Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial.

Importance: Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown. Objective: To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age. Design, Setting, and Participants: Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021. Interventions: Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism. Main Outcomes and Measures: The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve). Results: Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively). Conclusions and Relevance: Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk. Trial Registration: ClinicalTrials.gov Identifier: NCT00687882.

Ranolazine for the suppression of ventricular arrhythmia: a case series.

BACKGROUND: Premature ventricular complexes (PVCs) and ventricular tachycardia (VT) are associated with persistent symptoms and ventricular dysfunction. Approved medical therapies have undesirable side effects and proarrhythmic liability. Ranolazine is a novel antianginal that preferentially blocks the late sodium current. This current is enhanced among patients with cardiomyopathy; a promising target population for ranolazine. The utility of ranolazine, however, for ventricular arrhythmia suppression has not been well characterized. OBJECTIVES: We sought to determine the effectiveness of ranolazine for suppression of ventricular ectopy, particularly in the setting of ventricular dysfunction where enhanced efficacy might be expected. METHODS: We retrospectively evaluated eight patients (six with >10% PVC burden and two with incessant VT) treated with ranolazine. Arrhythmia frequency was evaluated by continuous monitoring before and after ranolazine initiation and the correlation between ventricular function and reduction in PVC burden was assessed. RESULTS: Among six patients with PVCs, ranolazine resulted in a median decrease in PVC burden of 60.2% (P = 0.06). In two cases of apparent PVC-induced cardiomyopathy, normalization of ventricular function was observed. A significant, inverse correlation between baseline ejection fraction and percentage reduction in PVCs was observed (rho = -0.89, P = 0.02). In two patients treated for incessant VT despite Class III antiarrhythmic therapy, ranolazine eliminated VT and prevented recurrent defibrillator therapy. CONCLUSIONS: Although not approved for this indication, ranolazine appears effective for symptomatic ventricular arrhythmias. The reduction in PVC burden was greatest among individuals with reduced ventricular function, perhaps due to enhanced late sodium current associated with cardiomyopathy. A confirmatory prospective trial seems warranted.

Treatment-Dose LMWH versus Prophylactic/Intermediate Dose Heparins in High-Risk COVID-19 Inpatients: Rationale and Design of the HEP-COVID Trial.

Coronavirus disease-2019 (COVID-19) has been associated with significant risk of venous thromboembolism (VTE), arterial thromboembolism (ATE), and mortality particularly among hospitalized patients with critical illness and elevated D-dimer (Dd) levels. Conflicting data have yet to elucidate optimal thromboprophylaxis dosing. HEP-COVID (NCT04401293) is a phase 3, multicenter, pragmatic, prospective, randomized, pseudo-blinded, active control trial to evaluate efficacy and safety of therapeutic-dose low-molecular-weight heparin (LMWH) versus prophylactic-/intermediate-dose LMWH or unfractionated heparin (UFH) for prevention of a primary efficacy composite outcome of VTE, ATE, and all-cause mortality 30 ± 2 days post-enrollment. Eligible patients have COVID-19 diagnosis by nasal swab or serologic testing, requirement for supplemental oxygen per investigator judgment, and Dd >4 × upper limit of normal (ULN) or sepsis-induced coagulopathy score ≥4. Subjects are randomized to enoxaparin 1 mg/kg subcutaneous (SQ)/two times a day (BID) (creatinine clearance [CrCl] ≥ 30 mL/min) or 0.5 mg/kg (CrCl 15-30 mL/min) versus local institutional prophylactic regimens including (1) UFH up to 22,500 IU (international unit) daily (divided BID or three times a day), (2) enoxaparin 30 and 40 mg SQ QD (once daily) or BID, or (3) dalteparin 2,500 IU or 5,000 IU QD. The principal safety outcome is major bleeding. Events are adjudicated locally. Based on expected 40% relative risk reduction with treatment-dose compared with prophylactic-dose prophylaxis, 308 subjects will be enrolled (assuming 20% drop-out) to achieve 80% power. Distinguishing design features include an enriched population for the composite endpoint anchored on Dd >4 × ULN, stratification by intensive care unit (ICU) versus non-ICU, and the ability to capture asymptomatic proximal deep venous thrombosis via screening ultrasonography prior to discharge.

Anti-chlamydial antibiotic therapy for symptom improvement in peripheral artery disease: prospective evaluation of rifalazil effect on vascular symptoms of intermittent claudication and other endpoints in Chlamydia pneumoniae seropositive patients (PROVIDENCE-1).

BACKGROUND: A potentially strong association exists between Chlamydia pneumoniae and atherosclerosis, but the clinical benefits of antibiotic therapy have not been demonstrated. Preliminary studies of antibiotic therapy in peripheral artery disease have shown a decreased need for revascularization and improved walking ability. The objective of this phase-III trial was to assess the effect of a potent anti-Chlamydial agent, rifalazil, on peak walking time in patients with symptomatic peripheral artery disease. METHODS AND RESULTS: Patients with intermittent claudication secondary to peripheral artery disease who were seropositive for C pneumoniae were randomized to 25 mg rifalazil once weekly for 8 weeks or matching placebo. Two hundred ninety-seven patients were enrolled from 3 countries and were followed up for 1 year. The mean+/-SD ankle brachial index at baseline was 0.63+/-0.16. The primary end point, change from baseline in log peak walking time on a graded treadmill, was assessed 180 days after randomization. Secondary end points included changes in claudication onset time and quality of life, assessed with the Walking Impairment Questionnaire and the Short Form Medical Outcomes 36. No benefit of rifalazil therapy was found in the primary or any secondary end point among this cohort of patients with peripheral artery disease. The group treated with rifalazil improved their peak walking times by 23% (95% confidence interval, 15 to 31) from baseline to day 180, whereas the placebo group improved by 18% (95% confidence interval, 11 to 26; P=0.38). Peak walking time, claudication onset time, Walking Impairment Questionnaire, and Short Form Medical Outcomes 36 showed no treatment-by-time interaction during the 360-day study period. Thirty-two adjudicated cardiovascular events occurred, 16 in each treatment group. CONCLUSIONS: Rifalazil did not improve exercise performance or quality of life in patients with intermittent claudication. No safety concerns were identified. Given the very small effect size, it is unlikely that larger studies would demonstrate a symptomatic benefit of this therapy in peripheral artery disease.

Effect of niacin ER/lovastatin on claudication symptoms in patients with peripheral artery disease.

In patients with peripheral artery disease (PAD), statins may improve the symptoms of claudication. The Intermittent Claudication Proof of Principle (ICPOP) study tested the hypothesis that the combination of extended release niacin plus lovastatin would improve exercise performance in patients with PAD and claudication compared with a diet intervention. A phase 3 double-blind, parallel-group, multi-center, 28-week multi-national study evaluated subjects with a history of claudication who had an ankle-brachial index (ABI) < or = 0.90, a reproducible peak treadmill walking time (PWT) of 1-20 minutes, and a low-density lipoprotein (LDL)-cholesterol level < 160 mg/dl (< 4.1 mmol/l). Subjects were randomly assigned to low-dose niacin 1000 mg plus lovastatin 40 mg (low niacin-statin), high-dose niacin 2000 mg plus lovastatin 40 mg (high niacin-statin), or diet intervention (diet). The co-primary efficacy endpoint of percent change in PWT and claudication onset time (COT) at 28 weeks was assessed using a graded treadmill protocol. At completion, 385 subjects were analyzed for safety and 370 subjects were analyzed for efficacy. The primary efficacy analysis showed no statistical significance for overall treatment effect at week 28 for the co-primary endpoint of PWT and COT. The PWT component of the primary endpoint increased 26.5% on diet, 37.8% on high niacin-statin (p = 0.137) and 38.6% on low niacin-statin (p = 0.096). Flushing as the most common event leading to discontinuation and treatment was associated with increases in liver enzymes, fasting blood glucose concentration and a decrease in platelet count.

Comparison of two point-of-care lipid analyzers for use in global cardiovascular risk assessments.

BACKGROUND: Point-of-care (POC) lipid testing is increasingly used in community- and office-based practice. Two analyzers commonly used in the US are CardioChek PA and Cholestech LDX. Both directly measure total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), mandatory values in calculating a Framingham Risk Score (FRS). The FRS in turn informs the clinician of the need for lipid-modifying therapy and the degree of therapeutic intensity. OBJECTIVE: To compare the performance of CardioChek PA and Cholestech LDX. METHODS: Staff members from the Colorado Prevention Center were included in the study, with all having fasted for 12 hours before the testing. No medical history was obtained. A venous blood sample was collected for lipid measurements conducted in a laboratory, and 2 finger sticks were obtained at that time and analyzed immediately on-site using the POC analyzers. Intraclass correlation coefficients (ICCs) were determined for each analyzer versus the laboratory analysis, with values greater than 0.75 defined as indicators of excellent reproducibility. We then assessed how interanalyzer differences in TC or HDL-C impacted the FRS lipid categorization. RESULTS: Thirty-four adults (aged 24-56 y) participated in the study. The ICC between Cholestech LDX and the laboratory standard exceeded 0.75 for all 4 lipid categories (TC, rho = 0.96; HDL-C, rho = 0.88; low-density lipoprotein cholesterol, rho = 0.87; triglycerides, rho = 0.99). By contrast, the only ICC exceeding 0.75 using CardioChek PA was for triglycerides (rho = 0.84). When applied in calculating the FRS, the Cholestech LDX analyzer misclassified fewer individuals for TC versus the CardioChek PA analyzer (5 vs 21). Overall, Cholestech LDX provided TC and HDL-C values in the correct FRS category more frequently versus CardioChek PA (TC, p < 0.001; HDL-C, p < 0.001). Limitations of the study include use of only 2 POC products and small sample size with no known risk factors. This project does not prove superior accuracy of either device, but reflects a real-world comparison of the analyzers conducted at a single center. CONCLUSIONS: The Cholestech LDX analyzer demonstrated better reproducibility than the CardioChek PA analyzer when compared with laboratory gold standard analysis and allowed more accurate categorization for FRS. Since results obtained from these analyzers have the potential to impact treatment decisions, larger, prospective, comparative studies seem warranted.

Heart rate recovery predicts mortality and cardiovascular events in patients with type 2 diabetes.

PURPOSE: Heart rate recovery (HRR) immediately after peak exercise has utility as a predictor of all-cause mortality. However, a prognostic role for HRR has not been specifically evaluated in patients with type 2 diabetes mellitus (T2DM), nor has an association between HRR and cardiovascular (CV) events been documented. This study investigated whether HRR is predictive of all-cause mortality, CV mortality, and CV events in asymptomatic patients with T2DM. METHODS: HRR in subjects with T2DM was obtained via chart review of peak exercise treadmill tests (N = 890) performed at entry into the Appropriate Blood Pressure Control in Diabetes trial. Survival analysis was used to test the association of 1- and 2-min HRR with all-cause mortality, CV mortality, and CV events during the follow-up period. RESULTS: Subjects were followed for a median of 5.0 yr. All-cause mortality and CV events were significantly greater among the lowest quintile (< 12 bpm) of 1-min HRR compared with the fourth (23-28 bpm) quintile. Similarly all-cause mortality and CV events were significantly greater among the lowest quintile (< 28 bpm) of 2-min HRR compared with the third quintile (37-42 bpm) quintile. After adjustment for traditional cardiac risk factors, attenuated 1- and 2-min HRR remained significantly associated with increased risk of CV events as compared with those without attenuation. CONCLUSIONS: HRR provides information beyond traditional CV risk factors that could aid in the clinical risk stratification of patients with T2DM. The results suggest that HRR results should be incorporated into standard diagnostic treadmill testing reports and target those patients with T2DM and attenuated HRR who can benefit from directed therapies.

Impact of prescription size on statin adherence and cholesterol levels.

BACKGROUND: Therapy with 3-Hydroxy-3-methylglutaryl Co-enzyme A reductase inhibitors (statins) improve outcomes in a broad spectrum of patients with hyperlipidemia. However, effective therapy requires ongoing medication adherence; restrictive pharmacy policies may represent a barrier to successful adherence, particularly among vulnerable patients. In this study we sought to assess the relationship between the quantity of statin dispensed by the pharmacy with patient adherence and total cholesterol. METHODS: We analyzed a cohort of 3,386 patients receiving more than one fill of statin medications through an integrated, inner-city health care system between January 1, 2000 and December 31, 2002. Our measure of adherence was days of drug acquisition divided by days in the study for each patient, with adequate adherence defined as > or = 80%. Log-binomial regression was used to determine the relative risk of various factors, including prescription size, on adherence. We also assessed the relationship between adherence and total cholesterol using multiple linear regression. RESULTS: After controlling for age, gender, race, co-payment, comorbidities, and insurance status, patients who obtained a majority of fills as 60-day supply compared with 30-day supply were more likely to be adherent to their statin medications (RR 1.41, 95% CI 1.28-1.55, P < 0.01). We found that statin non-adherence less than 80% was predictive of higher total serum cholesterol by 17.23 +/- 1.64 mg/dL (0.45 +/- 0.04 mmol/L). CONCLUSION: In a healthcare system serving predominantly indigent patients, the provision of a greater quantity of statin medication at each prescription fill contributes to improved adherence and greater drug effectiveness.

Relation of reduction in urinary albumin excretion to ten-year cardiovascular mortality in patients with type 2 diabetes and systemic hypertension.

Microalbuminuria is one of the strongest predictors of both adverse renal and cardiovascular disease (CVD) outcomes in patients with type 2 diabetes mellitus. Although measurement of urinary albumin excretion (UAE) is widely recommended, limited data are available to suggest that reducing UAE translates into a reduction in long-term cardiovascular mortality, particularly among patients without overt nephropathy, who constitute most patients with type 2 diabetes worldwide. We assessed whether changes in the UAE at 1 year were associated with cardiovascular mortality in 393 patients with hypertension and type 2 diabetes during a 10-year period. On univariate analysis, CVD history, age, diabetes duration, and change in UAE at 1 year were associated with cardiovascular mortality risk (hazard ratio 2.60 for those with CVD history, 95% confidence interval [CI] 1.47 to 4.62; hazard ratio 1.59 per 10 years of diabetes duration, 95% CI 1.12 to 2.25; and hazard ratio 1.49 per log UAE increase, 95% CI 1.13 to 1.96). In a stepwise Cox regression model that included baseline UAE and CVD history, the 10-year predicted mortality of those with a decrease in UAE of 2 logs at 1 year was 4.7% (95% CI 1.4% to 7.8%). For those with an increase in UAE of 2 logs at 1 year, it was 24.5% (95% CI 10.1% to 36.5%). In conclusion, these data support current guideline recommendations to screen for UAE in all patients with type 2 diabetes, even in the absence of nephropathy, and suggest that serial UAE measurements even after the initiation of antihypertensive therapy has prognostic value independent of traditional cardiovascular risk factors.