Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

Drug-Drug Interactions in the Treatment of Cancer-Associated Venous Thromboembolism with Direct Oral Anticoagulants.

Venous thromboembolism (VTE) is a frequent complication of cancer, and management of cancer-associated thrombosis (CAT) is challenging due to increased risks of bleeding and recurrent VTE. Recent trials have shown an acceptable efficacy and safety of direct oral anticoagulants (DOACs) in the treatment of CAT compared to low-molecular weight heparin. Although DOACs provide an effective and convenient treatment option in CAT, the need to assess the risk of drug-drug interactions (DDI) with antineoplastic therapies poses a barrier to their use in clinical practice. With the aim of supporting the assessment of CAT patients for treatment with DOAC, this review provides a comprehensive overview of the compatibility of antineoplastic therapies with the individual DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban). Using several data sources, we characterized 100 widely used antineoplastic agents with regard to their effect on p-glycoprotein and cytochrome P450, both important in the transport and elimination of DOACs. This enabled us to evaluate 400 "DOAC-antineoplastic agent"-pairs regarding their likelihood to interact (unlikely, potential, or likely), ultimately leading to clinical recommendations on the appropriateness of concomitant use for each pair. A potential or likely DDI was identified for 12% of the evaluated pairs. For nearly all antineoplastic agents, at least one DOAC was considered compatible.

Antithrombotic treatment for chronic coronary syndrome: Evidence and future perspectives.

Background The clinical presentation of coronary artery disease can range from asymptomatic, through stable disease in the form of chronic coronary syndrome, to acute coronary syndrome. Chronic coronary syndrome is a frequent condition, and secondary prevention of ischaemic events is essential. Summary Antithrombotic therapy is a key component of secondary prevention strategies, and it may vary in type and intensity depending on patient characteristics, comorbidities, and revascularisation modalities. Dual antiplatelet therapy is the default strategy in patients with chronic coronary syndrome and recent coronary stent implantation, while antiplatelet monotherapy is commonly prescribed for long-term prevention of cardiovascular events. Oral anticoagulation, in combination with antiplatelet therapy or alone, is used in patients with e.g., concomitant atrial fibrillation or venous thromboembolism. Key messages This review provides an overview of antithrombotic treatment strategies in patients with chronic coronary syndrome. Key messages from current guidelines are conveyed, and we provide future perspectives on long-term antithrombotic strategies.

Immature platelets and cardiovascular events in patients with stable coronary artery disease.

Many patients with coronary artery disease (CAD) have reduced the effect of aspirin, which may partly be explained by immature platelets. We aimed to investigate whether immature platelet markers can predict cardiovascular events in a large cohort of stable CAD patients. A total of 900 stable CAD patients were included and followed for a median of 3 years. We measured markers of immature platelets (platelet count, immature platelet count, immature platelet fraction, mean platelet volume, platelet distribution width, platelet mass, and thrombopoietin) using automated flow cytometry and studied their relation to cardiovascular events. Our primary endpoint was a composite of acute myocardial infarction (MI), ischemic stroke, and cardiovascular death. A composite of MI, ischemic stroke, stent thrombosis and all-cause mortality was analyzed as a secondary endpoint. We found no difference in immature platelet markers between CAD patients with or without cardiovascular events. Regression analysis using hazards rates showed that markers of immature platelets did not have any predictive value for endpoints (p-values >.05). Markers of immature platelets did not predict future cardiovascular events during a 3-year follow-up period in CAD patients. This suggests that immature platelets measured in a stable phase does not have a major role in predicting future cardiovascular events.

What is the context? Many patients with coronary artery disease (CAD) have reduced antiplatelet effect of aspirinThe reduced antiplatelet effect of aspirin is most likely multifactorial and may partly be explained by immature plateletsWhat is new? In a cohort of 900 stable CAD patients, we measured markers of immature platelets and studied their relation to cardiovascular events during a 3-year follow-upOur study demonstrated that markers of immature platelets did not predict cardiovascular events in our cohortWhat is the impact? The findings from the present study suggest that immature platelets, measured in a stable phase, do not have a major role in predicting future cardiovascular events in CAD patients.

Gastrointestinal bleeding and the risk of colorectal cancer in anticoagulated patients with atrial fibrillation.

AIMS: Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer. METHODS AND RESULTS: A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2-6.2] to 8.1% (95% CI 6.1-10.6) in the age groups ≤65 and 76-80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5-40.4) and 12.3 (95% CI 7.9-19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively. CONCLUSION: In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.

Remote Ischemic Conditioning for Acute Stroke: The RESIST Randomized Clinical Trial.

Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.

Cytoreductive treatment and association with platelet function and maturity in patients with essential thrombocythaemia.

Patients with essential thrombocythaemia (ET) have an increased risk of thromboembolic events, which may differ according to different cytoreductive drugs. We investigated the effect of cytoreductive treatment on platelet function and turnover in ET patients. Blood samples were obtained at 1 and 24 h after aspirin intake. Platelet function was evaluated by platelet aggregation and flow cytometry. Platelet turnover was assessed by immature platelet count, immature platelet fraction (IPF) and mean platelet volume (MPV). A total of 47 ET patients were included and grouped into 21 patients not receiving cytoreductive treatment, 15 patients receiving hydroxycarbamide and 11 patients receiving pegylated interferon alpha (peg-IFN). Patients receiving peg-IFN had significantly higher IPF and MPV than the other ET groups. Patients not receiving cytoreductive treatment had significantly higher platelet aggregation 24 h after aspirin intake than the other ET groups (p-values from 0.03 to 0.0002). Patients receiving hydroxycarbamide had significantly higher expression of platelet granule makers, P-selectin and CD63, than patients receiving peg-IFN (p-values ≤0.003). Cytoreduction provides more consistent platelet inhibition compared with no cytoreductive treatment. Moreover, peg-IFN provides superior inhibition of platelet activation markers than hydroxycarbamide, which in part may explain differences in risk of thromboembolic events in ET patients.

Oral anti-coagulant treatment patterns in atrial fibrillation patients diagnosed with cancer: A Danish nationwide cohort study.

Data on the use of oral anti-coagulants (OAC) for stroke prevention in cancer patients with atrial fibrillation (AF) are sparse. Nationwide cohort study of patients with AF (2012-2018) and an indication for OAC who were diagnosed with cancer at least one year later (N = 12 756). We identified treatment with OAC at cancer diagnosis and the following year and described the incidence of discontinuing or switching between warfarin and direct oral anti-coagulants (DOACs). We also described baseline characteristics associated with OAC non-persistence. One third of the cancer patients received no OAC therapy, whereas 42% received warfarin and 24% received DOAC treatment. Switching incidence between OACs was higher for those receiving warfarin treatment (8.6%) than DOAC treatment (1.7%) within one year. Treatment discontinuation was 61% for warfarin and 26% for DOAC. Females were less likely to discontinue DOAC than males (ratio 0.77, 95% confidence interval: 0.66, 0.90). Increasing cancer stage was associated with discontinuation of DOAC, but not warfarin. OAC for stroke prevention in AF was used by two thirds of patients with newly diagnosed cancer. Switching between OACs and discontinuation was more common for warfarin than DOAC, and females had higher persistence with DOACs.

Flow Cytometric Assessment of Changes in Platelet Reactivity after Acute Coronary Syndrome: A Systematic Review.

Increased platelet activity is an important predictor for recurrent cardiovascular events in patients with acute coronary syndromes (ACS). Flow cytometry is an advanced method for evaluation of platelet activity. We aimed to summarize the current literature on dynamic changes in platelet activity analyzed by flow cytometry in patients with ACS. Employing the guidelines of Preferred Report Items for Systematic Reviews and Meta-Analyses (PRISMA), we searched PubMed and Embase on October 26, 2021, and identified studies measuring platelet activity with flow cytometry in ACS patients in the acute phase (baseline) and at follow-up in a more stable phase. In the 12 included studies, fibrinogen receptor, α-granule secretion, platelet reactivity index, monocyte-platelet aggregates, neutrophil-platelet aggregates, and reticulated platelets were measured. The fibrinogen receptor and α-granule secretion were either unchanged or lower during follow-up measurements than in the acute phase. Platelet reactivity index showed inconsistent results. Values of monocyte-platelet aggregates and neutrophil-platelet aggregates were lower at follow-up than at baseline (p-values <0.05). Reticulated platelets were either unchanged (p-value >0.64) or lower at 1 to 2 months follow-up (p-value 0.04), and also lower at 5 months to 1-year follow-up (p-value >0.005) compared with baseline. Overall, flow cytometric analyses of platelet function in ACS patients showed that platelet activity was lower at follow-up than at baseline. However, in some patients, platelet activity remained unchanged from baseline to follow-up, possibly indicating a sustained high platelet activity that may increase the risk of recurrent cardiovascular events.

Gender disparities in time-to-initiation of cardioprotective glucose-lowering drugs in patients with type 2 diabetes and cardiovascular disease: a Danish nationwide cohort study.

BACKGROUND: We aimed to examine the impact of gender and specific type of cardiovascular disease (CVD) diagnosis (ischemic heart disease [IHD], heart failure, peripheral artery disease [PAD] or stroke) on time-to-initiation of either a sodium glucose cotransporter 2 inhibitor or glucagon-like peptide 1 analogue (collectively termed cardioprotective GLD) after a dual diagnosis of type 2 diabetes (T2DM) and CVD. METHODS: In a nationwide cohort study, we identified patients with a new dual diagnosis of T2DM and CVD (January 1, 2012 and December 31, 2018). Cumulative user proportion (CUP) were assessed. Poisson models were used to estimate the initiation rate of cardioprotective GLDs. The final analyses were adjusted for potential confounders. RESULTS: In total, we included 70,538 patients with new-onset T2DM and CVD (38% female, mean age 70 ± 12 years at inclusion). During 183,256 person-years, 6,276 patients redeemed a prescription of a cardioprotective GLD. One-year CUPs of cardioprotective GLDs were lower in women than men. Initiation rates of GLDs were lower in women (female-to-male initiation-rate-ratio crude: 0.76, 95% CI 0.72-0.81); adjusted 0.92, 95% CI 0.87-0.97). In CVD-stratified analysis, the adjusted initiation rate ratio was lower in female patients with IHD and heart failure (IHD: 0.91 [95% CI 0.85-0.98], heart failure: 0.85 [95% CI 0.73-1.00], PAD: 0.92 [95% CI 0.78-1.09], and stroke: 1.06 [95% CI 0.93-1.20]). CONCLUSIONS: Among patients with a new dual diagnosis of T2DM and CVD, female gender is associated with lower initiation rates of cardioprotective GLDs, especially if the patient has IHD or heart failure.

Safety and effectiveness of direct oral anticoagulants in patients with nephrotic syndrome: a report of 21 cases.

BACKGROUND: Nephrotic syndrome (NS) is associated with increased risk of thromboembolic events (TE) adding to the morbidity and mortality. International guidelines recommend prophylactic anticoagulation in patients with NS and high risk of TE, but no studies have identified the optimal type of anticoagulation in NS. We aimed to assess the effectiveness and safety of direct oral anticoagulant (DOAC) by analyzing the thromboembolic and bleeding events in NS patients prescribed DOAC as primary prophylaxis to prevent TE or as treatment for TE occurring in relation to NS. METHODS: We performed a single-center, retrospective study including patients with NS, a plasma albumin less than 25 g/L and prophylactic anticoagulation treatment with DOAC at the Department of Renal Medicine at Aarhus University Hospital, Denmark from July 2016 to June 2021. Patients treated with DOAC as thromboprophylaxis for other indications than NS were excluded. Baseline characteristics and outcomes, including TE, bleeding and other adverse effects associated with DOAC were obtained from medical records. RESULTS: We identified 268 patients treated with DOAC of which 21 patients with NS were included in the study. Nineteen patients were prescribed DOAC as thromboprophylaxis and two patients received DOAC due to previous TE, which was considered associated with the NS. The type of DOAC prescribed was apixaban (n = 10) and rivaroxaban (n = 11). No patients experienced TE during DOAC treatment, while five patients had a minor bleeding episode. Patients who experienced bleeding episodes were older (median 62 vs 51 years), more often female (80%) and had been on DOAC for a longer period (204 days vs 47 days). Neither the HAS-BLED score nor GN-risk-score predicted the risk of minor bleedings in this population. CONCLUSIONS: In this case series, no new TE and only minor bleeding complications were observed among adult NS patients treated with DOAC.

Management of antithrombotic therapy in patients undergoing transcatheter aortic valve implantation: a consensus document of the ESC Working Group on Thrombosis and the European Association of Percutaneous Cardiovascular Interventions (EAPCI), in collaboration with the ESC Council on Valvular Heart Disease.

Transcatheter aortic valve implantation (TAVI) is effective in older patients with symptomatic severe aortic stenosis, while the indication has recently broadened to younger patients at lower risk. Although thromboembolic and bleeding complications after TAVI have decreased over time, such adverse events are still common. The recommendations of the latest 2017 ESC/EACTS Guidelines for the management of valvular heart disease on antithrombotic therapy in patients undergoing TAVI are mostly based on expert opinion. Based on recent studies and randomized controlled trials, this viewpoint document provides updated therapeutic insights in antithrombotic treatment during and after TAVI.

Contemporary Clinical Use of Aspirin: Mechanisms of Action, Current Concepts, Unresolved Questions, and Future Perspectives.

The ability of aspirin to inhibit platelet aggregation has positioned this agent within the most frequently used drugs worldwide. The aim of this article is to review the contemporary clinical use of aspirin and also to discuss unresolved issues not yet translated into clinical practice. Results from several clinical trials have led to strong guideline recommendations for aspirin use in the acute management and secondary prevention of cardiovascular disease. On the contrary, guidelines regarding aspirin use as primary prevention of cardiovascular disease are almost conservative, supported by recent trials reporting that the bleeding risk outweighs the potential benefits in most patients. In pregnancy, aspirin has proved efficient in preventing preeclampsia and small-for-gestational-age births in women at high risk, and is hence widely recommended in clinical guidelines. Despite the vast amount of clinical data on aspirin, several unresolved questions remain. Randomized trials have reported that aspirin reduces the risk of recurrent venous thromboembolism, but the clinical relevance remains limited, because direct oral anticoagulants are more effective. Laboratory studies suggest that a twice-daily dosing regimen or evening intake may lead to more efficient platelet inhibition, and the potential clinical benefit of such strategies is currently being explored in ongoing clinical trials. Enteric-coated formulations of aspirin are frequently used, but it remains unclear if they are safer and as efficient as plain aspirin. In the future, aspirin use after percutaneous coronary interventions might not be mandatory in patients who also need anticoagulant therapy, as several trials support shorter aspirin duration strategies. On the other hand, new treatment indications for aspirin will likely arise, as there is growing evidence that aspirin may reduce the risk of colorectal cancer and other types of cancer.

Platelet Function and Turnover in Essential Thrombocythemia: A Systematic Review.

Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by increased platelet counts. ET has an incidence of 0.6 to 2.5 per 100,000 per year in Europe and North America. The disease is characterized by an increased thromboembolic risk, possibly caused by increased platelet counts. Furthermore, increased platelet function and/or increased platelet turnover may play a role. We aimed to explore: (1) whether platelet function and platelet turnover are increased in ET patients compared with healthy controls, and (2) whether these parameters are associated with increased thromboembolic risk and, therefore, may support decision-making on treatment in ET patients. We performed a systematic literature search on March 20, 2020 in Embase and PubMed following the Preferred Reporting Items for Systematic and Meta-Analysis (PRISMA) guidelines. In total, 1,923 articles were identified, 38 of which were included according to prespecified inclusion and exclusion criteria. Among the 38 studies, platelet activation (CD36 and CD62P) was investigated in 18 studies and was found to be increased in 12 of these. Platelet aggregation was investigated in 21 studies and was reported to be reduced in 20 of them. Platelet turnover (immature platelet count and mean platelet volume) was investigated in five studies with inconclusive results. No parameters were reported to predict the risk of thromboembolic events. In conclusion, platelet activation was increased in ET patients, but platelet aggregation was reduced. Future studies exploring markers of thromboembolic risk in ET patients are warranted.

Micro- and macrovascular cardiac allograft vasculopathy in relation to 91 cardiovascular biomarkers in heart transplant recipients-An exploratory study.

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation (HTx), and the pathogenesis is not fully clarified. We aimed to investigate a wide range of biomarkers and their correlation with micro- and macrovascular CAV and major adverse cardiac events in HTx patients. METHODS: We evaluated 91 cardiovascular disease-related proteins in 48 HTx patients using a novel proteomic panel. Patients were dichotomized according to micro- and macrovascular CAV burden determined by coronary angiography, optical coherence tomography, and 15 O-H2 O positron emission tomography imaging. Major adverse cardiac events included significant CAV progression, heart failure, treated rejection, and cardiovascular death. RESULTS: We found consistent differences in two proteins involved in cholesterol homeostasis: significantly increased proprotein convertase subtilisin/kexin type 9 (PCSK9) (p < .05) and significantly decreased paraoxonase 3 (PON3) (p < .05). N-terminal pro-brain natriuretic peptide (NT-proBNP) was significantly increased in patients with microvascular CAV (p < .05) and borderline significantly increased in patients experiencing major adverse cardiac events (p = .10) and patients with macrovascular CAV (p = .05). CONCLUSIONS: We identified consistent changes in two proteins involved in cholesterol homeostasis which may be important players in the pathogenesis of CAV: PON3 and PCSK9. NT-proBNP also showed consistent changes across all groups but only reached statistical significance in patients with microvascular CAV. Our results warrant further validation in future studies.

Computed Tomography-Derived Fractional Flow Reserve in Patients With Chronic Coronary Syndrome: A Real-World Cohort Study.

OBJECTIVE: This study aimed to investigate the outcome of computed tomography (CT) angiography with optional CT-derived fractional flow reserve (FFRCT) of intermediate-range coronary artery disease in non-emergent patients referred on a suspicion of chronic coronary syndrome. METHODS: Patients were classified as high risk and low-intermediate risk according to the presence of typical angina or either atypical or nonangina chest pain. Outcome was assessed as the cumulative incidence proportion of a composite end point of unstable angina pectoris, unplanned revascularization, nonfatal myocardial infarction, and all-cause mortality. RESULTS: The study included 743 patients. Mean follow-up was 2.2 (range, 0.1-2.5) years. Low-intermediate-risk and high-risk patients who had invasive coronary angiography deferred had comparable proportions of adverse events (1.4% vs 2.6% [P = 0.27]). Adverse events in high-risk patients with FFRCT >0.80 was 3.3% versus 1.4% in patients where no additional testing was performed (P = 0.79). CONCLUSIONS: Computed tomography-derived fractional flow reserve >0.8 conveys an excellent prognosis. Computed tomography angiography with optional FFRCT allows for the safe cancellation of invasive coronary angiography in high-risk patients.

Using the Case-Crossover Design to Assess Short-Term Risks of Bleeding and Arterial Thromboembolism After Switching Between Oral Anticoagulants in a Population-Based Cohort of Patients With Atrial Fibrillation.

Using nationwide Danish registries, we conducted a population-based case-crossover study evaluating the association between switching from a vitamin K antagonist (VKA) to a direct oral anticoagulant (DOAC), and vice versa, and 30-day risks of bleeding and arterial thromboembolism in patients with atrial fibrillation (AF). The case-crossover population was identified among oral anticoagulant users during 2011-2018 (n = 123,217) as patients with AF with 1) a case-defining outcome and 2) an anticoagulant switch during the 180 days preceding the outcome. Odds ratios were estimated using conditional logistic regression by comparing the occurrence of switching during the 30-day window immediately preceding the outcome to that in reference windows in the same individual 60-180 days before the outcome. The case-crossover populations for switching from VKA to DOAC and DOAC to VKA comprised 1,382 and 287 case patients, respectively. Switching from VKA to DOAC, but not from DOAC to VKA, was associated with an increased short-term risk of bleeding (odds ratio = 1.42; 95% confidence intervals: 1.13, 1.79, and 1.06; and 0.64, 1.75, respectively) and ischemic stroke (odds ratio = 1.74; 95% confidence intervals: 1.21, 2.51, and 0.92; and 0.46, 1.83, respectively). Our findings suggest that switching from VKA to DOAC is an intermittent risk factor of bleeding and ischemic stroke in patients with AF.

Benefits and Harm of Treatment with P2Y12 Inhibitors beyond 12 Months in Patients with Coronary Artery Disease.

The trade-off between the benefits and harm of long-term (> 12 months) treatment with P2Y12 inhibitors in patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI) remains controversial. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. PubMed and Embase were searched without time restrictions to identify randomized controlled trials comparing > 12-month P2Y12 inhibition versus ≤ 12-month treatment in patients with acute coronary syndrome (ACS) or stable CAD undergoing PCI. A qualitative assessment was performed using the assessment tool from the National Heart, Lung, and Blood Institute of the National Institutes of Health. We performed a meta-analysis of the following endpoints: primary outcome (primarily major cardiovascular events), all-cause death, and major bleeding. Eight trials, comprising 40,218 patients, were included. Five studies were rated "good," two studies "fair," and one study "poor." The meta-analysis showed that > 12-month P2Y12 inhibition significantly reduced the primary outcomes compared with ≤ 12-month treatment (hazard ratio [HR]: 0.85; 95% confidence interval (CI): 0.75-0.97; p = 0.01). No significant difference was demonstrated between groups in all-cause death (HR: 1.02; 95% CI: 0.76-1.36; p = 0.91) or major bleedings (HR: 1.26; 95% CI: 0.93-1.70; p = 0.14). I 2 test showed low to moderate heterogeneity among the included studies (21.6-62.3%). This systematic review and meta-analysis therefore demonstrates a reduction in major cardiovascular events during extended P2Y12-inhibitor treatment beyond 12 months compared with ≤ 12 months in patients with ACS or stable CAD undergoing PCI. There was no significant difference in all-cause death or major bleedings.

Primary Prevention of Cardiovascular Events with Aspirin: Toward More Harm than Benefit-A Systematic Review and Meta-Analysis.

Primary prevention of cardiovascular events with aspirin remains controversial, as the risk of bleeding might outweigh the benefits. Recently, new evidence has emerged from the ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events), ASCEND (A Study of Cardiovascular Events in Diabetes), and ASPREE (Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly) trials. The aim of this study was to perform a systematic review and meta-analysis of aspirin's efficacy and safety in the primary prevention of cardiovascular events in healthy individuals and in individuals with cardiovascular risk factors, and separately in those with diabetes. The Medline database was searched, without time restrictions, for relevant human trials published in English up to December 10, 2018, and additional trials were identified from reference lists. Data on efficacy (cardiovascular death and nonfatal myocardial infarction) and safety (major bleeding) were extracted for analysis. In total, 20 randomized trials were identified. Separate meta-analyses were performed on 10 trials including 144,930 individuals, who were healthy or had cardiovascular risk factors, and on 4 trials including 20,326 individuals with diabetes. In healthy individuals and individuals with cardiovascular risk factors, aspirin reduced the risk of nonfatal myocardial infarction by 21% (p < 0.001), but had no effect on cardiovascular death (p = 0.52), and increased the risk of major bleeding by 48% (p < 0.001). In individuals with diabetes, aspirin had no effect on nonfatal myocardial infarction (p = 0.93) or cardiovascular death (p = 0.92) and increased the risk of bleeding by 49% (p = 0.13). This meta-analysis suggests that aspirin should not be used on a routine basis in the primary prevention of cardiovascular events, especially in individuals with diabetes.

Once- versus twice-daily aspirin treatment in patients with essential thrombocytosis.

Insufficient platelet inhibition has been reported in up to 40% of aspirin-treated patients, including patients with essential thrombocytosis. To maintain sufficient platelet inhibition, a shorter dosing interval with aspirin has been suggested. We aimed to investigate the antiplatelet effect of low-dose aspirin given twice-daily compared to standard once-daily dosing in patients with essential thrombocytosis. We included 22 patients, who were treated for 7 days with standard once-daily aspirin (75 mg once-daily) followed by 7 days treatment of twice-daily aspirin (37.5 mg twice-daily). The two regimens were separated by 14 days aspirin washout. Blood samples were obtained 1h and 24h/12h after the last pill intake in each regimen. The effect of aspirin was evaluated by: (1) platelet aggregation measured by whole blood impedance aggregometry (Multiplate® Analyser) using arachidonic acid (ASPItest 0.5 mM) as agonist and (2) serum thromboxane B2 levels determined using an enzyme-linked immunosorbent assay. The difference in platelet aggregation from 1h to the end of the dosing interval (24h/12h) was used to compare the two regimens. We demonstrated a significantly smaller difference in platelet aggregation in the twice-daily regimen compared to the once-daily: mean of difference = 228 AU*min (95% confidence interval (CI): 92-363, p < 0.01). In addition, a significantly smaller difference in thromboxane B2 was demonstrated in the twice-daily regimen compared to the once-daily regimen: mean of difference = 16.3 ng/mL (95% CI: 9.9-22.7, p < 0.01). In conclusion, twice-daily dosing with low-dose aspirin provides a more consistent platelet inhibition compared with standard once-daily dosing in patients with essential thrombocytosis.