Does early detection of atrial fibrillation reduce the risk of thromboembolic events? Rationale and design of the Heartline study.

BACKGROUND: The impact of using direct-to-consumer wearable devices as a means to timely detect atrial fibrillation (AF) and to improve clinical outcomes is unknown. METHODS: Heartline is a pragmatic, randomized, and decentralized application-based trial of US participants aged ≥65 years. Two randomized cohorts include adults with possession of an iPhone and without a history of AF and those with a diagnosis of AF taking a direct oral anticoagulant (DOAC) for ≥30 days. Participants within each cohort are randomized (3:1) to either a core digital engagement program (CDEP) via iPhone application (Heartline application) and an Apple Watch (Apple Watch Group) or CDEP alone (iPhone-only Group). The Apple Watch Group has the watch irregular rhythm notification (IRN) feature enabled and access to the ECG application on the Apple Watch. If an IRN notification is issued for suspected AF then the study application instructs participants in the Apple Watch Group to seek medical care. All participants were "watch-naïve" at time of enrollment and have an option to either buy or loan an Apple Watch as part of this study. The primary end point is time from randomization to clinical diagnosis of AF, with confirmation by health care claims. Key secondary endpoint are claims-based incidence of a 6-component composite cardiovascular/systemic embolism/mortality event, DOAC medication use and adherence, costs/health resource utilization, and frequency of hospitalizations for bleeding. All study assessments, including patient-reported outcomes, are conducted through the study application. The target study enrollment is approximately 28,000 participants in total; at time of manuscript submission, a total of 26,485 participants have been enrolled into the study. CONCLUSION: The Heartline Study will assess if an Apple Watch with the IRN and ECG application, along with application-facilitated digital health engagement modules, improves time to AF diagnosis and cardiovascular outcomes in a real-world environment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04276441.

Rivaroxaban thromboprophylaxis in ambulatory patients with pancreatic cancer: Results from a pre-specified subgroup analysis of the randomized CASSINI study.

BACKGROUND: Pancreatic cancer patients are at risk for venous thromboembolism (VTE); the value of thromboprophylaxis has not been definitively established. METHODS: This trial randomized cancer patients initiating a new regimen and at high risk for VTE (Khorana score ≥2) to rivaroxaban 10 mg or placebo up to day 180. This analysis examined the subset of pancreatic cancer patients. The primary efficacy endpoint was the composite of symptomatic deep-vein thrombosis (DVT), asymptomatic proximal DVT, any pulmonary embolism, and VTE-related death. The primary safety endpoint was International Society on Thrombosis and Haemostasis-defined major bleeding. RESULTS: In total, 49/1080 (4.5%) patients enrolled had baseline VTE on screening, with higher rates (24/362 [6.6%]) in pancreatic cancer and they were not randomized. Of 841 randomized patients, 273 (32.5%) had pancreatic cancer; 155/273 (57% in each arm) completed the double-blind period. The primary endpoint occurred in 13/135 (9.6%) patients in the rivaroxaban group and in 18/138 (13.0%) in the placebo group (hazard ratio [HR] = 0.70; 95% CI, 0.34-1.43; P = .328) in up-to-day-180 period and 5/135 (3.7%) patients receiving rivaroxaban and 14/138 (10.1%) receiving placebo in the intervention period (HR = 0.35; 95% CI, 0.13-0.97; P = .034). Major bleeding was similar (2 [1.5%] receiving rivaroxaban and 3 [2.3%] receiving placebo). Correlative biomarker studies demonstrated significant decline in D-dimer (weeks 8 and 16) in patients randomized to rivaroxaban compared to placebo (P < .01). CONCLUSIONS: In ambulatory pancreatic cancer patients, rivaroxaban did not result in significantly lower incidence of VTE or VTE-related death in the 180-day period. During the intervention period, however, rivaroxaban substantially reduced VTE without increasing major bleeding, suggesting benefit of rivaroxaban prophylaxis in this setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02555878.

Assessing Full Benefit of Rivaroxaban Prophylaxis in High-Risk Ambulatory Patients with Cancer: Thromboembolic Events in the Randomized CASSINI Trial.

Introduction In the CASSINI study, rivaroxaban thromboprophylaxis significantly reduced primary venous thromboembolism (VTE) endpoints during the intervention period, but several thromboembolic events designated as secondary efficacy endpoints were not included in the primary analysis. This study was aimed to evaluate the full impact of rivaroxaban thromboprophylaxis on all prespecified thromboembolic endpoints occurring on study. Methods CASSINI was a double-blind, randomized, placebo-controlled study in adult ambulatory patients with cancer at risk for VTE (Khorana score ≥2). Patients were screened at baseline for deep-vein thrombosis (DVT) and randomized if none was found. The primary efficacy endpoint was a composite of lower extremity proximal DVT, symptomatic upper extremity, or lower extremity distal DVT, any pulmonary embolism, and VTE-related death. This analysis evaluated all prespecified thromboembolic endpoints occurring on study to determine the full benefit of rivaroxaban prophylaxis. All endpoints were independently adjudicated. Results Total thromboembolic events occurred in fewer patients randomized to rivaroxaban during the full study period (29/420 [6.9%] and 49/421 [11.6%] patients in rivaroxaban and placebo groups, respectively [hazard ratio (HR) = 0.57; 95% confidence interval (CI): 0.36-0.90; p = 0.01]; number needed to treat [NNT] = 21). Similarly, fewer patients randomized to rivaroxaban experienced thromboembolism during the intervention period (13/420 [3.1%] patients) versus placebo (38/421 [9.0%] patients; HR = 0.33; 95% CI: 0.18-0.62; p < 0.001; NNT = 17). Conclusion Our findings confirm the substantial benefit of rivaroxaban thromboprophylaxis when considering all prespecified thromboembolic events, even after excluding baseline screen-detected DVT. The low NNT, coupled with prior data demonstrating a high number needed to harm, should assist clinicians in determining the risk/benefit of thromboprophylaxis in high-risk patients with cancer.

Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer.

BACKGROUND: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain. METHODS: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding. RESULTS: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49). CONCLUSIONS: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.).

A double-blind, randomized comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis.

OBJECTIVES: A clinical study was conducted to compare the efficacy and safety of levofloxacin 750 mg once daily for 5 days to ciprofloxacin twice daily for 10 days for the treatment of complicated urinary tract infections (cUTI) or acute pyelonephritis (AP). METHODS: A multicenter, double-blind, randomized, noninferiority study enrolled subjects with AP or cUTI. Subjects received either levofloxacin 750 mg intravenously or orally once daily for 5 days or ciprofloxacin 400 mg intravenously and/or ciprofloxacin 500 mg orally twice daily for 10 days and were evaluated at end of therapy, posttherapy, and poststudy for microbiologic eradication and clinical outcome. RESULTS: A total of 1109 subjects were enrolled; 619 with confirmed diagnosis of AP or cUTI and a study entry uropathogen with a colony count 10(5) CFU/mL or greater and were included in the modified intent-to-treat population. Five hundred six subjects met all criteria for inclusion and were included in the microbiologically evaluable population. At end of therapy, eradication rates in the modified intent-to-treat population were 79.8% for levofloxacin and 77.5% for ciprofloxacin-treated subjects (95% CI, -8.8% to 4.1%). In the microbiologically evaluable population, eradication rates were 88.3% for levofloxacin and 86.7% for ciprofloxacin-treated subjects (95% CI, -7.4% to 4.2%). Outcomes were comparable for the 2 treatments at posttherapy and poststudy. CONCLUSIONS: This study demonstrates that both drug regimens are safe and effective and that a 5-day course of therapy with levofloxacin, administered at a dose of 750 mg once daily, is noninferior to a 10-day course of therapy with ciprofloxacin for the treatment of AP and cUTI.

Identification and pretherapy susceptibility of pathogens in patients with complicated urinary tract infection or acute pyelonephritis enrolled in a clinical study in the United States from November 2004 through April 2006.

OBJECTIVE: The purpose of this study was to assess the pretherapy microbiology and fluoroquinolone susceptibility of pathogens from 650 patients with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP) as part of a multicenter, randomized, controlled clinical trial. METHODS: In this post hoc analysis of a multicenter, randomized, double-blind study, adults with a clinical diagnosis of cUTI or AP were recruited from 130 community-based and institution-based study centers in the United States from November 2004 through April 2006. Urine and blood culture specimens were identified and tested for susceptibility according to Clinical and Laboratory Standards Institute methods. Presence of a pathogen in the urine culture was confirmed by a colony count of =105 colony-forming units per milliliter. Susceptibility to nonstudy drugs (trimethoprim/sulfamethoxazole [TMP/SMX] and ampicillin) and to study drugs (levofloxacin and ciprofloxacin) was categorized as susceptible, intermediate, or resistant. RESULTS: Six hundred fifty patients (417 women, 233 men; age range, 18-94 years) with a diagnosis of cUTI or AP were recruited. A total of 68.2% patients (224 men, 219 women) were diagnosed with cUTI, and 31.8% (198 women, 9 men), with AP. Most (646/650 [99.4%]) infections were community acquired. The most common pathogen was Escherichia coli (65.6%), although 12.2% of patients had gram-positive pathogens. Testing for susceptibility to ampicillin and TMP/SMX found that 50.1% and 22.1% of gramnegative pathogens were fully resistant to ampicillin and TMP/SMX, respectively. However, 91.9% of isolates were susceptible to levofloxacin and ciprofloxacin, with 6.5% of isolates resistant or intermediately resistant to levofloxacin, and 9.7% of isolates resistant or intermediately resistant to ciprofloxacin at study entry (P < 0.001 [Stuart-Maxwell test]). All isolates resistant to levofloxacin were also resistant to ciprofloxacin, whereas 6 isolates that were fully susceptible to levofloxacin were fully resistant to ciprofloxacin. CONCLUSION: In this study, the level of fluoroquinolone susceptibility of urinary pathogens was high (90.6% in cUTI; 98.1% in AP).

A trial of levofloxacin 750 mg once daily for 5 days versus ciprofloxacin 400 mg and/or 500 mg twice daily for 10 days in the treatment of acute pyelonephritis.

OBJECTIVE: A double-blind, noninferiority trial was conducted to establish the safety and efficacy of a once-daily, 5-day course of levofloxacin 750 mg compared to a twice-daily, 10-day course of ciprofloxacin in complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). This report focuses on subjects with AP. RESEARCH DESIGN AND METHODS: Adult male and female subjects with clinical signs and symptoms of AP and laboratory confirmation of their diagnosis were randomized to receive one dose of levofloxacin 750 mg once daily intravenously (i.v.) or orally and one dose of placebo for 5 days, followed by placebo; or ciprofloxacin 400 mg i.v. and/or 500 mg orally twice daily for 10 days. MAIN OUTCOME MEASURES: The primary, prospectively defined end point was microbiologic eradication at post-therapy (study days 15-22). Secondary outcomes included clinical response and safety and tolerability. RESULTS: In the modified intent-to-treat (mITT) population (levofloxacin 94, ciprofloxacin 98), 83% of levofloxacin-treated and 79.6% of ciprofloxacin-treated subjects achieved microbiological eradication (difference -3.4, 95% CI -14.4%, 7.6%). In the microbiologically evaluable (ME) population (levofloxacin 80, ciprofloxacin 76), 92.5% of levofloxacin-treated vs. 93.4% of ciprofloxacin-treated subjects (difference -0.9, 95% CI -7.1%, 8.9%) achieved microbiologic eradication. Clinical success was achieved in 86.2% vs. 80.6% (mITT) and in 92.5% vs. 89.5% (ME) of levofloxacin-treated and ciprofloxacin-treated subjects, respectively. Escherichia coli was the most commonly isolated uropathogen. Few (2.1%) of the pathogens were fluoroquinolone-resistant. Adverse events (AEs) were similar to those seen previously with both agents. Potential limitations are that this analysis is based on a subset of subjects from a larger study and, because of different durations of therapy, the results may be biased against levofloxacin. CONCLUSIONS: High-dose, short-course therapy with levofloxacin in subjects with AP is at least as effective as standard 10-day therapy with ciprofloxacin.