43 (0.54-3.77) for stroke excluding TIA, 1.25 (0.61-2.55) for stroke or TIA, 0.57 (0.18-1.78) for vascular death, and 1.12 (0.64-1.98) for APTC events. Hazard ratio 95% CIs included 1, indicating no significant treatment differences, for all endpoints for comparison of ranibizumab 0.5 mg versus sham or verteporfin. The rates of cardiovascular and cerebrovascular events were low in these patients with nAMD and not clinically meaningfully different for patients treated with ranibizumab 0.5 mg versus sham or verteporfin, which supports the favorable benefit-risk profile of ranibizumab in the patient population with nAMD. Pooling these studies allows an analysis with higher power and precision compared with individual study analyses.

Clinical implementation of rapid CYP2C19 genotyping to guide antiplatelet therapy after percutaneous coronary intervention

BackgroundThe CYP2C19 nonfunctional genotype reduces clopidogrel effectiveness after percutaneous coronary intervention (PCI). Following clinical implementation of CYP2C19 genotyping at University Florida (UF) Health Shands Hospital in 2012, where genotype results are available approximately 3 days after PCI, testing was expanded to UF Health Jacksonville in 2016 utilizing a rapid genotyping approach. We describe metrics with this latter implementation.MethodsPatients at UF Health Jacksonville undergoing left heart catheterization with intent to undergo PCI were targeted for genotyping using the Spartan RX™ system. Testing metrics and provider acceptance of testing and response to genotype results were examined, as was antiplatelet therapy over the 6 months following genotyping.ResultsIn the first year, 931 patients, including 392/505 (78%) total patients undergoing PCI, were genotyped. The median genotype test turnaround time was 96 min. Genotype results were available for 388 (99%) PCI patients prior to discharge. Of 336 genotyped PCI patients alive at discharge and not enrolled in an antiplatelet therapy trial, 1/6 (17%) poor metabolizers (PMs, with two nonfunctional alleles), 38/93 (41%) intermediate metabolizers (IMs, with one nonfunctional allele), and 119/237 (50%) patients without a nonfunctional allele were prescribed clopidogrel (p = 0.110). Clopidogrel use was higher among non-ACS versus ACS patients (78.6% vs. 42.2%, p < 0.001). Six months later, among patients with follow-up data, clopidogrel was prescribed in 0/4 (0%) PMs, 33/65 (51%) IMs, and 115/182 (63%) patients without a nonfunctional allele (p = 0.008 across groups; p = 0.020 for PMs versus those without a nonfunctional allele).ConclusionThese data demonstrate that rapid genotyping is clinically feasible at a high volume cardiac catheterization facility and allows informed chronic antiplatelet prescribing, with lower clopidogrel use in PMs at 6 months.Trial registration ClinicalTrials.gov Identifier: NCT02724319; registered March 31, 2016; https://www.clinicaltrials.gov/ct2/show/NCT02724319?term=angiolillo&rank=7

The Systemic Safety of Ranibizumab in Patients 85 Years and Older with Neovascular Age-Related Macular Degeneration

Ranibizumab safety is well established for treatment of neovascular age-related macular degeneration (nAMD), but less is known about the risk of systemic serious adverse events (SAEs), specifically among patients with heightened baseline risk due to age (≥85 years). This analysis examines whether patients ≥85 years of age versus those <85 years experience an increased risk of key systemic SAEs during intravitreal ranibizumab treatment for nAMD. Retrospective, pooled analysis of safety data from 5 phase III/IIIb multicenter randomized clinical trials in patients with nAMD: ANCHOR, MARINA, PIER, SAILOR, and HARBOR. Patients with nAMD receiving ranibizumab (n= 4347) or control (sham/verteporfin photodynamic therapy, n= 441) treatment included in the safety-evaluable set of the 5 trials. The incidence of nonocular SAEs was analyzed stratified by age (<85 years [n= 3795] vs ≥85 years [n= 993]), treatment (control, ranibizumab 0.3 mg, ranibizumab 0.5 mg, ranibizumab 2.0 mg), and injection frequency (monthly, as needed [PRN]). Incidence of key systemic SAEs, defined as total nonocular SAEs, deaths, cardiovascular events, cerebrovascular (CBV) events, and Antiplatelet Trialists' Collaboration events. The MARINA and ANCHOR trials had greater rates of key SAEs for patients ≥85 years versus those <85 years. Ranibizumab exposure did not increase the risk of most SAEs in elderly patients; for CBV events and death, the effect of ranibizumab versus control treatment for age ≥85 years was not interpretable due to small number of events (CBV: n= 2, 2, 5 for control, ranibizumab 0.3 mg, and ranibizumab 0.5 mg, respectively; death: n= 2, 4, 5, respectively). Across all 5 trials, an increased risk was found for age ≥85 years versus <85 years for the marketed dose of ranibizumab 0.5 mg. In the HARBOR trial, increased rates of key SAEs (excluding total nonocular SAEs) for age ≥85 years versus <85 years were observed with monthly dosing but not with PRN dosing; event rates were similar for 2.0 mg versus 0.5 mg. Consistent with general trends, the risk of key systemic SAEs was associated with age ≥85 years versus <85 years, but not with ranibizumab drug exposure. The difference between monthly versus PRN was inconclusive. There was no evidence of a dose effect. Interpretation of this retrospective analysis is limited because it was not prospectively powered for statistically definitive conclusions.

Ten years of migalastat treatment in a patient with Fabry disease: A case report

To determine efficacy and safety of intravitreal aflibercept in patients with neovascular age-related macular degeneration (AMD) during a second year of variable dosing after a first-year fixed-dosing period.Two randomized, double-masked, active-controlled, phase 3 trials.Two thousand four hundred fifty-seven patients with neovascular AMD.From baseline to week 52, patients received 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), 2 mg aflibercept every 4 weeks (2q4), 0.5 mg aflibercept every 4 weeks (0.5q4), or 2 mg aflibercept every 8 weeks (2q8) after 3 monthly injections. During weeks 52 through 96, patients received their original dosing assignment using an as-needed regimen with defined retreatment criteria and mandatory dosing at least every 12 weeks.Proportion of eyes at week 96 that maintained best-corrected visual acuity (BCVA; lost <15 letters from baseline); change from baseline in BCVA.Proportions of eyes maintaining BCVA across treatments were 94.4% to 96.1% at week 52 and 91.5% to 92.4% at week 96. Mean BCVA gains were 8.3 to 9.3 letters at week 52 and 6.6 to 7.9 letters at week 96. Proportions of eyes without retinal fluid decreased from week 52 (60.3% to 72.4%) to week 96 (44.6% to 54.4%), and more 2q4 eyes were without fluid at weeks 52 and 96 than Rq4 eyes (difference of 10.4% [95% confidence interval {CI}, 4.9–15.9] and 9.0% [95% CI, 3.0–15.1]). Patients received on average 16.5, 16.0, 16.2, and 11.2 injections over 96 weeks and 4.7, 4.1, 4.6, and 4.2 injections during weeks 52 through 96 in the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively. The number of injections during weeks 52 through 96 was lower in the 2q4 and 2q8 groups versus the Rq4 group (differences of −0.64 [95% CI, −0.89 to −0.40] and −0.55 [95% CI, −0.79 to −0.30]; P < 0.0001, post hoc analysis). Incidences of Antiplatelet Trialists' Collaboration–defined arterial thromboembolic events were similar across groups (2.4% to 3.8%) from baseline to week 96.All aflibercept and ranibizumab groups were equally effective in improving BCVA and preventing BCVA loss at 96 weeks. The 2q8 aflibercept group was similar to ranibizumab in visual acuity outcomes during 96 weeks, but with an average of 5 fewer injections. Small losses at 96 weeks in the visual and anatomic gains seen at 52 weeks in all arms were in the range of losses commonly observed with variable dosing.

Aspirin Monotherapy Should Not Be Recommended for Cardioprotection in Patients With Symptomatic Peripheral Artery Disease.

Patients with peripheral artery disease (PAD), regardless of disease stage, are at a marked increased risk for systemic cardiovascular events. Therefore, cardiovascular risk reduction is central to the management of these patients. Treatment of hypertension, use of statins, and strategies for smoking cessation are all well-established, evidence-based interventions in the patient with PAD. In contrast, the rationale for use of antiplatelet agents has been more controversial. The 2016 American Heart Association/American College of Cardiology guideline for management of the patient with PAD indicates, “Antiplatelet therapy with aspirin alone (range, 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI [myocardial infarction], stroke and vascular death in patients with symptomatic PAD.”1 Per the guideline, this class I recommendation (strong) was supported by level A evidence (high quality from more than 1 randomized controlled trial or meta-analyses of randomized controlled trials). The primary evidence supporting the recommendation was the work of the Antiplatelet Trialists’ Collaboration (ATC).2 The ATC found a 22% reduction in vascular events associated with antiplatelet therapy compared with …