UNIVERSIDAD AUTÓNOMA DE MADRID FACULTAD DE MEDICINA
DEPARTAMENTO DE MEDICINA
SAFETY EVALUATION OF ORAL ANTICOAGULATION IN PULMONARY ARTERIAL HYPERTENSION:
OBSERVATIONAL STUDY OF PATIENTS FOLLOWED IN TWO PULMONARY HYPERTENSION REFERRAL CENTERS IN
SPAIN AND UNITED STATES
EVALUACIÓN DE LA SEGURIDAD DE LA ANTICOAGULACIÓN ORAL EN HIPERTENSIÓN ARTERIAL PULMONAR:
ESTUDIO OBSERVACIONAL DE PACIENTES EN SEGUIMIENTO EN DOS CENTROS DE REFERENCIA EN HIPERTENSIÓN PULMONAR EN
ESPAÑA Y ESTADOS UNIDOS
DOCTORAL THESIS TAMARA ROLDÁN SEVILLA
2016
UNIVERSIDAD AUTÓNOMA DE MADRID FACULTAD DE MEDICINA
DEPARTAMENTO DE MEDICINA
SAFETY EVALUATION OF ORAL ANTICOAGULATION IN PULMONARY ARTERIAL HYPERTENSION:
OBSERVATIONAL STUDY OF PATIENTS FOLLOWED IN TWO PULMONARY HYPERTENSION REFERRAL CENTERS
IN SPAIN AND UNITED STATES
EVALUACIÓN DE LA SEGURIDAD DE LA
ANTICOAGULACIÓN ORAL EN HIPERTENSIÓN ARTERIAL PULMONAR:
ESTUDIO OBSERVACIONAL DE PACIENTES EN SEGUIMIENTO EN DOS CENTROS DE REFERENCIA EN HIPERTENSIÓN PULMONAR EN
ESPAÑA Y ESTADOS UNIDOS
RESEARCH PRESENTED TO OBTAIN THE DOCTORAL DEGREE IN MEDICINE
Author: TAMARA ROLDÁN SEVILLA Direction: JUAN JOSÉ RÍOS BLANCO
ELENA VILLAMAÑÁN BUENO
2016
D. Juan Jose Ríos Blanco, Profesor Asociado del Departamento de Medicina de la Facultad de Medicina de la Universidad Autónoma de Madrid y Subdirector Médico del Hospital Universitario La Paz y Dª Elena Villamañan Bueno, Farmacéutica Adjunta del Hospital Universitario La Paz, consideran que el trabajo presentado por Dª Tamara Roldán Sevilla y titulado “Evaluación de la seguridad de la anticoagulación oral en hipertensión arterial pulmonar: Estudio observacional de pacientes en seguimiento en dos centros de referencia en hipertensión pulmonar en España y Estados Unidos” reúne las características para ser definido como Tesis Doctoral en Medicina.
Madrid, 9 de Septiembre de 2016
Juan Jose Ríos Blanco Elena Villamañan Bueno
A mi familia
To my family
To Professor D. Juan José Ríos Blanco for his support, guidance, interest and faith in me.
He has my complete admiration and respect. To my mentor and beloved friend D. Elena Villamañán Bueno for her passion, optimism, and encouraging attitude at all times. For her dedication and enthusiasm on everything that she does. Without D. Ríos and Villamañán’s exemplary direction this work would have never been possible.
To Professor D. Aaron Waxman for his consideration and believing in the value of this work. Thanks for the time and the interest taken.
To D. Rosario Madero Jarabo for her valuable help and advice on the statistical analysis.
To the Alfonso Martin Escudero Foundation, an organization that supports young researchers to make their way into foreign countries. Thanks for the opportunity and the two amazing years that changed my life.
To my colleges in the Anticoagulation Management Service, for their warm welcome and for everything I have learned from them. Thanks to Julie Atay, whose good will and cooperation were key in the completion of the project. Thanks to D. Mattia Migliore for her kindness and the time taken on the evaluation of this research.
To the Lewis family for their love, support and dedication on the English editing, to make this manuscript shine.
1. INTRODUCTION ... 41
1.1. PULMONARY HYPERTENSION ... 41
1.1.1. HISTORY OF PULMONARY HYPERTENSION ... 41
1.1.2. DEFINITION ... 43
1.1.3. CLASSIFICATION ... 44
1.1.4. EPIDEMIOLOGY ... 47
1.1.5. SYMPTOMS, DIAGNOSIS AND PROGNOSIS ... 49
1.1.6. TREATMENT OF PULMONARY HYPERTENSION ... 54
1.2. ANTICOAGULATION THERAPY ... 62
1.2.1. COAGULATION ... 62
1.2.2. ANTICOAGULANTS ... 64
1.2.3. ANTICOAGULATION MANAGEMENT ... 70
1.2.4. ANTICOAGULATION MANAGEMENT IN PULMONARY ARTERIAL HYPERTENSION ... 73
1.2.5. EFFICACY AND SURVIVAL OF ANTICOAGULATION IN PULMONARY ARTERIAL HYPERTENSION ... 75
1.2.6. DIRECT ORAL ANTICOAGULANTS IN THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION ... 80
1.2.7. COMPLICATION OF ANTICOAGULATION IN PULMONARY ARTERIAL HYPERTENSION ... 81
1.2.8. STUDY JUSTIFICATION ... 85
2. HYPOTHESIS AND OBJECTIVES ... 87
2.1. HYPOTHESIS... 87
2.2. PRIMARY OBJECTIVE ... 87
2.3. SECONDARY OBJECTIVES ... 87
3. METHODOLOGY ... 89
3.1. DESCRIPTION AND SELECTION OF PARTICIPANTS ... 89
3.1.1. STUDY CALENDAR ... 89
3.1.2. PATIENTS ... 89
3.1.3. INCLUSION, EXCLUSION AND WITHDRAWAL CRITERIA ... 91
3.1.4. STUDY VARIABLES ... 92
3.1.4.1. Demographics ... 92
3.1.4.2. Clinical ... 92
3.1.4.3. Pharmacotherapy at the beginning of follow-up ... 93
3.1.4.6. Secondary end points variables ... 96
3.2. INSTRUMENTS AND DATA COLLECTION ... 101
3.2.1. DATA COLLECTION AT HOSPITAL UNIVERSITARIO LA PAZ ... 102
3.2.2. DATA COLLECTION AT BRIGHAM AND WOMEN’S HOSPITAL ... 104
3.2.3. DATA COLLECTION FORM ... 106
3.3. DATA ANALYSIS AND STATISTICAL TREATMENT ... 110
3.3.1. GENERAL ASPECTS ... 110
3.3.2. STUDY POPULATION CHARACTERISTICS ... 111
3.3.3. MAIN OBJECTIVE: SAFETY OF ANTICOAGULATION ANALYSIS ... 111
3.3.4. SECONDARY OBJECTIVES ... 112
3.3.4.1. Modifying risk of major bleeding factors and poor anticoagulation predictors ... 112
3.3.5. SAMPLE SIZE ASPECTS ... 112
3.4. ETHICAL ASPECTS ... 113
3.4.1. GENERAL CONSIDERATIONS ... 113
3.4.2. BENEFIT-RISK ASSESSMENT ... 113
3.4.3. PATIENT INFORMATION SHEET AND CONSENT FORM ... 113
3.4.4. DATA CONFIDENTIALITY ... 113
4. RESULTS... 115
4.1. CHARACTERISTICS AND DESCRIPTION OF THE STUDY POPULATION ... 115
4.1.1. DEMOGRAPHICS ... 115
4.1.2. PULMONARY HYPERTENSION... 116
4.1.3. PHARMACOTHERAPY... 118
4.1.4. PATIENTS’ BASELINES AT THE BEGINNING OF FOLLOW-UP ... 119
4.2. PRIMARY OBJECTIVE: SAFETY OF ANTICOAGULATION IN PULMONARY ARTERIAL HYPERTENSION ... 121
4.2.1. RISK ASSOCIATION ANALYSIS ... 121
4.2.2. KAPLAN-MEYER ANALYSIS ... 126
4.2.3. MULTIVARIATE ANALYSIS ... 128
4.3. SECONDARY OBJECTIVE: ANTICOAGULATION ASSESSMENT IN PULMONARY ARTERIAL HYPERTENSION ... 128
4.3.1. DESCRIPTION OF THE ANTICOAGULATION GROUP ... 128
4.4.1. RISK OF BLEEDING MODIFYING FACTORS ... 132
4.4.2. ANTICOAGULATION CONTROL ALTERING FACTORS ... 134
4.4.3. MULTIVARIATE ANALYSIS ... 136
4.5. SECONDARY OBJECTIVE: DESCRIPTION AND SAFETY EVALUATION OF PULMONARY ARTERIAL HYPERTENSION SPECIFIC PHARMACOTHERAPY ... 138
4.5.1. DESCRIPTION OF PULMONARY ARTERIAL HYPERTENSION SPECIFIC PHARMACOTHERAPY 138 4.5.2. SAFETY OF PULMONARY ARTERIAL HYPERTENSION TREATMENT ... 143
5. DISCUSSION ... 149
5.1. CLINICAL SIGNIFICANCE ... 149
5.2. CHARACTERISTICS AND DESCRIPTION OF THE STUDY POPULATION ... 149
5.2.1. EPIDEMIOLOGY OF PULMONARY ARTERIAL HYPERTENSION ... 149
5.2.2. FUNCTIONAL AND PROGNOSTIC ASSESSMENT AT PULMONARY ARTERIAL HYPERTENSION DIAGNOSIS ... 151
5.2.3. PHARMACOTHERAPY OF STUDY POPULATION ... 152
5.2.4. PATIENTS’ BASELINES AT THE BEGINNING OF THE FOLLOW-UP ... 152
5.3. PRIMARY OBJECTIVE: SAFETY OF ANTICOAGULATION IN PULMONARY ARTERIAL HYPERTENSION ... 154
5.3.1. COMPLICATIONS DUE TO SUPRATHERAPEUTIC ANTICOAGULATION ... 154
5.3.2. COMPLICATIONS DUE TO INFRATHERAPEUTIC ANTICOAGULATION ... 159
5.4. SECONDARY OBJECTIVE: CHARACTERISTICS AND MANAGEMENT OF ANTICOAGULATION IN PULMONARY ARTERIAL HYPERTENSION ... 162
5.5. SECONDARY OBJECTIVE: POTENTIAL RISK FACTORS IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION AND ANTICOAGULATION THERAPY ... 166
5.5.1. RISK MODIFYING FACTORS FOR BLEEDING ... 166
5.5.2. RISK MODIFYING FACTORS FOR POOR ANTICOAGULATION ... 170
5.5.2.1. Non-pulmonary arterial hypertension factors ... 170
5.5.2.2. Pulmonary arterial hypertension specific factors ... 172
5.6. SECONDARY OBJECTIVE: DESCRIPTION AND SAFETY OF THE PULMONARY ARTERIAL HYPERTENSION PHARMACOTHERAPY ... 175
5.6.1. DESCRIPTION OF THE PULMONARY ARTERIAL HYPERTENSION TREATMENT IN THE STUDY POPULATION ... 175
5.7. STUDY LIMITATIONS ... 182 5.8. FUTURE PERSPECTIVES ... 182 6. CONCLUSIONS ... 185
ABSTRACT
Introduction
Pulmonary hypertension is a severe disease characterized by molecular and anatomical changes in the pulmonary circulation. It is associated with increased pulmonary vascular resistance, which if left untreated leads to right-sided heart failure, and ultimately death. The revised World Health Organization classification system includes five groups, each one differing in associated pathophysiology. This research was carried out on patients from group 1. Group 1 or pulmonary arterial hypertension (PAH) consists of idiopathic PAH, heritable PAH (also known as familial PAH), and PAH due to diseases related to the small pulmonary muscular arterioles. These include PAH due to drugs and toxins, connective tissue diseases (CTD), human immunodeficiency virus infection, portal hypertension, congenital heart disease, and schistosomiasis. PAH is considered a rare disease. Several registries have described the epidemiology of PAH. In Europe, the PAH prevalence is within the range of 15-60 subjects per million people.
The pharmacotherapy of patients with PAH starts with the treatment of the underlying cause, but most types of PAH have no effective primary treatments so PAH specific vasodilators are needed, especially in advanced disease. The treatment algorithm includes anticoagulation as part of the supportive therapy. Anticoagulation became widely used in patients with PAH to prolong survival after observational studies demonstrated a high prevalence of vascular thrombotic lesions in post mortem evaluations of idiopathic PAH patients. Abnormalities in the anticoagulation cascade may contribute to a pro-thrombotic state in idiopathic PAH patients. These physiological changes, along with concomitant conditions requiring anticoagulation such as valve replacement, atrial fibrillation, antiphospholipid syndrome, and risk factors for thromboembolic disease (slow pulmonary blood flow, dilated right heart chambers, venous stasis, and a sedentary lifestyle), are thought to be the rationale for the use of oral anticoagulation in PAH. However, the efficacy of anticoagulation therapy on prolonging survival has never been confirmed by randomized controlled trials, nor has it been authorized by regulatory agencies as PAH indication except for chronic thromboembolic pulmonary hypertension (group 4). The use of vitamin K antagonists (VKAs) implies special attention due a narrow therapeutic margin and significant
characteristics in patients with PAH that may increase the risk of bleeding (PAH etiology and certain PAH medications), but data on anticoagulation complications in patients with PAH is scarce, with only one study published. Furthermore, achieving a successful anticoagulation control in medically complex patients, such as those with PAH, can be challenging. There are no publications assessing the quality of anticoagulation therapy in PAH.
Given the lack of scientific evidence mentioned above, we presented a study to analyze the characteristics of PAH patients and their implications in the appearance of anticoagulation-related complications, along with the appropriate management of VKAs.
HYPOTHESIS:
The complications associated with the use of oral anticoagulation in patients with pulmonary arterial hypertension outweigh the questionable benefits of this non- approved indication.
PRIMARY OBJECTIVE:
To compare the rates of major hemorrhagic and thrombotic events between pulmonary arterial hypertension patients treated with oral anticoagulants and those not treated with oral anticoagulants.
SECONDARY OBJECTIVES:
1. To assess the quality of anticoagulation in pulmonary arterial hypertension patients taking vitamin K antagonists.
2. To analyze possible factors that modify the risk of major bleeding in patients with pulmonary arterial hypertension treated with oral anticoagulants.
3. To identify potential factors that affect the quality of the anticoagulation management in patients with pulmonary arterial hypertension.
4. To describe and evaluate the safety profile of the pharmacotherapy specific to pulmonary arterial hypertension.
Methods
To evaluate the safety of routine administration regarding oral anticoagulants in
study of patients with PAH from two centers: Brigham and Women’s Hospital in Boston, and Hospital Universitario La Paz in Madrid. Patients were followed from January 2009 to August 2015. Selected patients had a confirmed PAH diagnosis by catheterization before or within the study period. Patients who received therapeutic anticoagulation before or throughout the study period were classified as the anticoagulation group.
Patients who never received therapeutic anticoagulation during the study period were classified as the control group. Patients from the anticoagulation subgroup whose anticoagulant treatment was stopped at any time during the study period were no longer monitored. Patients who started oral anticoagulants before the PAH diagnosis were monitored from the PAH diagnosis date. Patients who were treated with oral anticoagulants and terminated their treatment before the beginning of the study were included in the control group. Control group patients that experienced a thrombotic event during the course of the study period were switched to the treated group at the beginning of the anticoagulation treatment. These patients were included in the control cohort when assessing thrombotic-related events. Data collection included demographic variables, clinical variables (PAH etiology, time with disease, functional capacity and poor prognosis), hemodynamics, echocardiographics, pharmacotherapy (specific PAH pharmacotherapy, PAH combined treatment and concomitant medications), morbidity, risk of bleeding, death, and blood parameters. To evaluate the safety of anticoagulation, the following events were collected: major hemorrhage (clinically overt and associated with a fall in hemoglobin of at least 20 g.L-1 (≥1.2 mmol-L-1); resulted in the need for transfusion of at least two units of red cells; involved a critical site; or if it was fatal), minor hemorrhages, hematomas and thrombotic events. Among the anticoagulation group we recorded anticoagulant agents, target INRs, indications for anticoagulation, time on anticoagulation, time spent in therapeutic range (TTR), and interactions with anticoagulants. To identify risk factors for major bleeding and poor anticoagulation control, several PAH patients’ characteristics were evaluated including age, sex, time with disease, risk of bleeding, functional capacity, comorbidities, and PAH treatment. To evaluate the safety of PAH specific pharmacotherapy, we collected adverse drug reactions related to pulmonary vasodilators. Central tendency measures were used to describe quantitative variables. Categorical variables were described through absolute and relative frequencies using percentages. Quantitative variable comparisons between the study group (anticoagulation) and the control group (non-anticoagulation) were
compared using the Pearson’s chi-square test for independence. To evaluate the association between the exposure (anticoagulation) and the outcome (anticoagulation- related event) we used the odds ratio (OR) with the associated 95% confidence interval (CI) and p value. The frequency with which new anticoagulation-related events occurred per population at risk during the study period was calculated by using the incidence rate (IR). The incidence rate ratio (IRR) was used to compare the two incidence rates from the exposure group and the control group. To analyze anticoagulation-related event-free survival time and cumulative incidences we used Kaplan-Meyer life tables. To identify possible risk of bleeding and poor anticoagulation altering factors in the anticoagulation group the following tests were performed: t-test for independent samples and analysis of variance (ANOVA) test in parametric distributions, the Mann-Whitney U-test in non-parametric distributions, Chi-square test in categorical variables, COX-regression multivariate analysis for major bleeding risk factors and binary logistic regression for poor anticoagulation risk factors.
Results
There were 201 patients included in the study, 100 (49.8%) diagnosed with PAH before the beginning of the follow-up (January 2009) and 101 diagnosed after (50.2%). Of those 201 patients, 121 (60.2%) were treated with oral anticoagulants and 80 (39.8%) were not treated. The average age at diagnosis was 53 ± 17 years old, the median WHO functional class was III [II-III] and the average 6-minute walking test distance was 353 ± 119. Regarding PAH targeted treatment with vasodilators, a total of 192 (95.5%) patients were treated with targeted vasodilators. The median number of prescribed medications per patient was 10 [7-13], and 179 patients (89.1%) had 5 or more prescribed medications (polypharmacy). The most prevalent comorbidities were high blood pressure, obesity, and hyperlipidemia with 89 (44.3%), 76 (37.8%), and 59 (29.4%) patients respectively. The Charlson Index score median at diagnosis was 4.0 [2- 6]. There were 30 patients (14.9%) who died during the follow-up, 16 patients belonged to the anticoagulation group (13.2%) and 14 patients belonged to the non- anticoagulation group (17.5%). There were no significant differences between both
score median was 2 [1-3] per patient at the beginning of the follow-up. A total of 155 events were documented in 93 patients (46.3%) during the study. The event OR for the anticoagulation group versus non-anticoagulation was 2.0 (95% CI 1.1-3.5; p=0.021). A total of 26 patients (12.9%) suffered 33 major bleedings, 20 of whom belonged to the treated group (16.5%) and 6 to the non-treated group (7.5%). The major bleeding incidence rate for the treatment group was 4.8 events per 100 patient-years (95% CI 3.1-7.1) and the incidence rate ratio was 1.9 (95% CI 0.8-4.8; p=0.113). The COX- regression model revealed a major bleeding hazard ratio of 2.7 (95% CI 1.07-6.75;
p=0.036) when adjusted by follow-up time and prior history of bleeding. The most frequent major hemorrhage was gastrointestinal (GI) bleeding with 24 cases (72.7%) in 20 patients, 16 (13.2%) of whom were taking oral anticoagulants and 4 of whom were not (5.0%). The incidence rate of major GI bleeding in the anticoagulation group was 3.9 events per 100 patients-years (95% CI 2.4-6.0), with an incidence rate ratio of 3.0 (95%
CI 1.0-12.1; p=0.034). The PAH etiology with the highest major bleeding incidence rate was porto-PH with 7.0 events per 100 patient-year (95% CI 0.2-38.7) in the anticoagulation group. There were 14 thrombotic episodes in 14 patients, 6 from the anticoagulation group (5.3%) and 8 from the non-anticoagulation group (9.2%). The incidence ratio of thrombotic events was 1.2 (95% CI 0.4-2.6) and 2.4 (95% CI 1.0-4.8) events per 100 patient-years for the anticoagulation and non-anticoagulation groups respectively. The thrombotic event incidence rate ratio was 0.5 (95% CI 0.1-1.6;
p=0.190). The most frequent thrombotic event was venous thromboembolism (VTE) with 7 episodes (50.0%). The incidence rate of VTE in the treated group was 2.0 events per 1000 patient-years (95% 0.1-11.2) and 18.4 per 1000 patient-years (95% CI 6.8- 40.6) in the non-treated group. The incidence rate ratio was 0.11 (95% CI 0.002-0.891;
p=0.012). Regarding anticoagulation control quality, the study population time spent within range (TTR) was 57.0%. The TTRs per center were 59.8% for the Brigham and Women’s Hospital Anticoagulation Management Service, 55.4% for Brigham and Women’s Hospital (non-Anticoagulation Management Service), and 49.4% for Hospital Universitario La Paz. Among the statistically significant factors (and those that approached significance) that might indicate a higher risk of major bleeding events within the anticoagulation population were: 6-minute walking distance at diagnosis, HAS-BLED score, history of bleeding, poor anticoagulation control, diabetes, and high target international normalized ratio (INR). Indicators that were significant to the
end of the study, 85 patients (44.3%) were on monotherapy with specific pulmonary vasodilators, and the rest were on combined treatment (55.7%) with statistical differences. The pulmonary vasodilator combinations most frequently used were the dual-therapy tadalafil + treprostinil (16 patients; 15.0%) and tadalafil + bosentan (9 patients, 8.4%). At the end of the study, the vasodilator family used to treat the highest number of patients was the phosphodiesterase-inhibitors (143 treatments, 41.9%), followed by endothelin receptor antagonists (108 treatments, 31.7%) and prostacyclin analogs (86 treatments, 25.2%). The vasodilator included in a larger number of treatments was treprostinil with 78 patients (40.6%), followed by tadalafil with 72 patients (37.5%), sildenafil with 67 (34.9%), ambrisentan with 54 (28.1%), and bosentan with 51 (26.6%). There were 265 adverse drug reactions (ADRs) related to the specific PAH vasodilator treatment, with an ADRs incidence rate of 32 ADRs per 100 patients-years. The pulmonary vasodilator class that accumulated the highest number of ADRs was prostacyclin analogs. The incidence rate in patients using combination therapy was 38 ADRs per 100 patient-years. In patients using a single PAH vasodilator the incidence rate was 22 ADRs per 100 patients-years.
Conclusions
1. Study patients who started oral anticoagulation as part of the supportive treatment for pulmonary arterial hypertension had a risk of having a major bleeding almost three times greater than non-treated patients.
2. Pulmonary arterial hypertension patients obtained an annual incidence rate of major bleeding higher than those found in populations with other indications for anticoagulation.
3. Gastrointestinal bleeding was the most frequent form of major bleeding. Study patients receiving anticoagulants had a significantly higher risk of gastrointestinal bleeding than non-anticoagulant users.
4. Patients who did not take anticoagulants had a higher annual incidence rate of venous thromboembolism than patients on anticoagulants.
5. The results of this study suggest that the harms of anticoagulation outweigh the
anticoagulants should be on a case by case basis and should not be systematically recommended.
6. The quality of the anticoagulation throughout the study was insufficient as the overall time spent in therapeutic range did not reach the recommended threshold of 65%, and it was within the range of what is considered poor and ineffective (<60%).
Specialized centers had better outcomes than Primary Care settings for this matter.
7. Among HAS-BLED score factors, prior bleeding or predisposition to bleed, poor anticoagulation control, and a score ≥3 in this scale, were factors that indicated a significantly higher risk of major bleeding in the anticoagulation study group.
8. Diabetes and the number of medications in the treatment impacted patients’ risk of major bleeding. Prostacyclin analogs showed a non-significant trend toward an increased risk of bleeding-related events.
9. Age, sex, high intensity anticoagulation, and atrial fibrillation are non-pulmonary arterial hypertension factors that affected the anticoagulation control of the study patients. Among pulmonary arterial hypertension specific factors, the treatment with bosentan and a low 6-minute walking test distance at diagnosis were associated with a worse quality of the anticoagulation.
10. The use of pulmonary advanced specific pharmacotherapy involved numerous adverse drug reactions, especially in the treatment with prostacyclin analogs partly due to a troublesome administration. Combination treatment caused significantly more adverse reactions than monotherapy. Gastrointestinal side effects due to pulmonary vasodilators did not contribute to the onset of major gastrointestinal bleeding.
KEY WORDS: PULMONARY HYPERTENSION, ANTICOAGULANTS, COUMARINS, WARFARIN, HEMORRHAGE, THROMBOSIS, SAFETY
RESUMEN
Introducción
La hipertensión pulmonar es una enfermedad severa caracterizada por cambios anatómicos y a nivel molecular en la circulación pulmonar. Está asociada con un incremento en la resistencia vascular pulmonar, que si no es tratada puede conducir a insuficiencia cardiaca derecha y finalmente muerte. La clasificación revisada por la Organización Mundial de la Salud incluye cinco grupos, diferenciándose cada uno en la fisiopatología asociada. El grupo de hipertensión pulmonar en el que se centra esta investigación es el grupo 1 o hipertensión arterial pulmonar (HAP). Dentro del grupo 1 encontramos las siguientes etiologías: idiopática, heredable (también conocida como familiar), y HAP debida a enfermedades relacionadas con la musculatura de las pequeñas arteriolas pulmonares. Éstas incluyen HAP debido a fármacos y toxinas, enfermedades del tejido conectivo, infección con el virus de la inmunodeficiencia humana, hipertensión portal, enfermedades cardiacas congénitas y esquistosomiasis. La HAP está considerada enfermedad rara. Varios registros han descrito la epidemiología de la HAP. En Europa, la prevalencia de la HAP se encuentra entre 15-60 sujetos por el millón de población. La farmacoterapia de los pacientes con HAP comienza tratando la causa subyacente, pero la mayoría de las causas de HAP no tiene un tratamiento efectivo, por lo que se necesitan vasodilatadores pulmonares específicos, sobre todo en enfermedad avanzada. El algoritmo del tratamiento incluye la anticoagulación como parte de la terapia de soporte. La anticoagulación se empezó a utilizar ampliamente en pacientes con HAP para prolongar su supervivencia después de que estudios observacionales demostraran una alta prevalencia de lesiones vasculares trombóticas en autopsias de pacientes con HAP idiopática. Las anormalidades presentes en la cascada de la anticoagulación pueden contribuir a un estado protrombótico en la HAP idiopática. Estos cambios fisiológicos, junto con otras condiciones concomitantes que requieren anticoagulación como son: recambio valvular, fibrilación auricular, síndrome antifosfolípido y factores de riesgo de enfermedad tromboembólica (flujo sanguíneo pulmonar lento, cavidades dilatadas en el corazón derecho, estasis venoso y vida sedentaria), son los motivos por los que se justifica el tratamiento con anticoagulantes orales. Sin embargo, la eficacia de la terapia anticoagulante en la prolongación de la
hipertensión pulmonar tromboembólica crónica (grupo 4) cuenta con esta autorización.
El uso de antagonistas de la vitamina K implica una atención especial debido al estrecho margen terapéutico y la notable variabilidad entre pacientes. Una anticoagulación insuficiente o excesiva puede conducir a complicaciones trombóticas o hemorrágicas respectivamente. Existen ciertas características en pacientes con HAP que pueden incrementar el riesgo de sangrado (etiología de la HAP y ciertos fármacos específicos de la HAP), pero la información sobre las complicaciones de la anticoagulación en pacientes con HAP es escasa con solo un único estudio publicado. Además, lograr una anticoagulación satisfactoria en pacientes complejos como lo son los pacientes con HAP puede ser dificultoso. No hay publicaciones a día de hoy que evalúen la calidad de la terapia anticoagulante en HAP.
Dada la falta de evidencia científica comentada anteriormente, elaboramos un estudio que a analice las características de los pacientes con HAP y sus implicaciones en la aparición de complicaciones relacionadas con la anticoagulación y en el control adecuado de los antagonistas de la vitamina K.
HIPÓTESIS:
Las complicaciones asociadas con el uso de anticoagulación oral en pacientes con hipertensión arterial pulmonar sobrepasan los beneficios cuestionables de esta indicación no aprobada.
OBJETIVO PRIMARIO:
Comparar las tasas de hemorragia mayor y eventos trombóticos entre pacientes con hipertensión arterial pulmonar tratados con anticoagulantes orales y aquellos no tratados con anticoagulantes orales.
OBJETIVOS SECUNDARIOS:
1. Evaluar la calidad de la anticoagulación en pacientes con hipertensión arterial pulmonar en tratamiento con antagonistas de la vitamina K.
2. Analizar posibles factores que modifican el riesgo de sangrado mayor en pacientes con hipertensión arterial pulmonar tratados con anticoagulantes orales.
3. Identificar posibles factores que afecten la calidad del control de la anticoagulación
4. Describir y evaluar el perfil de seguridad de la farmacoterapia especifica de la hipertensión arterial pulmonar.
Métodos
El estudio contó con un diseño de cohortes analítico, observacional, retrospectivo de pacientes con HAP provenientes de dos centros, Brigham and Women’s Hospital en Boston y Hospital Universitario La Paz en Madrid. El seguimiento de los pacientes se realizó desde enero 2009 hasta agosto 2015. Los pacientes seleccionados tenían diagnóstico de HAP confirmado por cateterismo anterior o durante el periodo de estudio. Los pacientes que recibieron anticoagulación antes o durante el periodo de estudio fueron asignados al grupo de anticoagulación. Los pacientes que no recibieron anticoagulación durante el periodo de estudio fueron designados al grupo control. A los pacientes del subgrupo de anticoagulación cuyo tratamiento anticoagulante fue suspendido durante el periodo de estudio se les interrumpió el seguimiento. Los pacientes que empezaron la anticoagulación oral antes del diagnóstico de HAP, fueron considerados en el estudio desde la fecha del diagnóstico de HAP. Los pacientes que se trataron con anticoagulantes orales y suspendieron el tratamiento antes del comienzo del estudio, fueron incluidos en el grupo control. Los pacientes del grupo control que en el transcurso del estudio sufrieron un evento trombótico se les cruzó al grupo de anticoagulación cuando se inició el tratamiento anticoagulante como consecuencia del evento. La recogida de datos incluyó variables demográficas, clínicas (etiología de la HAP, duración de la enfermedad, capacidad funcional, parámetros de mal pronóstico), hemodinámicas, ecocardiográficas, farmacoterápicas (tratamiento específico/combinado de HAP y medicaciones concomitantes), morbilidad, riesgo de sangrado, exitus y parámetros analíticos. Para evaluar la seguridad de la anticoagulación se recogieron los siguientes eventos: hemorragia mayor (hemorragia con evidencia clínica y asociada a una bajada en hemoglobina de al menos 20 g.L-1 (≥1.2 mmol-L-1); que resulte en la necesidad de transfusión de al menos dos concentrados de hematíes; que ésta involucre un órgano crítico; o que fuera fatal), hemorragia menor, hematomas y eventos trombóticos. Respecto al grupo de anticoagulación se recogieron:
fármaco anticoagulante, INR objetivo, indicación de anticoagulación, tiempo en anticoagulación, tiempo en rango terapéutico (TTR) e interacciones con anticoagulantes. Para identificar factores de riesgo de presentar hemorragia mayor y
comorbilidades y tratamiento de la HAP. Para evaluar la seguridad del tratamiento de la HAP se recogieron efectos adversos relacionados con los vasodilatadores específicos. Se utilizaron medidas de tendencia central para describir variables cuantitativas. Las variables categóricas se describieron por medio de frecuencias relativas y absolutas con porcentajes. Para las comparaciones de variables cuantitativas entre el grupo de estudio (anticoagulación) y el grupo control (no anticoagulación) se utilizó la t-student para muestras independientes en distribuciones paramétricas y el test U de Mann-Whitney en distribuciones no paramétricas. Las variables categóricas se compararon usando el test de independencia de Chi-cuadrado de Pearson. Para evaluar la asociación entre la exposición (anticoagulación) y el resultado (evento relacionado con anticoagulación), se utilizó la odds ratio (OR) con el intervalo de confianza del 95% (IC 95%) y valor p. La frecuencia con la que ocurrieron nuevos episodios relacionados con la anticoagulación en la población de riesgo durante el periodo de estudio se calculó utilizando tasa de incidencia (IR). El cociente de la tasa de incidencia (IRR) se utilizó para comparar las dos tasas de incidencia del grupo expuesto y del grupo control. Para analizar la supervivencia libre de evento relacionado con anticoagulación y la incidencia acumulada se utilizaron las tablas de supervivencia de Kaplan-Meyer. Para identificar posibles factores de riesgo de sangrado y de mala anticoagulación en el grupo de anticoagulación se realizaron las siguientes pruebas: t-student para muestras independientes y análisis de la varianza (ANOVA) en distribuciones paramétricas, el test U de Mann-Whitney en no paramétricas, Chi-cuadrado en variables categóricas, análisis multivariante con la regresión de COX en factores de riesgo de hemorragia mayor y regresión logística binaria en factores de riesgo de anticoagulación pobre.
Resultados
Se incluyeron un total de 201 pacientes en el estudio, 100 (49,8%) diagnosticados de HAP antes del comienzo del seguimiento (enero 2009) y 101 diagnosticados después (50,2%). De esos 201 pacientes, 121 (60,2%) recibieron tratamiento con anticoagulantes orales y 80 pacientes (39,8%) no fueron tratados. El promedio de la edad al diagnóstico de HAP fue 53 ± 17 años, la mediana de clase funcional WHO fue III
tratamiento específico de HAP con vasodilatadores, un total de 192 (95,5%) pacientes fueron tratados con vasodilatadores pulmonares. La mediana del número de medicaciones prescritas por paciente fue 10 [7-13], y 179 pacientes (89,1%) tuvieron 5 o más medicamentos prescritos (polimedicados). Las comorbilidades más prevalentes fueron hipertensión arterial, obesidad e hiperlipidemia con 89 (44,3%), 76 (37,8%), y 59 (29,4%) pacientes respectivamente. La mediana de la puntuación del índice de Charlson al diagnóstico fue 4.0 [2-6]. Hubo 30 pacientes (14,9%) que murieron durante el seguimiento, 16 pacientes pertenecientes al grupo de anticoagulación (13,2%) y 14 pacientes pertenecientes al grupo control (17,5%). No hubo diferencias significativas entre grupos al respecto. En referente al riesgo de sangrado, la mediana de la puntuación del HAS-BLED al comienzo del seguimiento fue 2 [1-3] por paciente. Se recogieron un total de 155 eventos en 93 pacientes (46,3%) durante el estudio. La OR de tener un evento en el grupo de anticoagulación frente al de no anticoagulación fue 2,0 (IC 95% 1,1-3,5; p=0,021). Un total de 26 pacientes (12,9%) sufrieron 33 sangrados mayores, 20 de los cuales pertenecieron al grupo de tratamiento (16,5%) y 6 al grupo control (7,5%). La tasa de incidencia para el grupo de tratamiento fue 4,8 eventos por 100 paciente-años y el cociente de las tasas de incidencia fue 1,9 (IC 95% 0,8-4,8;
p=0,113). El modelo de regresión COX mostro un hazard ratio para hemorragia mayor de 2,7 (IC 95% 1.07-6.75; p=0.036) cuando se ajustó por tiempo de seguimiento y antecedentes de sangrado. La hemorragia mayor más frecuente fue la gastrointestinal con 24 casos (72,7%) en 20 pacientes, 16 (13,2%) recibieron anticoagulantes orales y 4 no (5,0%). La tasa de incidencia de sangrado digestivo mayor en el grupo de anticoagulación fue 3,9 por 100 pacientes-años (IC 95% 2,4-6,0) con un cociente de tasas de incidencia de 3,0 (IC 95% 1,0-12,1; p=0,034). La etiología de HAP con la mayor tasa de incidencia de sangrado mayor fue la HAP portal con 7,0 eventos por 100 paciente-años (IC 95% 0,2-38,7) en el grupo de anticoagulación. Hubo 14 eventos trombóticos en 14 pacientes, 6 del grupo de anticoagulación (5,3%) y 8 del grupo no anticoagulado (9,2%). La tasa de incidencia de eventos trombótico fue 1,2 (IC 95% 0,4- 2,6) y 2,4 (IC 95% 1,0-4,8) eventos por 100 paciente-años para el grupo anticoagulado y no anticoagulado respectivamente. El cociente de las tasa de incidencia fue 0,5 (IC 95%
0,1-1,6; p=0,190). El evento trombótico más frecuente fue el tromboembolismo venoso con 7 episodios (50,0%). La tasa de incidencia de tromboembolismo venoso en el grupo de tratamiento fue 2,0 eventos por 1000 paciente-años y 18,4 por 1000 (IC 95% 6,8-
tiempo en rango terapéutico (TTR) de la población de estudio fue 57,0%. Los TTRs por centros fueron 59,8 para el Servicio de Anticoagulación del Brigham and Women’s Hospital; 55,4% para el Brigham and Women’s Hospital (fuera del Servicio de Anticoagulación); y 49,4% para el Hospital Universitario La Paz. Entre los posibles factores de riesgo evaluados que pudieron haber incrementado el riesgo de hemorragia mayor en la población de anticoagulados, los siguientes mostraron significación estadística o se aproximaron: distancia recorrida en el test de la marcha en el diagnóstico, puntación del HAS-BLED, antecedentes de sangrado, control pobre de la anticoagulación, diabetes, índice internacional normalizado (INR) objetivo alto.
Respecto a los factores que pueden haber afectado la calidad de la anticoagulación los siguientes fueron identificados: edad, sexo, fibrilación auricular, distancia del test de la marcha en el diagnóstico, bosentan, tratamiento combinado de HAP e INR objetivo elevado. Al final del estudio, 85 (44,3%) pacientes estaban en monoterapia con vasodilatadores específicos para la HAP y el resto en tratamiento combinado (55,7%) con diferencias significativas. La combinación de vasodilatadores pulmonares usada más frecuentemente fue la doble terapia con tadalafilo + treprostinil (16 pacientes;
15,0%), y tadalafilo + bosentan (9 pacientes, 8,4%). Al final del estudio, la familia de vasodilatadores con un mayor número de pacientes tratados fue los inhibidores de la fosfodiesterasa-5 (143 tratamientos; 41,9%), seguidos por los antagonistas del receptor de endotelina (108 tratamientos; 31,7%) y análogos de prostaciclinas (86 tratamientos;
25,2%). El vasodilatador incluido en más tratamientos fue el treprostinil con 78 (40,6%), seguido por tadalafilo con 72 pacientes (37,5%), sildenafilo con 67 (34,9%), ambrisentan con 54 (28,1%) y bosentan con 51 (26,6%). El número de reacciones adversas relacionadas con el tratamiento vasodilatador específico recogidas fue 265, con una tasa de reacciones adversas de 32 reacciones adversas por 100 paciente-años.
El grupo de vasodilatadores pulmonares que acumuló un mayor número de reacciones adversas fue los análogos de prostaciclina.
Conclusiones
1. Los pacientes del estudio que iniciaron anticoagulación oral como parte del tratamiento de soporte de la hipertensión arterial pulmonar tuvieron un riesgo de hemorragia mayor casi tres veces superior a aquellos pacientes no anticoagulados.
2. Los pacientes con hipertensión arterial pulmonar presentaron una incidencia anual de sangrado mayor superior a las obtenidas en otras poblaciones en tratamiento anticoagulante.
3. El sangrado gastrointestinal fue la hemorragia mayor más frecuente. Los pacientes del estudio que recibieron anticoagulantes tuvieron un riesgo de sangrado gastrointestinal significativamente mayor que los pacientes no anticoagulados.
4. Los pacientes que no recibieron tratamiento anticoagulante tuvieron una incidencia anual de tromboembolismo venoso superior a la de los pacientes anticoagulados.
5. De los resultados de este estudio se deduce que las complicaciones de la anticoagulación en pacientes con hipertensión arterial pulmonar sobrepasan sus posibles beneficios. Por tanto, la indicación de tratamiento anticoagulante debería valorarse de manera individualizada y no ser recomendada sistemáticamente.
6. La calidad de la anticoagulación a lo largo del estudio fue insuficiente ya que el tiempo global en rango terapéutico no alcanzó el limite recomendado del 65% y estuvo dentro del rango considerado pobre es inefectivo (<60%). Los centros especializados tuvieron mejores resultados que los de Atención Primaria en este sentido.
7. Entre los factores de la escala HAS-BLED que valora el riesgo hemorrágico en pacientes anticoagulados, en este trabajo destacaron por incrementar significativamente el riesgo de sangrado mayor: el sangrado previo o la predisposición al mismo, el manejo inadecuado del tratamiento anticoagulante y tener una puntuación en la escala ≥3.
8. Presentar diabetes y un mayor número de medicamentos en el tratamiento impactaron sobre el riesgo de sangrado mayor de los pacientes. Los análogos de prostaciclina mostraron una tendencia no significativa en el incremento del riesgo de evento hemorrágicos.
9. La edad, el sexo, la anticoagulación de alta intensidad y la fibrilación auricular son factores no relacionados con la hipertensión arterial pulmonar que afectaron al
un bajo resultado en el test de la marcha se asociaron con una peor calidad de la anticoagulación.
10. El uso de la farmacoterapia especifica avanzada implicó la aparición de numerosas reacciones adversas, sobretodo por análogos de prostaciclinas, principalmente debido a su compleja administración. El tratamiento combinado se asoció con un aumento significativo de eventos frente a la monoterapia. Los efectos adversos gastrointestinales relacionados con los vasodilatadores pulmonares no contribuyeron a la aparición de hemorragias mayores de tipo gastrointestinal.
DESCRIPTORES: HIPERTENSIÓN PULMONAR, ANTICOAGULANTES, CUMARINAS, WARFARINA, HEMORRAGIA, TROMBOSIS, SEGURIDAD
LIST OF TABLES
Table 1. Hemodynamic definitions of pulmonary hypertension Table 2. Risk assessment in pulmonary hypertension
Table 3. Vitamin K antagonists indications and recommended INR ranges
Table 4. Recommendation of anticoagulation in pulmonary arterial hypertension Table 5. Observational studies of anticoagulant therapy in pulmonary arterial
hypertension
Table 6. Observational studies of anticoagulant therapy in pulmonary hypertension:
safety results
Table 7. Time spent in therapeutic range and risk of anticoagulated-related events Table 8. Demographic data at pulmonary arterial hypertension diagnosis
Table 9. Frequency of Group 1 (pulmonary arterial hypertension) etiologies Table 10. Baseline catheterization and echocardiogram parameters at diagnosis Table 11. Frequency of clinical characteristics comprising the HAS-BLED score Table 12. Baseline laboratory levels at the beginning of follow-up
Table 13. Frequency of non-thrombotic events
Table 14. Cox regression analysis with hazard ratios for major bleeding in the entire population
Table 15. Potential factors that increased the risk of non-thrombotic events Table 16. Potential factors that increased the risk of major bleeding
Table 17. Potential predictors of poor anticoagulation
Table 18. COX regression analysis with hazard ratios for specific variables of potential influence on major bleeding in anticoagulation population
Table 19. Binary logistic regression analysis with odds ratios for potential influence variables on time spent in therapeutic range
Table 20. Combination of pulmonary arterial hypertension targeted vasodilators at the end of the study
vitamin K antagonists
Table 23. Time spent within range in different study settings
LIST OF FIGURES
Figure 1. Pathogenesis of pulmonary arterial hypertension Figure 2. Diagnosis algorithm of pulmonary hypertension
Figure 3. Treatment algorithm for pulmonary arterial hypertension Figure 4. Coagulation cascade and anticoagulation agents
Figure 5. Follow-up scenarios Figure 6. Rosendaal Method
Figure 7. Research Patient Data Registry Figure 8. Estación Clínica®
Figure 9. HORUS®
Figure 10. Longitudinal Medical Record (LMR) Figure 11. DAWN®AC anticoagulation software Figure 12. RedCap® data collection form
Figure 13. Queriable Patient Inference Dossier
Figure 14. Anticoagulation treatment by World Health Organization Functional Class Figure 15. Comorbidities at the beginning of the follow-up
Figure 16. Events description in patients with pulmonary arterial hypertension Figure 17. Major bleedings (N=33) and thrombotic events (N=14)
Figure 18. Odds ratios of different events in patients taking oral anticoagulants only due to pulmonary arterial hypertension
Figure 19. Incidence rates (per 100 patient-years) in different etiologies
Figure 20. Incidence rate of major bleedings by pulmonary arterial hypertension etiologies (per 100 patient-years)
Figure 21. Cumulative major bleeding (1) and major gastrointestinal bleeding (2) incidence in patients with pulmonary arterial hypertension
Figure 23. Cumulative thrombosis (1) and venous thromboembolism (2) incidences in pulmonary arterial hypertension patients
Figure 24. Patients’ targeted International Normalized Ratio Figure 25. Anticoagulation indications
Figure 26. Patients’ time spent in therapeutic range, below range and above range per centers
Figure 27. Forest plot of potential influence on major bleeding studied variables Figure 28. Prescriptions of pulmonary arterial hypertension vasodilator families by
functional class
Figure 29. Pulmonary arterial hypertension pharmacotherapy strategy and monotherapy analysis at the end of the study
Figure 30. Number of pulmonary arterial hypertension vasodilators by group of patients (a) and functional class (b)
Figure 31. Number of pulmonary arterial hypertension vasodilator prescriptions per families at the end of the study
Figure 32. Pulmonary arterial hypertension vasodilator prescriptions at the end of the study
Figure 33. Pulmonary arterial hypertension vasodilator prescriptions by centers at the end of the study
Figure 34. Number of adverse drug reactions per prescribed treatments
Figure 35. Use of pulmonary arterial hypertension vasodilator families by registries
ABBREVIATIONS AND SYMBOLS
AF: atrial fibrillation
ADR: adverse drug reaction AMB: ambrisentan
AMS: Anticoagulation Management Service aPTT: activated prothrombin time
AT: antithrombin
BMPR2: bone morphogenetic protein receptor 2 BNP: brain natriuretic peptide
BOS: bosentan
BWH: Brigham and Women’s Hospital CCBs: calcium channel blockers
CHD: congenital heart disease CIn: cardiac index
CI: confidence interval
COPD: chronic obstructive pulmonary disease CT: computed tomography
CTD: connective tissue diseases
CTEPH: chronic thromboembolic pulmonary hypertension DPAH: drug-induced pulmonary arterial hypertension DVT: deep venous thromboembolism
EMA: European medicine Agency EMR: electronic medical record EPO: epoprostenol
ERA: endothelin receptor antagonist FC: functional class
FDA: US Food and Drug Administration GI: gastrointestinal bleeding
HIPAA: Health Insurance Portability and Accountability Act HIV: human immunodeficiency virus
HF-pEF: heart failure with preserved ejection fraction HIT: heparin-induced thrombocytopenia
ILO: iloprost
INR: international normalized ratio IR: incidence rate
IRR: incidence rate ratio
IRB: Institutional Review Board
ISMP: Institute for Safe Medication Practices i.v.: intravenous
LHD: left heart disease LV: left ventricle/ventricular
LMWH: low molecular weight heparin MACI: macitentan
MR: magnetic resonance
mPAP: mean pulmonary arterial pressure NIH: National Institute of Health
DOAC: direct oral anticoagulant
NSAIDs: non-steroidal anti-inflammatory drugs NYHA: New York Heart Association
NO: Nitric Oxyde
NT-proBNP: N-terminal pro-brain natriuretic peptide OR: odds ratio
OSA: Obstructive sleep apnea
PAH: pulmonary arterial hypertension PAP: pulmonary arterial pressure
PAWP: pulmonary artery wedge pressure PC: protein C
PCA: prostacyclin analogue
PDE-5i: phosphodiesterase type 5 inhibitor PS: protein S
PT: prothrombin time
PTE: pulmonary thromboembolism
PPHN: persistent pulmonary hypertension of the newborn PVOD: pulmonary veno-occlusive disease
PVR: pulmonary vascular resistance RAP: right atrial pressure
RHC: right heart catheterization RIO: riociguat
RPDR: Research patient data registry RV: right ventricular/ventricle
6MWD/6MWT: six-minute walking distance sGC: soluble guanylate cyclase
SIL: sildenafil
SLE: systemic lupus erythematosus SSc: systemic sclerosis
TAD: tadalafil
TAR: time above therapeutic range TBR: time below therapeutic range TRE: treprostinil
TTR: time spent in therapeutic range UFH: unfractionated heparin
VTE: venous thromboembolism WHO: World Health Organization
SAFETY EVALUATION OF ORAL ANTICOAGULATION IN PULMONARY ARTERIAL HYPERTENSION:
OBSERVATIONAL STUDY OF PATIENTS FOLLOWED IN TWO PULMONARY
HYPERTENSION REFERRAL CENTERS IN SPAIN AND UNITED STATES
1. INTRODUCTION
1.1. PULMONARY HYPERTENSION
1.1.1. HISTORY OF PULMONARY HYPERTENSION
The first mention of pulmonary hypertension (PH) dates back to 1891 when German internist, Dr. Ernst von Romberg, filed the first case report for a patient he described as having “pulmonary vascular sclerosis” (1). Several years later, in 1897, the Viennese Dr.
Victor Eisenmenger reported similar histopathology in a patient with ventricular septal defect (2). There was no knowledge on the pathogenesis of these changes. In 1902, Abel Ayerza from the University of Buenos Aires suggested that a syndrome of chronic cyanosis, dyspnea, polycythemia and sclerosis of the pulmonary arteries called the
“cardiaco negro” was the result of a syphilis infection (3). The association between syphilis and PH has never been proved. The first publication that introduced the term
“Ayerza’s disease” to define PH came from one of his students.
In 1935 Brenner reviewed a series of 20 presumed cases of Ayerza’s disease and stated that the lesions observed where merely those of heart failure associated with chronic pulmonary disease and therefore, there was no reason for retaining the term Ayerza’
disease. Brenner came up with the concept and criteria for primary PH (known today as idiopathic/hereditary pulmonary arterial hypertension) what has been considered for many years later. He provided a detailed description of histopathological changes in disease and called for ruling out any other cause of secondary pulmonary vascular sclerosis (4). The concentric, plexiform and thrombotic lesions were first described here and systematically analyzed later mainly by von Heath and Wagenvoort (5,6). A clinical diagnosis of PH was not possible at that time because the catheterization of the pulmonary circulation was still unknown. This possibility emerged only after the pioneering efforts of André Cournand in the late 40s, inspired by the self-tests of Werner Forssmann (1929 as an assistant physician in Eberswalde). Cournand received the Nobel Prize for Medicine in 1956, together with his boss Forssmann and Dickinson W. Richards(7). Ten years after Cournand presented his studies on the physiology of the pulmonary circulation, cardiologist Paul Wood determined the upper limit of normal pulmonary arterial pressure (PAP) to be 20 mmHg(8). For the first time, PH brought more public attention due to the “Menocil epidemic”, in which the number of
severe PH increased after the release of a new appetite suppressant agent (aminorex) in 1965 in Europe(9). The incidence of PH decreased after it was withdrawn from the market in 1968. Under the epidemic influence, in 1973 the World Health Organization (WHO) celebrated the first conference on PH in Geneva. At this conference, the first valid hemodynamic definition of PH was adopted and the upper limit pulmonary artery pressure was set at 25 mmHg at rest or 30 mmHg during exercise. After this meeting, the US National Institute of Health (NIH) funded the first PH registry which collected patients from 1981-1984 and followed them for at least three years. The goal of the registry was to find out more about the epidemiology and characteristics of this rare disease. The next WHO conference took place in 1998 in Evian, France. Here for the first time the division of PH was determined in 5 groups (Group I: Pulmonary arterial hypertension (PAH); Group II: PH associated with left heart diseases (LHD); Group III:
PH associated with lung diseases; Group IV: chronic thromboembolic forms and group V: Other forms). This Evian-classification has been amended during the following WHO sponsored World Symposia for PH in 2003 in Venice, 2008 in Dana Point, California and 2014 in Nice, France, but its frame has been maintained. At the 2008 conference in Venice, the concept of primary PH was renamed to idiopathic PAH (IPAH) in order to replace the vague notion of secondary PH by a more specific terminology.
Regarding PH pharmacotherapy, very little was done before the 80s. During the first registry decade (80s) the measures were limited to conventional therapy to treat right heart failure (digoxin, diuretics, anticoagulants and oxygen). A very small percentage of patients, less than 10%, were treated with calcium channel blockers (CCBs) only if significant acute pulmonary vaso-reactivity was demonstrated during catheterization (10). The last therapeutic option at that point was transplantation. With the therapy available at that time, the outcomes were quite poor with a 5-year survival of approximately 30% of the overall patients and a median survival of 2.8 years(11). In 1990 there was no treatment algorithm to treat this deadly disease.
The first attempts to treat PH were carried out in the 50s using vasodilators after Paul Wood had expressed the hypothesis that the disease would be initially introduced by vasoconstrictive factors. In the 70s and 80s, all available vasodilators were tested for their efficacy in PH, without favorably results on the course of the disease. Stuart Rich of the University of Chicago was able to demonstrate that only a small proportion of
modern therapy of PH began with the introduction of i.v. prostacyclin (epoprostenol) in the years 1980-1981. This therapy was initially intended for use as a bridge to transplantation in patients with primary PH(12). However, some of the epoprostenol treated patients improved significantly, so a transplant in many cases was no longer necessary. Over the past 25 years, new agents have been developed as knowledge of the physiopathology of PH increased. Besides prostacyclins and analogues, the endothelin and nitric oxide (NO) pathways were studied. As a result, two families of PH drugs appeared: endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitors (PDE-5is). In 2001 the first oral US Food and Drug Administration (FDA)-approved drug, bosentan, came to the market. In 2002 the FDA approved treprostinil subcutaneous, then in 2004 the i.v. formulation. In the same year, a new inhaled formulation of prostacyclin was developed (iloprost). In 2005 sildenafil, the first PDE-5i and second oral treatment was approved. Between 2005 and 2009 new agents of these families came out attempting to solve pharmacodynamic and administration issues:
ambrisentan, tadalafil, inhaled treprostinil and i.v. sildenafil. Most recently, macitentan, riociguat and oral treprostinil have been also approved by the FDA. The focus of most studies was IPAH, but given that group-1 PH patients have very similar clinical characteristics and pathophysiology, the indication was extended to group-1 PH or PAH.
In parallel, a solid infrastructure for PH patients care was developed (13). There are some well-established and internationally renowned centers of excellence for this disorder and regional networks to ensure a comprehensive care of these patients. This applies not only for the medical treatment, but also for other therapeutic methods such as pulmonary endarterectomy for chronic thromboembolic PH or the lung and heart- lung transplantation for patients with refractory stages.
1.1.2. DEFINITION
PH is a severe clinical condition characterized by molecular and anatomical changes in the pulmonary circulation. It is associated with increased pulmonary vascular resistance (PVR), which if left untreated will lead to right-sided heart failure, and ultimately death. The hemodynamic definition describes PH as an increase in mean pulmoary arterial pressure (PAPm) ≥25 mmHg at rest assessed by right heart catheterization (RHC). Available data have shown that the normal PAPm at rest is 14+3 mmHg with an upper limit of approximately 20 mmHg (14).
The term PAH describes a group of PH patients characterized hemodynamically by the presence of pre-capillary PH, defined by a pulmonary artery wedge pressure (PAWP)
≤15 mmHg and a PVR >3 Wood Units in the absence of other causes of pre-capillary PH such as PH due to lung diseases, chronic thromboembolic pulmonary hypertension, (CTEPH) or other rare diseases (14)(table 1).
Table 1. Hemodynamic definitions of pulmonary hypertension adapted from 2015 European guidelines (15)
Definition Characteristics Clinical group(s)
PH PAPm ≥25 mmHg All
Pre-capillary PH PAPm ≥25 mmHg PAWP ≤15 mmHg
1. Pulmonary arterial hypertension 3. PH due to lung diseases
4. Chronic thromboembolic PH 5. PH with unclear and/or multifactorial mechanisms Post-capillary PH PAPm ≥25 mmHg
PAWP >15 mmHg
2. PH due to left heart disease 5. PH with unclear and/or multifactorial mechanisms Isolated post-capillary PH
Combined post-capillary and pre-capillary PH
DPG < 7 mmHg and/or PVR ≤3 WU
DPG ≥ 7 mmHg and/or PVR > 3 WU
PH = pulmonary hypertension; PAPm = mean pulmonary artery pressure; PAWP = pulmonary arterial wedge pressure; PVR = pulmonary vascular resistance; DPG = diastolic pressure gradient; WU = Wood units
1.1.3. CLASSIFICATION
The revised WHO classification system includes five groups, each one differing in associated pathophysiology (16). Previously, PH was classified as primary (no identifiable cause) or secondary PH (identifiable cause). Primary PH is currently called IPAH, which is part of the group 1. There are additional causes of PH with a pathophysiology, natural history, and response to therapy similar to IPAH, therefore the WHO re-classified PH based upon etiology and mechanisms into those five groups.
Patients in the first group are considered to have PAH, whereas patients in the remaining four groups are considered to have PH. When all five groups are discussed
Group 1 – PAH
Group 2 – PH due to LHD
Group 3 – PH due to chronic lung disease and/or hypoxemia
Group 4 –CTEPH
Group 5 – PH due to unclear multifactorial mechanisms
Group 1 PAH - PAH consists of IPAH, heritable PAH (HPAH) (also known as familial PAH), and PAH due to diseases related to the small pulmonary muscular arterioles.
These include PAH due to drugs and toxins, connective tissue diseases (CTD), human immunodeficiency virus (HIV) infection, portal hypertension, congenital heart disease (CHD), and schistosomiasis (16).
IPAH and HPAH – Patients with IPAH are clinically indistinguishable from patients with HPAH. HPAH exists when heritable genetic defects known to cause PAH can be identified. The most common heritable genetic mutation is bone morphogenetic protein receptor 2 (BMPR2) (80%), a dominant autosomal mutation.
Drugs and toxins – The following drugs are considered definite risk factors for PAH:
appetite suppressants (aminorex, fenfluramine, dexfenfluramine, and diethylpropion), toxic rapeseed oil, and benfluorex. Drugs considered likely or possible risk factors for PAH are: amphetamines, L-tryptophan, methamphetamines, cocaine, phenylpropanolamine, St. John's Wort, dasatinib, and interferon (16).
CTD – Systemic sclerosis (SSc, also called scleroderma) causes PAH through the obliteration of alveolar capillaries and narrowing of small arteries and arterioles by an unknown mechanism. Patients with long standing disease and those with limited SSc are at greatest risk (17,18). Rheumatoid arthritis and systemic lupus erythematosus (SLE) can also lead to fibrous obliteration of the pulmonary vascular bed. There is a female predominance and a frequent association with the Raynaud phenomenon in patients with SSc and SLE who develop PAH.
HIV – PAH occurs in approximately 1 out of every 200 HIV-infected patients (0.5%) (16). The cause of HIV-related PAH is uncertain.
Portal hypertension – PAH associated with portal hypertension (most often due to chronic liver disease), is an occasional complication of portal hypertension. It is of unknown etiology, and can improve or resolve with liver transplantation.
CHD – PAH can develop in patients with left to right intracardiac shunts (atrial,
ventricular, and great artery defects), especially when they are large and nonrestrictive, due to increased pulmonary blood volume or pressure overload.
Eisenmenger syndrome is the most severe and end-stage form of shunt-related PAH (16).
Schistosomiasis – PAH can develop in patients infected with schistosomiasis species, particularly those with hepatosplenic involvement. It is the most prevalent cause of PAH worldwide. Schistosome Ova can embolize to the lung and induce a granulomatous reaction in the pulmonary arterioles.
Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn (PPHN) are designated as separate categories, 1’ and 1’’ respectively, because these entities have more differences than similarities with PAH (16).
PVOD (Group 1’) – PVOD is characterized by extensive diffuse occlusion of the pulmonary veins resulting in tortuous dilation of the pulmonary capillaries. The results are identical to that of pulmonary capillary hemangiomatosis.
PPHN (Group 1’’) – PPHN occurs in term or late preterm infants and is characterized by abnormal development of the pulmonary vasculature. The proportion of infants and children with PPHN that reach adulthood with pulmonary vascular disease is unknown.
Group 2 PH (LHD) - PH due to LHD is associated with left ventricular (LV) systolic or diastolic dysfunction, valvular heart disease, inflow/outflow tract obstruction, and congenital cardiomyopathies. Heart failure with preserved ejection fraction (HFpEF;
diastolic heart failure) is one of the most common causes of WHO group 2 PH and is a growing cause of PH in general (19). Patients are characterized by chronic elevation of left atrial and pulmonary venous pressure (pulmonary venous hypertension). The pulmonary artery pressure increases in proportion to the elevated pulmonary venous pressure (passive elevation). If the pressure remains elevated, over time the small pulmonary arteries can remodel resulting in an occlusive vasculopathy similar to that seen in patients with WHO group 1 PAH. It is critical to accurately measure the pulmonary capillary wedge pressure and/or LV end diastolic pressure when assessing hemodynamics in patients with PH to determine the primary cause and therefore the PH classification.
