Fast versus ultra-slow thrombolytic infusion regimens in patients with obstructive mechanical prosthetic valve thrombosis: a pilot randomized clinical trial

Background Thrombolysis is an alternative to surgery for mechanical prosthetic valve thrombosis (MPVT). Randomized clinical trials have yet to test safety and efficacy of a proposed ultraslow thrombolytic infusion regimen. Methods and Results This single-center, open-label, pilot randomized clinical trial randomized adult patients with acute obstructive MPVT to an ultraslow thrombolytic regimen (25 mg of recombinant tissue-type plasminogen activator [rtPA] infused in 25h) and a fast thrombolytic regimen (50 mg of rtPA infused in 6h). If thrombolysis failed, a repeated dose of 25 mg of rtPA for 6h was administered in both groups up to a cumulative dose of 150 mg or the occurrence of a complication. Primary outcome was a complete MPVT resolution (>75% fall in the obstructive gradient by transthoracic echocardiography, <10° limitation in opening and closing valve motion angles by fluoroscopy, and symptom improvement). Key safety outcome was a BARC type III or V major bleeding. Overall, 120 patients, including 63 (52.5%) women, at a mean age of 36.3±15.3 years, were randomized. Complete thrombolysis success was achieved in 51 patients (85.0%) in the ultraslow-regimen group and 47 patients (78.3%) in the fast-regimen group (OR, 1.58; 95% CI, 0.25 to 1.63; P = 0.34). One case of transient ischemic attack and 3 cases of intracranial hemorrhage (absolute risk difference, −12.5%; 95% CI, −23.1% to −1.0%; P = 0.04). were observed only in the fast-regimen group. Conclusions The ultraslow thrombolytic regimen conferred a high thrombosis resolution rate without major complications. Such findings should be replicated in more adequately powered trials (IRCT20181022041406N2).

Cardiovascular risks associated with use of non-steroidal anti-inflammatory drugs in patients with non-obstructive coronary artery disease

Aim To examine whether non-aspirin non-steroidal anti-inflammatory drugs (NSAID) use is associated with increased cardiovascular risks in patients with non-obstructive coronary artery disease (CAD). Methods and results Using Danish medical registries, we conducted a population-based cohort study in Western Denmark during 2008–2017. We identified all patients undergoing first-time coronary computed tomography angiography (CCTA) due to suspected CAD (n = 35,399), with results showing no (n = 28,581) or non-obstructive CAD (n = 6,818). Multivariate Cox regression was used to compute hazard ratios of major adverse cardiac events (MACE) including incident myocardial infarction, coronary intervention, or death. The rate of MACE increased by 33% for any NSAID use compared with non-use (hazard ratio 1.33, 95% confidence interval (CI) 1.06 to 1.68) in patients with no CAD and by 48% (1.48, 95% CI 1.06 to 2.07) in patients with non-obstructive CAD. Rate difference of MACE, per 100 person-years, was 0.38 (95% CI 0.08 to 0.67) in patients with no CAD (number needed to harm 267) and 1.08 (95% CI 0.06 to 2.11) in patients with non-obstructive CAD (number needed to harm 92). Current use of older COX-2 inhibitors was associated with the highest hazard ratio in patients with non-obstructive CAD, both when ascertained as pre-CCTA use (2.9-fold increase) and from time-varying use (1.8-fold increase). Conclusion NSAID use in patients with CCTA-confirmed no and non-obstructive CAD was associated with an increased cardiovascular risk compared with non-use. The absolute risk differences and numbers needed to harm were considered clinically relevant, particularly in patients with non-obstructive CAD.

Interleukin-1 blockade with Anakinra and heart failure following ST-segment elevation myocardial infarction: results from a pooled analysis of the VCUART clinical trials

Aims ST segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). In this study we sought to evaluate the effect of anakinra, a recombinant interleukin-1 receptor antagonist, on the incidence of HF. Methods and Results We performed a pooled analysis of three early phase randomized clinical trials. The endpoints included the composite of all-cause death and new-onset HF, and the composite of all-cause death and hospitalization for HF at 1 year follow-up. Safety events, including injection site reaction and serious infections, were also recorded. We analyzed 139 patients with STEMI from three separate trials: VCUART (N = 10), VCUART2 (N = 30), and VCUART3 (N = 99). Of these, 84 (60%) patients were randomized to anakinra and 55 (40%) to placebo. Treatment with anakinra significantly reduced the incidence of all-cause death or new-onset HF (7 [8.2%] vs 16 [29.1%], log-rank P = 0.002) and of all-cause death or HF hospitalization (0 [0] vs 5 [9.1%], log-rank P = 0.007). Patients treated with anakinra had significantly higher injection site reactions (19 [22.6%] vs 3 [5.5%], P = 0.016) without a significant difference in the incidence of serious infections (11 [13.1%] vs 7 [12.7%], P = 0.435). Treatment with anakinra significantly reduced the area under the curve for high-sensitivity C-Reactive-Protein between baseline and 14 days (75.48 [41.7–147.47] vs 222.82 [222.82 [117.22–399.28] mg•day/L, P < 0.001) Conclusions IL-1 blockade with anakinra for 14 days in patients with STEMI reduces the incidence of new onset HF or hospitalization for HF at 1 year following STEMI.

Challenges in Cardiovascular Pharmacogenomics Implementation: A viewpoint from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy

Pharmacogenomics promises to advance cardiovascular therapy, but there remain pragmatic barriers to implementation. These are particularly important to explore within Europe, as there are differences in the populations, availability of resources and expertise, as well as in ethico-legal frameworks. Differences in healthcare delivery across Europe present a challenge, but also opportunities to collaborate on PGx implementation. Clinical work force upskilling is already in progress but will require substantial input. Digital infrastructure and clinical support tools are likely to prove crucial. It is important that widespread implementation serves to narrow rather than widen any existing gaps in health equality between populations. This viewpoint supplements the working group position paper on cardiovascular pharmacogenomics to address these important themes.