Anticoagulation Therapy by Age and Embolic Risk for Nonvalvular Atrial Fibrillation in Mexico, an Upper-Middle-Income Country: The CARMEN-AF Registry.

Background: Documenting the patterns of oral anticoagulation therapy (OAT) is essential to prevent thromboembolic complications of nonvalvular atrial fibrillation (NVAF). Objective: To report the patterns of OAT according to age and thromboembolic risk in patients included in CARMEN-AF, a nationwide registry of NVAF in Mexico, an upper middle-income country. Material and methods: There were 1,423 consecutive patients ≥18 years old and with at least one thromboembolic risk factor enrolled in the CARMEN-AF Registry at their regular clinical visit during a three-year period. They were analyzed according to 1) age, 2) AF type, and 3) CHA2DS2-VASc score. Results: Overall, 16.4% of patients did not receive antithrombotic treatment, 19.4% received antiplatelet drugs (APD), 29.2% vitamin K antagonists (VKA), and 34.6% direct oral anticoagulants (DOAC). With increasing age, the proportion of subjects treated with VKA decreased significantly from 36.2% in subjects <65 years to 22.5% in those ≥75 years old (P <0.0001). Concomitantly, an increase in both APD and no antithrombotic treatment was observed with increasing age. DOAC were prescribed equally among all age groups (34.2% in <65, 36.0% in 65-74, and 33.9% in ≥75). According to the type of AF, VKA use was more common in patients with permanent AF (32.7%). A lower use of DOAC was observed in high thromboembolic risk subjects (33.6% in CHA2DS2-VASc ≥2) compared with the moderate risk group (41% in CHA2DS2-VASc = 1). Conclusions: VKA use for NVAF in Mexico decreased in relation to increasing age. The proportion of DOAC therapy was the same in all age groups. Nevertheless, elderly patients with high thromboembolic risk received a suboptimal thromboprophylaxis. These data could help to improve gaps in the implementation of global guidelines. Clinical trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT02334852. Highlights: CARMEN-AF is a nationwide multi-centric registry seeking to bridge the data gap on anticoagulation therapy for NVAF in Mexico.Elderly patients are more prone to receive suboptimal OAT for NVAF.DOAC were less frequently used in high thromboembolic risk patients (CHA2DS2-VASc ≥2).

De la tromboembolia pulmonar aguda a la hipertensión pulmonar tromboembólica crónica: implicaciones en la patobiología y fisiopatología / From acute pulmonary embolism to chronic thromboembolic pulmonary hypertension: Pathobiology and pathophysiology

Resumen: La hipertensión pulmonar tromboembólica crónica (HPTEC) es un subtipo de hipertensión pulmonar (HP) caracterizada por la obstrucción mecánica de las arterias pulmonares causada por una tromboembolia pulmonar. Sin tratamiento es una enfermedad progresiva y devastadora, y es el único subgrupo de HP potencialmente curable mediante la endarterectomía pulmonar. La magnitud, así como la recurrencia de la embolia pulmonar, son determinantes y contribuyen al desarrollo de la HPTEC aun cuando está asociada solo a algunos factores trombofílicos. Una hipótesis es que la enfermedad es consecuencia de la resolución incompleta y la organización del trombo, favorecido por fenómenos de inflamación, inmunitarios y/o genéticos que promueven el desarrollo de estenosis de tipo fibroso que culminan con el remodelado vascular oclusivo de vasos proximales y distales. Los mecanismos involucrados en la fallida resolución del trombo aún no están esclarecidos. Los pacientes con HPTEC con frecuencia exhiben HP severa que no puede ser explicada por el grado de obstrucción vascular demostrada en estudios por imagen. En tales casos la arteriopatía pulmonar y las lesiones trombóticas obstructivas, distales al nivel subsegmentario, pueden contribuir al incremento fuera de proporción de las resistencias vasculares pulmonares. Los procesos que llevan al desarrollo de la arteriopatía pulmonar y los cambios microvasculares que ocurren en la HPTEC explican el comportamiento progresivo de la HP y el deterioro clínico gradual con pobre pronóstico para los pacientes, así como también la falta de correlación entre la magnitud de la obstrucción vascular y la medición de parámetros hemodinámicos, aun en ausencia de tromboembolismo venoso recurrente. Esta revisión resume los aspectos más relevantes y actuales de la patobiología y fisiopatología de la HPTEC.

Abstract: Chronic thromboembolic pulmonary hypertension (CTEPH) represents a unique subtype of pulmonary hypertension characterized by the presence of mechanical obstruction of the major pulmonary vessels caused by venous thromboembolism. CTEPH is a progressive and devastating disease if not treated, and is the only subset of PH potentially curable by a surgical procedure known as pulmonary endarterectomy. The clot burden and pulmonary embolism recurrence may contribute to the development of CTEPH however only few thrombophilic factors have been found to be associated. A current hypothesis is that CTEPH results from the incomplete resolution and organization of thrombus modified by inflammatory, immunologic and genetic mechanisms, leading to the development of fibrotic stenosis and adaptive vascular remodeling of resistance vessels. The causes of thrombus non-resolution have yet to be fully clarified. CTEPH patients often display severe PH that cannot be fully explained by the degree of pulmonary vascular obstruction apparent on imaging studies. In such cases, the small vessel disease and distal obstructive thrombotic lesions beyond the sub-segmental level may contribute for out of proportion elevated PVR. The processes implicated in the development of arteriopathy and microvascular changes might explain the progressive nature of PH and gradual clinical deterioration with poor prognosis, as well as lack of correlation between measurable hemodynamic parameters and vascular obstruction even in the absence of recurrent venous thromboembolism. This review summarizes the most relevant up-to-date aspects on pathobiology and pathophysiology of CTEPH.

[From acute pulmonary embolism to chronic thromboembolic pulmonary hypertension: Pathobiology and pathophysiology]. / De la tromboembolia pulmonar aguda a la hipertensión pulmonar tromboembólica crónica: implicaciones en la patobiología y fisiopatología.

Chronic thromboembolic pulmonary hypertension (CTEPH) represents a unique subtype of pulmonary hypertension characterized by the presence of mechanical obstruction of the major pulmonary vessels caused by venous thromboembolism. CTEPH is a progressive and devastating disease if not treated, and is the only subset of PH potentially curable by a surgical procedure known as pulmonary endarterectomy. The clot burden and pulmonary embolism recurrence may contribute to the development of CTEPH however only few thrombophilic factors have been found to be associated. A current hypothesis is that CTEPH results from the incomplete resolution and organization of thrombus modified by inflammatory, immunologic and genetic mechanisms, leading to the development of fibrotic stenosis and adaptive vascular remodeling of resistance vessels. The causes of thrombus non-resolution have yet to be fully clarified. CTEPH patients often display severe PH that cannot be fully explained by the degree of pulmonary vascular obstruction apparent on imaging studies. In such cases, the small vessel disease and distal obstructive thrombotic lesions beyond the sub-segmental level may contribute for out of proportion elevated PVR. The processes implicated in the development of arteriopathy and micro-vascular changes might explain the progressive nature of PH and gradual clinical deterioration with poor prognosis, as well as lack of correlation between measurable hemodynamic parameters and vascular obstruction even in the absence of recurrent venous thromboembolism. This review summarizes the most relevant up-to-date aspects on pathobiology and pathophysiology of CTEPH.

Inhibidores de fosfodiesterasa-5 para el tratamiento de la hipertensión arterial pulmonar / Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension

En cardiología clínica y experimental, los inhibidores de fosfodiesterasa-5 (PDE-5) han atraído el interés científico en años recientes como herramienta terapéutica para el tratamiento de la HAP. Las fosfodiesterasas son una superfamilia de enzimas que inactivan el adenosín monofosfato cíclico y el guanosín monofosfato cíclico, los segundos mensajeros de la prostaciclina y del óxido nítrico. El razonamiento para utilizar los inhibidores de PDE-5 en HAP se basa en su relativa selectividad por la circulación pulmonar y en su capacidad para sobreexpresar la vía del óxido nítrico por inhibición de la hidrólisis del guanosín monofosfato cíclico e incrementar sus concentraciones, lo cual produce efectos vasodilatadores, antiproliferativos y proapoptóticos que pueden revertir el remodelado vascular pulmonar. Además, pueden aumentar el inotropismo ventricular derecho al incrementar el adenosín monofosfato cíclico mediado por la inhibición de la fosfodiesterasa tipo 3 sensible al guanosín monofosfato cíclico. El sildenafil, el tadalafil y el vardenafil son 3 inhibidores de PDE-5 actualmente en uso clínico que comparten similar mecanismo de acción aunque presentan algunas diferencias significativas en potencia, selectividad por la PDE-5 y propiedades farmacocinéticas. Para el tratamiento de la HAP en pacientes en clase funcional II y III (NYHA/WHO), el sildenafil fue aprobado por la Food and Drug Administration y la European Medicines Agency en 2005; y tadalafil por la Food and Drug Administration y la European Medicines Agency en 2009. En México, el sildenafil y el tadalafil recibieron la aprobación por parte de la Comisión Federal para la Protección contra Riesgos Sanitarios para la misma indicación en 2010 y 2011 respectivamente.

In experimental and clinical cardiology, phosphodiesterase type 5 (PDE-5) inhibitors have brought scientific interest as a therapeutic tool in pulmonary arterial hypertension (PAH) management in recent years. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide. The rationale for the use of PDE-5 inhibitors in PAH is based on their capacity to overexpresss the nitric oxide pathway pursued inhibition of cyclic guanosine monophosphate hydrolysis. By increasing cyclic guanosine monophosphate levels it promotes vasodilation, antiproliferative and pro-apoptotic effects that may reverse pulmonary vascular remodeling. There is also evidence that these drugs may directly enhance right ventricular contractility through an increase in cyclic adenosine monophosphate mediated by the inhibition of the cyclic guanosine monophosphate -sensitive PDE-3. Sildenafil, tadalafil and vardenafil are 3 specific PDE-5 inhibitors in current clinical use, which share similar mechanisms of action but present some significant differences regarding potency, selectivity for PDE-5 and pharmacokinetic properties. Sildenafil received approval in 2005 by the Food and Drug Administration and the European Medicines Agency and tadalafil in 2009 by the Food and Drug Administration and the European Medicines Agency for the treatment of PAH in patients classified as NYHA/WHO functional class II and III. In Mexico, sildenafil and tadalafil were approved by Comisión Federal de Protección contra Riesgos Sanitarios for this indication in 2010 and 2011, respectively.

[Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension]. / Inhibidores de fosfodiesterasa-5 para el tratamiento de la hipertensión arterial pulmonar.

In experimental and clinical cardiology, phosphodiesterase type 5 (PDE-5) inhibitors have brought scientific interest as a therapeutic tool in pulmonary arterial hypertension (PAH) management in recent years. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide. The rationale for the use of PDE-5 inhibitors in PAH is based on their capacity to overexpresss the nitric oxide pathway pursued inhibition of cyclic guanosine monophosphate hydrolysis. By increasing cyclic guanosine monophosphate levels it promotes vasodilation, antiproliferative and pro-apoptotic effects that may reverse pulmonary vascular remodeling. There is also evidence that these drugs may directly enhance right ventricular contractility through an increase in cyclic adenosine monophosphate mediated by the inhibition of the cyclic guanosine monophosphate -sensitive PDE-3. Sildenafil, tadalafil and vardenafil are 3 specific PDE-5 inhibitors in current clinical use, which share similar mechanisms of action but present some significant differences regarding potency, selectivity for PDE-5 and pharmacokinetic properties. Sildenafil received approval in 2005 by the Food and Drug Administration and the European Medicines Agency and tadalafil in 2009 by the Food and Drug Administration and the European Medicines Agency for the treatment of PAH in patients classified as NYHA/WHO functional class II and III. In Mexico, sildenafil and tadalafil were approved by Comisión Federal de Protección contra Riesgos Sanitarios for this indication in 2010 and 2011, respectively.