Contemporary Predictors of Major Adverse Cardiovascular Events Following Percutaneous Coronary Intervention: A Nationally Representative US Sample.

Background: Patient outcomes after percutaneous coronary intervention (PCI) have improved over the last 30 years due to better techniques, therapies, and care processes. This study evaluated contemporary predictors of post-PCI major adverse cardiovascular events (MACE) and summarized risk in a parsimonious risk prediction model. Methods: The Cardiovascular Patient-Level Analytical Platform (CLiPPeR) is an observational dataset of baseline variables and longitudinal outcomes from the American College of Cardiology's CathPCI Registry® and national claims data. Cox regression was used to evaluate 2-6 years of patient follow-up (mean: 2.56 years), ending in December 2017, after index PCI between 2012 and 2015 (N = 1,450,787), to examine clinical and procedural predictors of MACE (first myocardial infarction, stroke, repeat PCI, coronary artery bypass grafting, and mortality). Cox analyses of post-PCI MACE were landmarked 28 days after index PCI. Results: Overall, 12.4% (n = 179,849) experienced MACE. All variables predicted MACE, with cardiogenic shock, cardiac arrest, four diseased coronary vessels, and chronic kidney disease having hazard ratios (HRs) ≥ 1.50. Other major predictors of MACE were in-hospital stroke, three-vessel disease, anemia, heart failure, and STEMI presentation. The index revascularization and discharge prescription of aspirin, P2Y12 inhibitor, and lipid-lowering medication had HR ≤ 0.67. The primary Cox model had c-statistic c = 0.761 for MACE versus c = 0.701 for the parsimonious model and c = 0.752 for the parsimonious model plus treatment variables. Conclusions: In a nationally representative US sample of post-PCI patients, predictors of longitudinal MACE risk were identified, and a parsimonious model efficiently encapsulated them. These findings may aid in assessing care processes to further improve care post-PCI outcomes.

Hospitalization for Myocardial Infarction with Ticagrelor or Clopidogrel in Patients with Acute Coronary Syndrome: An On-Treatment Comparative Effectiveness Analysis.

INTRODUCTION: Prescribing patterns and suboptimal adherence present methodological challenges for real-world head-to-head comparisons of ticagrelor and clopidogrel in intent-to-treat studies. The aim of this study was to compare ticagrelor and clopidogrel in an on-treatment population. METHODS: This retrospective cohort study used the Optum™ Clinformatics™ database to identify patients with acute coronary syndrome (ACS) discharged on ticagrelor or clopidogrel between January 1, 2012 and September 30, 2019. The primary end point was hospitalization for myocardial infarction (MI); the secondary end point was hospitalization for major bleeding. The ticagrelor and clopidogrel cohorts were balanced by propensity score matching (PSM) 1:3 for demographic and clinical characteristics. Outcomes were ascertained from day 31 until day 365 or end of follow-up. RESULTS: Of 339,387 patients with ACS, 14,110 ticagrelor- and 57,482 clopidogrel-treated patients met the study criteria. After PSM, 13,373 ticagrelor- and 29,656 clopidogrel-treated patients provided 4945 and 13,895 patient-years of data, respectively, for the primary end point. Hospitalization for MI was significantly lower in the ticagrelor compared to the clopidogrel cohort (2.22 vs. 3.52 per 100 patient-years; 36.8% relative risk reduction [RRR]; P < 0.0001). Hospitalization for major bleeding was similar in the ticagrelor and clopidogrel cohorts (2.04 vs. 2.06 per 100 patient-years; 1.1% RRR, P = 0.9214). CONCLUSIONS: In this real-world on-treatment analysis, hospitalization for MI was significantly lower with ticagrelor compared to clopidogrel, with similar rates of hospitalization for major bleeding. Study findings underscore the importance of being on the appropriate guideline-recommended therapy and support the use of ticagrelor over clopidogrel.

New Heart Failure After Myocardial Infarction (From the National Cardiovascular Data Registries [NCDR] Linked With All-Payer Claims).

Heart failure (HF) is common in patients presenting with acute myocardial infarction (MI), but incidence and predictors of new onset HF after hospitalization for MI are less well characterized. We evaluated patients hospitalized for acute MI without preceding or concurrent HF in the National Cardiovascular Data Registry (NCDR) CathPCI and Chest Pain-MI registries linked with claims data between April 2010 and March 2017. Cumulative incidence and independent predictors of HF after discharge were determined, and a simplified risk score was developed to predict incident HF following MI. In 337,274 patients with acute MI and no history of HF, 8.0% developed incident HF within 1 year after discharge and 18.8% developed HF within 5 years. Significant predictors of HF after MI included advanced chronic kidney disease (CKD) (HR 2.34, 95% confidence interval [CI] 2.23-2.46 for Stage IV vs Stage I, and HR 2.18, 95% CI 2.07-2.29 for Stage V vs. Stage I), recurrent MI following index MI (HR 2.24, 95% CI 2.19-2.28), African-American race (HR 1.44, 95% CI 1.40-1.48), and diabetes (HR 1.39, 95% CI 1.37-1.42). A risk score of 8 variables predicted HF with modest discrimination (optimism-corrected c-statistic 0.64) and good calibration. In conclusion, nearly 1 in 5 patients in a large nationally representative cohort without preceding or concurrent heart failure at time of MI developed incident HF within 5 years after discharge. Advanced CKD and recurrent MI were the strongest predictors of future HF. Increased recognition of specific risk factors for HF may help inform care strategies following MI.

Assessment of The High risk and unmEt Need in patients with CAD and type 2 diabetes (ATHENA): US healthcare resource use, cost, and burden of illness in a commercially insured population.

AIMS: THEMIS (NCT01991795) demonstrated cardioprotective benefits of ticagrelor plus acetylsalicylic acid (ASA) compared with placebo plus ASA in patients with type 2 diabetes (T2D), stable coronary artery disease (CAD) and no history of myocardial infarction (MI) or stroke. To complement these findings, we assessed clinical outcomes and healthcare costs in commercially insured US patients similar to those in THEMIS. METHODS: This retrospective, observational study used data from Optum. The T2D-CAD cohort (n = 154,369) included patients (≥50 years old) either with high cardiovascular risk or taking a P2Y12 inhibitor. The THEMIS-like cohort (n = 126,938) comprised patients (≥50 years old) at high cardiovascular risk; the THEMIS-PCI-like cohort comprised a subset of these patients with prior percutaneous coronary intervention (PCI) (n = 18,394). RESULTS: Mean follow-up was 2.4-2.5 years. Incidence rates of the composite outcome (death, MI, and stroke) were 6.56 (95% CI 6.50-6.63), 6.21 (6.14-6.28), and 5.57 (5.39-5.74) per 100 person-years, and annualized healthcare costs per patient were US$15,848, US$16,044, and US$20,934 for the T2D-CAD, THEMIS-like, and THEMIS-PCI-like cohorts, respectively. CONCLUSIONS: Commercially insured patients similar to those in THEMIS had high cardiovascular event rates and healthcare costs, highlighting a need for improved preventive strategies.

Disease Burden Following Non-Cardioembolic Minor Ischemic Stroke or High-Risk TIA: A GWTG-Stroke Study.

BACKGROUND: Limited real-world data are available on outcomes following non-cardioembolic minor ischemic stroke (IS) or high-risk transient ischemic attack (TIA), particularly in the United States (US). We examined outcomes and Medicare payments following any severity IS or TIA as well as the subgroup with minor IS or high-risk TIA. METHODS: Medicare beneficiaries >65 years were identified using US nationwide Get with the Guidelines (GWTG)-Stroke Registry linked to Medicare claims data. The cohort consisted of patients enrolled in Medicare fee-for-service plan, hospitalized with non-cardioembolic IS or TIA between 2011 and 2014, segmenting a subgroup with minor IS (National Institute of Health Stroke Scale [NIHSS] ≤5) or high-risk TIA (ABCD2-score ≥6) compatible with the THALES clinical trial population. Outcomes included functional status at discharge, clinical outcomes (all-cause mortality, ischemic stroke, and hemorrhagic stroke, individually and as a composite), hospitalizations, and population average inpatient Medicare payments following non-cardioembolic IS or TIA. RESULTS: The THALES-compatible cohort included 62,518 patients from 1471 hospitals. At discharge, 37.0% were unable to ambulate without assistance, and 96.2% were prescribed antiplatelet therapy. Cumulative incidences at 30 days, 90 days, and 1 year for the composite outcome were 3.7%, 7.6%, and 17.2% and 2.4%, 4.0%, and 7.3% for subsequent stroke. The mean Medicare payment for the index hospitalization was $7951. The cumulative all-cause inpatient Medicare spending per patient (with or without any subsequent admission) at 30 days and 1 year from discharge was $1451 and $8105, respectively. CONCLUSIONS: The burden of illness for minor IS/high-risk TIA patients indicates an important unmet need. Improved therapeutic options may offer a significant impact on both patient outcomes and Medicare spending.

Translating clinical evidence into value-based payment models: pooled analyses of innovative real-world outcomes agreements for ticagrelor in the United States.

Innovative value strategies for reimbursement of medications include value-based agreements (VBAs) between payers and pharmaceutical manufacturers, which have the potential to improve affordability and patient access to therapy, as well as lead to a reduction in downstream health events and associated medical costs. VBAs link payment for a medication to its performance in real-world clinical practice measured against prespecified outcomes that are aligned to existing evidence. Given its high prevalence, economic burden, and impact on mortality, cardiovascular disease (namely, coronary heart disease) represents an opportunity for VBAs to contribute to improved health outcomes and patient experiences while reducing or containing total medical costs. AstraZeneca developed a VBA framework directly comparing 2 antiplatelet therapies indicated to treat acute coronary syndrome (ACS)-ticagrelor and clopidogrel-based on the PLATO trial, which demonstrated superiority for ticagrelor in reducing the incidence of recurrent myocardial infarction (MI) in patients with ACS. Between 2015 and 2018, 11 contract-years of VBAs utilizing this framework were implemented in commercial and Part D health insurance plans, totaling nearly 32,000 unique patients in which pooled analyses were conducted. Aggregated VBA results indicate that ticagrelor consistently outperformed expectations in reducing recurrent MI vs clopidogrel, while also illustrating how comparative VBA frameworks of this nature may overcome challenges noted for VBAs and be utilized more broadly in future applications.

Oral Antiplatelet Therapy Administered Upstream to Patients With NSTEMI.

OBJECTIVE: To describe from a noninterventional registry (Utilization of Ticagrelor in the Upstream Setting for Non-ST-Segment Elevation Acute Coronary Syndrome), the short-term ischemic and hemorrhagic outcomes in patients with non-ST elevation myocardial infarction (MI) are managed with a loading dose (LD) of a P2Y12 inhibitor (P2Y12i) given at least 4 hours before diagnostic angiography and delineation of coronary anatomy. Prior data on the effects of such "upstream loading" have been inconsistent. METHODS: In 53 US hospitals, we evaluated the in-hospital care and outcomes of patients with confirmed non-ST elevation MI managed with an interventional strategy and loaded upstream (at least 4 h before diagnostic angiography) with oral P2Y12i therapy. Patients entered into the database were grouped into 1 of 4 cohorts for analysis: (1) overall cohort, (2) thienopyridine (clopidogrel or prasugrel) load, (3) ticagrelor load, and (4) ticagrelor-consistent. The fourth cohort is a subset of cohort 3 that received ticagrelor throughout the index hospital stay and at discharge. We evaluated in-hospital clinical course and ischemic and bleeding outcomes in all patients and also 30-day outcomes in the ticagrelor-consistent cohort. RESULTS: A total of 3355 patients were enrolled, of whom 1087 had 30-day follow-up. The mean (±SD) age was 63.3 ± 12.5 years, and 62.6% were male. Thrombolysis in MI and Global Registry of Acute Coronary Events scores placed these patients in the intermediate risk range, and CRUSADE scores were in the moderate risk range. The LD in Utilization of Ticagrelor in the Upstream Setting for Non-ST-Segment Elevation Acute Coronary Syndrome was clopidogrel in 45.6%, ticagrelor in 53.6%, and prasugrel in 0.8%. The median upstream interval (LD to angiography) was 17:27 hours and did not change appreciably over the course of the data collection period (2/15-10/19). Access was radial in 48.6% and femoral in 51.4%. Postangiography management was medical only in 32.3%, percutaneous coronary intervention in 59.4%, and coronary artery bypass grafting in 8.3%. Median length of stay was 2.7 days, and median time from angiography to coronary artery bypass grafting was 3.6 days. In-hospital mortality was 0.51%, and major bleeding (thrombolysis in MI) was 0.24%; the in-hospital major adverse cardiovascular events rate was 0.7%, and stent thrombosis occurred in 0.18%. No significant differences were seen between the ticagrelor and clopidogrel cohorts in hospital, but 16% received more than 1 P2Y12i in-hospital. On follow-up (93.2% response), 86.7% of patients reported taking ticagrelor as directed. CONCLUSIONS: Upstream loading of P2Y12i was associated with very low rates of bleeding and short length of stay in a large cohort of non-ST elevation MI (NSTEMI) patients managed invasively.

Assessment of the high risk and unmet need in patients with CAD and type 2 diabetes (ATHENA): US healthcare resource utilization, cost and burden of illness in the Diabetes Collaborative Registry.

BACKGROUND: THEMIS (NCT01991795) showed that in patients with type 2 diabetes (T2D) and stable coronary artery disease (CAD) but with no prior myocardial infarction (MI) or stroke, ticagrelor plus acetylsalicylic acid (ASA) decreased the incidence of ischaemic cardiovascular events compared with placebo plus ASA. To complement these findings, we assessed disease burden and healthcare resource utilization (HRU) in US patients with CAD and T2D, but without a prior MI or stroke. METHODS: This observational study used 2013-2014 data from the Diabetes Collaborative Registry linked to Medicare administrative claims. Two cohorts of patients with T2D were studied: patients at high cardiovascular risk (THEMIS-like cohort; N = 56 040) and patients at high cardiovascular risk or taking P2Y12 inhibitors (CAD-T2D cohort; N = 69 790). Outcomes included the composite of all-cause death, MI and stroke; the individual events from the composite endpoint; HRU; and costs. RESULTS: Median age was 73.0 years, and median follow-up was 1.3 years in both cohorts. Event rates of the composite outcome were 16.34 (95% confidence interval: 16.31-16.37) and 17.64 (17.61-17.67) per 100 person-years for the THEMIS-like and CAD-T2D cohorts, respectively. The incidence rate of bleeding events was 0.13 events per 100 person-years in both cohorts. Healthcare costs per patient-year were USD 8741 and USD 9150 in the THEMIS-like and CAD-T2D cohorts, respectively. CONCLUSIONS: Patients in the THEMIS-like cohort and the broader CAD-T2D population had similarly substantial cardiovascular event rates and healthcare costs, indicating that patients with CAD and T2D similar to the THEMIS population are at an increased cardiovascular risk.

Copayment Reduction Voucher Utilization and Associations With Medication Persistence and Clinical Outcomes: Findings From the ARTEMIS Trial.

BACKGROUND: Cost is frequently cited as a barrier to optimal medication use, but the extent to which copayment assistance interventions are used when available, and their impact on evidence-based medication persistence and major adverse cardiovascular events is unknown. METHODS AND RESULTS: The ARTEMIS trial (Affordability and Real-World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study) randomized 301 hospitals to usual care versus the ability to provide patients with vouchers that offset copayment costs when filling P2Y12 inhibitors in the 1 year post-myocardial infarction. In the intervention group, we used multivariable logistic regression to identify patient and medication cost characteristics associated with voucher use. We then used this model to stratify both intervention and usual care patients by likelihood of voucher use, and examined the impact of the voucher intervention on 1-year P2Y12 inhibitor persistence (no gap in pharmacy supply >30 days) and major adverse cardiovascular events (all-cause death, myocardial infarction, or stroke). Among 10 102 enrolled patients, 6135 patients were treated at hospitals randomized to the copayment intervention. Of these, 1742 (28.4%) never used the voucher, although 1729 (99.2%) voucher never-users filled at least one P2Y12 inhibitor prescription in the 1 year post-myocardial infarction. Characteristics most associated with voucher use included: discharge on ticagrelor, planned 1-year course of P2Y12 inhibitor treatment, white race, commercial insurance, and higher out-of-pocket medication costs (c-statistic 0.74). Applying this propensity model to stratify all enrolled patients by likelihood of voucher use, the intervention improved medication persistence the most in patients with high likelihood of voucher use (adjusted interaction P=0.03, odds ratio, 1.86 [95% CI, 1.48-2.33]). The intervention did not significantly reduce major adverse cardiovascular events in any voucher use likelihood group, although the odds ratio was lowest (0.86 [95% CI, 0.56-1.16]) among patients with high likelihood of voucher use (adjusted interaction P=0.04). CONCLUSIONS: Among patients discharged after myocardial infarction, those with higher copayments and greater out-of-pocket medication costs were more likely to use a copayment assistance voucher, but some classes of patients were less likely to use a copayment assistance voucher. Patients at low likelihood of voucher use benefitted least from copayment assistance, and other interventions may be needed to improve medication-taking behaviors and clinical outcomes in these patients. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02406677.

Impact of a Copayment Reduction Intervention on Medication Persistence and Cardiovascular Events in Hospitals With and Without Prior Medication Financial Assistance Programs.

Background Hospitals commonly provide a short-term supply of free P2Y12 inhibitors at discharge after myocardial infarction, but it is unclear if these programs improve medication persistence and outcomes. The ARTEMIS (Affordability and Real-World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study) trial randomized hospitals to usual care versus waived P2Y12 inhibitor copayment costs for 1-year post-myocardial infarction. Whether the impact of this intervention differed between hospitals with and without pre-existing medication assistance programs is unknown. Methods and Results In this post hoc analysis of the ARTEMIS trial, we examined the associations of pre-study free medication programs and the randomized copayment voucher intervention with P2Y12 inhibitor persistence (measured by pharmacy fills and patient report) and major adverse cardiovascular events using logistic regression models including a propensity score. Among 262 hospitals, 129 (49%) offered pre-study free medication assistance. One-year P2Y12 inhibitor persistence and major adverse cardiovascular events risks were similar between patients treated at hospitals with and without free medication programs (adjusted odds ratio 0.93, 95% CI, 0.82-1.05 and hazard ratio 0.92, 95% CI, 0.80-1.07, respectively). The randomized copayment voucher intervention improved persistence, assessed by pharmacy fills, in both hospitals with (53.6% versus 44.0%, adjusted odds ratio 1.45, 95% CI, 1.20-1.75) and without (59.0% versus 48.3%, adjusted odds ratio 1.46, 95% CI, 1.25-1.70) free medication programs (Pinteraction=0.71). Differences in patient-reported persistence were not significant after adjustment. Conclusions While hospitals commonly report the ability to provide free short-term P2Y12 inhibitors, we did not find association of this with medication persistence or major adverse cardiovascular events among patients with insurance coverage for prescription medication enrolled in the ARTEMIS trial. An intervention that provided copayment assistance vouchers for 1 year was successful in improving medication persistence in hospitals with and without pre-existing short-term medication programs. Registration URL: https://www.clini​caltr​ials.gov/. Unique identifier: NCT02406677.

Ticagrelor in Peripheral Artery Disease Endovascular Revascularization (TI-PAD): Challenges in clinical trial execution.

There is limited evidence to guide clinical decision-making for antiplatelet therapy in peripheral artery disease (PAD) in the setting of lower extremity endovascular treatment. The Ticagrelor in Peripheral Artery Disease Endovascular Revascularization Study (TI-PAD) evaluated the role of ticagrelor versus aspirin as monotherapy in the management of patients following lower extremity endovascular revascularization. The trial failed to recruit the targeted number of patients, likely due to aspects of the design including the lack of option for dual antiplatelet therapy, and inability to identify suitable patients at study sites. In response, the protocol underwent amendments, but these changes did not adequately stimulate recruitment, and thus TI-PAD was prematurely terminated. This article describes the rationale for TI-PAD and challenges in trial design, subject recruitment and trial operations to better inform the conduct of future trials in PAD revascularization. ClinicalTrials.gov Identifier: NCT02227368.

A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study.

OBJECTIVES: This study conducted a prospective, single-arm, multicenter trial to evaluate the safety and efficacy of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis, using the EkoSonic Endovascular System (EKOS, Bothell, Washington). BACKGROUND: Systemic fibrinolysis for acute pulmonary embolism (PE) reduces cardiovascular collapse but causes hemorrhagic stroke at a rate exceeding 2%. METHODS: Eligible patients had a proximal PE and a right ventricular (RV)-to-left ventricular (LV) diameter ratio ≥0.9 on chest computed tomography (CT). We included 150 patients with acute massive (n = 31) or submassive (n = 119) PE. We used 24 mg of tissue-plasminogen activator (t-PA) administered either as 1 mg/h for 24 h with a unilateral catheter or 1 mg/h/catheter for 12 h with bilateral catheters. The primary safety outcome was major bleeding within 72 h of procedure initiation. The primary efficacy outcome was the change in the chest CT-measured RV/LV diameter ratio within 48 h of procedure initiation. RESULTS: Mean RV/LV diameter ratio decreased from baseline to 48 h post-procedure (1.55 vs. 1.13; mean difference, -0.42; p < 0.0001). Mean pulmonary artery systolic pressure (51.4 mm Hg vs. 36.9 mm Hg; p < 0.0001) and modified Miller Index score (22.5 vs. 15.8; p < 0.0001) also decreased post-procedure. One GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries)-defined severe bleed (groin hematoma with transient hypotension) and 16 GUSTO-defined moderate bleeding events occurred in 15 patients (10%). No patient experienced intracranial hemorrhage. CONCLUSIONS: Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis decreased RV dilation, reduced pulmonary hypertension, decreased anatomic thrombus burden, and minimized intracranial hemorrhage in patients with acute massive and submassive PE. (A Prospective, Single-arm, Multi-center Trial of EkoSonic® Endovascular System and Activase for Treatment of Acute Pulmonary Embolism (PE) [SEATTLE II]; NCT01513759).

Prevention of contrast induced nephropathy: recommendations for the high risk patient undergoing cardiovascular procedures.

Contrast induced nephropathy (CIN) is the third leading cause of hospital acquired renal failure and is associated with significant morbidity and mortality. Chronic kidney disease is the primary predisposing factor for CIN. As estimated glomerular filtration rate<60 ml/1.73 m2 represents significant renal dysfunction and defines patients at high risk. Modifiable risk factors for CIN include hydration status, the type and amount of contrast, use of concomitant nephrotoxic agents and recent contrast administration. The cornerstone of CIN prevention, in both the high and low risk patients, is adequate parenteral volume repletion. In the patient at increased risk for CIN it is often appropriate to withhold potentially nephrotoxic medications, and consider the use of n-acetylcysteine. In patients at increased risk for CIN the use of low or iso-osomolar contrast agents should be utilized and strategies employed to minimize contrast volume. In these patients serum creatinine should be obtained forty-eight hours post procedure and it is often appropriate to continue withholding medications such as metformin or non steroidal anti-inflammatories until renal function returns to normal.