Steven P. Dunn

Purpose of Review This review sought to define the mechanism of the drug-drug interaction between phosphodiesterase-type-5 (PDE-5) inhibitors and organic nitrates as well as the clinical impact and recommended management across different clinical scenarios. Recent Findings This drug-drug interaction results in hemodynamically significant hypotension during episodic PDE-5 use and acute nitrate administration mainly during cardiovascular emergencies with multiple studies describing the expected impact. Chronic co-administration of long-acting nitrates and PDE-5 inhibitors has been observed in practice in a small percentage of patients despite the labeled contraindication without noted adverse effects. Summary Acute nitrate therapy should be avoided in the context of episodic PDE-5 exposure, likely identified through systematic processes. Few data exist defining risk with lower-intensity daily PDE-5 administration. Chronic co-administration is not recommended but may be navigated with careful risk-benefit determination. Future directions also aim to identify potential areas where nitrate synergy may achieve clinical benefit.

Iron deficiency is common in patients with heart failure and has been associated with worse outcomes, including increases in mortality, disease progression, and hospitalizations. As such, several studies have evaluated the role of iron supplementation in mitigating these risks. Evidence for the role of intravenous iron in improving exercise capacity, quality of life, and hospitalizations is promising, although the benefits of oral iron remain less clear. This review will evaluate the literature surrounding iron supplementation in heart failure and provide practical recommendations for its management.

Background: Gout is a common comorbidity in heart failure (HF) patients and is frequently associated with acute exacerbations during treatment for decompensated HF. Although colchicine is often used to manage acute gout in HF patients, its impact on clinical outcomes when used during acute decompensated HF is unknown.Methods: This was a single center, retrospective study of hospitalized patients treated for an acute HF exacerbation with and without acute gout flare between March 2011 and December 2020. We assessed clinical outcomes in patients treated with colchicine for a gout flare compared to those who did not experience a gout flare or receive colchicine. The primary outcome was in‐hospital all‐cause mortality.Results: Among 1047 patient encounters for acute HF during the study period, there were 237 encounters (22.7%) where the patient also received colchicine for acute gout during admission. In‐hospital all‐cause mortality was significantly reduced in the colchicine group compared with the control group (2.1% vs. 6.5%, p = .009). The colchicine group had increased length of stay (9.93 vs. 7.96 days, p < .001) but no significant difference in 30‐day readmissions (21.5% vs. 19.5%, p = .495). In a Cox proportional hazards model adjusted for age, inpatient colchicine use was associated with improved survival to discharge (hazards ratio [HR] 0.163, 95% confidence interval [CI] 0.051−0.525, p = .002) and a reduced rate of in‐hospital CV mortality (HR 0.184, 95% CI 0.044−0.770, p = .021).Conclusion: Among patients with a HF exacerbation, treatment with colchicine for a gout flare was associated with significantly lower in‐hospital mortality compared with those not treated for acute gout.

Anticoagulation of patients treated with the Impella percutaneous mechanical circulatory support (MCS) devices is complex and lacks consistency across centers, potentially increasing the risk of complications. In order to optimize safety and efficacy, an expert committee synthesized all available evidence evaluating anticoagulation for patients receiving Impella support in order to provide consensus recommendations for the management of anticoagulation with these devices. The evidence synthesis led to the creation of 42 recommendations to improve anticoagulation management related to the use of the Impella devices. Recommendations address purge solution management, intravenous anticoagulation, monitoring, evaluation and management of heparin‐induced thrombocytopenia (HIT), and management during combination MCS support. The use of a heparinized, dextrose‐containing purge solution is critical for optimal device function, and a bicarbonate‐based purge solution may be an alternative in certain situations. Likewise, intravenous (ie, systemic) anticoagulation with heparin is often necessary, although evidence supporting the optimal assay and target range for monitoring the level of anticoagulation is generally lacking. Patients treated with an Impella MCS device may develop HIT, which is more difficult to evaluate and treat in this setting. Lastly, the use of Impella with extracorporeal membrane oxygenation or for biventricular support creates additional anticoagulation challenges.

Background: Proton pump inhibitors ( PPI s) may interfere with the metabolic activation of clopidogrel via inhibition of cytochrome P450 2C19, but the clinical implications remain unclear. Methods and Results: The impact of PPI use on the 1‐year primary end point (ischemic stroke, myocardial infarction [ MI ], or vascular death) in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial and the 28‐day (all‐cause death, MI , or urgent target vessel revascularization) and 1‐year (all‐cause death, MI , or stroke) primary end points in the Clopidogrel for Reduction of Events During Observation (CREDO) trial were examined. Clopidogrel appeared to elevate risk for the primary end point in CAPRIE among PPI users (estimated hazard ratio [ EHR ] 2.66, 95% CI 0.94 to 7.50) while lowering it for non‐ PPI users ( EHR 0.90, 95% CI 0.83 to 0.99, interaction P =0.047). Moreover, PPI use was associated with worse outcomes in patients receiving clopidogrel ( EHR 2.39, 95% CI 1.74 to 3.28) but not aspirin ( EHR 1.04, 95% CI 0.70 to 1.57, interaction P =0.001). Clopidogrel did not significantly alter risk for the 1‐year primary end point in CREDO among PPI users ( EHR 0.82, 95% CI 0.48 to 1.40) while lowering it for non‐ PPI users ( EHR 0.71, 95% CI 0.52 to 0.98, interaction P =0.682). Also, PPI use was associated with worse outcomes in both patients receiving clopidogrel ( EHR 1.67, 95% CI 1.06 to 2.64) and those receiving placebo ( EHR 1.56, 95% CI 1.06 to 2.30, interaction P =0.811). Conclusions: In CREDO , the efficacy of clopidogrel was not significantly affected by PPI use. However, in CAPRIE , clopidogrel was beneficial to non‐ PPI users while apparently harmful to PPI users. Whether this negative interaction is clinically important for patients receiving clopidogrel without aspirin needs further study.

Platelet activation results in the release and upregulation of mediators responsible for immune cell activation and recruitment, suggesting that platelets play an active role in immunity. Animal models and retrospective data have demonstrated benefit of antiplatelet therapy on inflammatory mediator expression and clinical outcomes. This study sought to characterize effects of clopidogrel on the incidence and severity of community-acquired pneumonia (CAP). A retrospective cohort study was conducted of Kentucky Medicaid patients (2001–2005). The exposed cohort consisted of patients receiving at least six consecutive clopidogrel prescriptions; the non-exposed cohort was comprised of patients not prescribed clopidogrel. Primary endpoints included incidence of CAP and inpatient treatment. Secondary severity endpoints included mortality, intensive care unit admission, mechanical ventilation, sepsis, and acute respiratory distress syndrome/acute lung injury. CAP incidence was significantly greater in the exposed cohort (OR 3.39, 95 % CI 3.27–3.51, p < 0.0001) that remained after adjustment (OR 1.48, 95 % CI 1.41–1.55, p < 0.0001). Inpatient treatment was more common in the exposed cohort (OR 1.96, 95 % CI 1.85–2.07, p < 0.0001), but no significant difference remained after adjustment. Trends favoring the exposed cohort were found for the secondary severity endpoints of mechanical ventilation (p = 0.07) and mortality (p = 0.10). Pooled analysis of published studies supports these findings. While clopidogrel use may be associated with increased CAP incidence, clopidogrel does not appear to increase—and may reduce—its severity among inpatients. Because this study was retrospective and could not quantify all variables (e.g., aspirin use), these findings should be explored prospectively.

Abstract: Antiplatelet therapy is of paramount importance in the treatment and prevention of adverse cardiovascular events and stroke. Drug-drug interactions (DDIs) among antiplatelet therapies have been growing in both prevalence and clinical importance. Most DDIs with antiplatelet therapies are pharmacodynamic in nature. DDIs with thienopyridines and proton pump inhibitors have resulted in advisories from regulatory agencies although the full significance of this interaction is unknown. Other DDIs with thienopyridines may potentially exist with statins, calcium channel blockers, and warfarin but lack demonstratable evidence of harm. Aspirin may interact with a variety of medications, including non-steroidal anti-inflammatory agents and angiotensin inhibitors. DDIs requiring some level of intervention may also be present with dipyridamole and cilostazol. Overall, DDIs with antiplatelet drugs are biologically plausible and potentially clinically relevant. However, the full significance of these DDIs is largely unknown due to reliance on research of voluntary reports, registries, and claims databases to determine significance.

The European Medicines Agency (EMEA) recently issued a public statement on a possible interaction between clopidogrel and proton pump inhibitors (PPIs) and recommended that the product information for all medicines containing clopidogrel be amended to discourage concomitant use of PPIs unless absolutely necessary. This follows a prior alert issued by the United States Food and Drug Administration (FDA) earlier this year, stating that PPIs might interfere with the effectiveness of clopidogrel and that clinicians should reevaluate starting or continuing treatment with a PPI in patients taking clopidogrel. However, several experts have voiced their concern that the clopidogrel-PPI interaction has been given undue importance, given that all clinical studies suggesting this problem are observational. In this review, we critically analyze the available data and make practical suggestions for the clinician regarding appropriate use of PPIs in patients receiving clopidogrel. Based on currently available evidence, we suggest that the decision to prescribe a PPI to a patient on clopidogrel must be made on an individual patient basis balancing the gastrointestinal risk with the possible thrombotic risk and that PPIs should only be used for truly appropriate indications.

Variable platelet response to clopidogrel has been widely observed. Studies have shown that the mean aggregation response to clopidogrel can be changed by a higher maintenance dose. However, these studies have not focused on individual changes. This study examined the platelet function effects of increasing the maintenance clopidogrel dose from 75 to 150 mg/day with a focus on inter-individual response. Twenty patients with known coronary artery disease receiving 75 mg/day clopidogrel were recruited and given 150 mg/day clopidogrel for 30 days, then returned to 75 mg/day for an additional 30 days. Platelet function was assessed through light-transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay at baseline, 30 days, and 60 days. Mean platelet inhibition was significantly improved with the increased maintenance dose when measured by the VerifyNow P2Y12 assay (P2Y12 reaction units: 191±15 vs. 158±17, P=0.013), but not when measured by LTA (LTA-adenosine diphosphate 5: 40±3 vs. 36±3, P = 0.11; LTA-adenosine diphosphate 20: 50±3 vs. 47±3, P = 0.23). However, only 50% of individual patients experienced improved platelet inhibition, as measured by the VerifyNow P2Y12 assay, when treated with the increased maintenance dose. Furthermore, poor baseline platelet response did not predict improved responsiveness at the increased dose. Despite changing the population's mean antiplatelet response, an increased maintenance dose of clopidogrel did not improve antiplatelet response in a substantial number of patients; nor did baseline platelet function predict response to a higher maintenance dose.