Advertisement

Monitoring for Pulmonary Hypertension Following Pulmonary Embolism: The INFORM Study

      Abstract

      Background

      Pulmonary hypertension and chronic thromboembolic pulmonary hypertension may develop after a pulmonary embolism event. A ventilation-perfusion scan is recommended as a first-line modality for suspected chronic thromboembolic pulmonary hypertension. In this study, we determined the prevalence of pulmonary hypertension following incident pulmonary embolism and the disease-monitoring patterns in this population.

      Methods

      We conducted a retrospective claims database analysis of incident pulmonary embolism cases (July 1, 2010 to September 30, 2011) and extracted data for 1 year prior to and 2 years after the incident pulmonary embolism event. Data were analyzed for diagnoses and symptoms related to pulmonary hypertension, claims consistent with other heart or lung diseases, diagnostic imaging tests, and time to first diagnostic imaging test post pulmonary embolism.

      Results

      Of the 7068 incident pulmonary embolism patients that met eligibility criteria, 87% had a claim for a pulmonary hypertension-related symptom and 7.6% had a claim for pulmonary hypertension during follow-up. Only 55% of all pulmonary embolism patients had diagnostic procedural claim(s) post pulmonary embolism: echocardiogram, 47%; computed tomographic angiography, 20%; ventilation-perfusion scan, 6%; and right heart catheterization or pulmonary angiography, <1%. The mean time from pulmonary embolism diagnosis to first screening test was 131 days.

      Conclusions

      Despite exhibiting pulmonary hypertension-related symptoms, many pulmonary embolism patients did not undergo imaging tests that could diagnose pulmonary hypertension or chronic thromboembolic pulmonary hypertension. This study suggests that physician education about the risk of pulmonary hypertension and chronic thromboembolic pulmonary hypertension after pulmonary embolism may need to be improved.

      Keywords

      Clinical Significance
      • A majority (87%) of incident pulmonary embolism (PE) patients experienced persistent symptoms suggestive of pulmonary hypertension, but only 61% of these patients underwent follow-up diagnostic testing.
      • We observed underutilization of the ventilation-perfusion scan, which is recommended to screen for chronic thromboembolic pulmonary hypertension in patients with persistent respiratory symptoms following a PE.
      • The 2-year cumulative incidence of pulmonary hypertension was 7.6%, suggesting the need to closely monitor this patient population.
      Pulmonary embolism affects 300,000 to 600,000 people each year in the US and is a major public health concern.

      Centers for Disease Control and Prevention (CDC). CDC figure: Venous thromboembolism (blood clots). Available at: http://www.cdc.gov/ncbddd/dvt/data.html. Accessed June 6, 2015.

      Chronic thromboembolic pulmonary hypertension, a form of pulmonary hypertension, is commonly seen as a long-term sequela of acute pulmonary embolism.
      • Tapson V.F.
      • Humbert M.
      Incidence and prevalence of chronic thromboembolic pulmonary hypertension.
      Studies suggest that chronic thromboembolic pulmonary hypertension occurs in 1% to 3.8% of patients surviving acute pulmonary embolism.
      • Pengo V.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      Thromboembolic Pulmonary Hypertension Study Group
      Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism.
      • Becattini C.
      • Agnelli G.
      • Pesavento R.
      • et al.
      Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism.
      The natural history of pulmonary embolism typically includes restoration of normal hemodynamics and gas exchange and total resolution of thromboemboli or resolution with minimal residua within 30 days.
      • Lang I.M.
      Chronic thromboembolic pulmonary hypertension—not so rare after all.
      However, up to 50% of patients will experience residual defects for at least 11 months
      • Nijkeuter M.
      • Hovens M.M.
      • Davidson B.L.
      • Huisman M.V.
      Resolution of thromboemboli in patients with acute pulmonary embolism: a systematic review.
      and may be at risk for developing chronic thromboembolic pulmonary hypertension.
      Chronic thromboembolic pulmonary hypertension is a rare and serious disease characterized by progressive dyspnea, and if unrecognized and untreated, right heart failure and death.
      • Galie N.
      • Hoeper M.M.
      • Humbert M.
      • et al.
      Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT).
      • McLaughlin V.V.
      • Archer S.L.
      • Badesch D.B.
      • et al.
      ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association.
      In many patients with chronic thromboembolic pulmonary hypertension, dyspnea is attributed to other conditions, leading to a delayed diagnosis. The mean duration from onset of symptoms to chronic thromboembolic pulmonary hypertension diagnosis was estimated to be 2.7 years.
      • Galie N.
      • Hoeper M.M.
      • Humbert M.
      • et al.
      Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT).
      • McLaughlin V.V.
      • Archer S.L.
      • Badesch D.B.
      • et al.
      ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association.
      • Ali J.M.
      • Hardman G.
      • Page A.
      • Jenkins D.P.
      Chronic thromboembolic pulmonary hypertension: an underdiagnosed entity?.
      • Pepke-Zaba J.
      • Delcroix M.
      • Lang I.
      • et al.
      Chronic Thromboembolic Pulmonary Hypertension (CTEPH): results from an international prospective registry.
      • Escribano-Subias P.
      • Blanco I.
      • Lopez-Meseguer M.
      • et al.
      Survival in pulmonary hypertension in Spain: insights from the Spanish registry.
      • Mayer E.
      • Jenkins D.
      • Lindner J.
      • et al.
      Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry.
      • Jaff M.R.
      • McMurtry M.S.
      • Archer S.L.
      • et al.
      Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association.
      • Mehta S.
      • Helmersen D.
      • Provencher S.
      • et al.
      Diagnostic evaluation and management of chronic thromboembolic pulmonary hypertension: A clinical practice guideline.
      Effective diagnosis is crucial, as chronic thromboembolic pulmonary hypertension is a treatable condition. The treatment of choice is pulmonary endarterectomy, in which the chronic thromboembolic material is dissected from the vessel wall, usually resulting in marked improvement or resolution of pulmonary hypertension. However, 20% to 40% of patients are deemed inoperable, while another 10% to 40% of patients experience recurrent or persistent pulmonary hypertension post pulmonary endarterectomy.
      • Kim N.H.
      Riociguat: an upcoming therapy in chronic thromboembolic pulmonary hypertension?.
      • Galie N.
      • Kim N.H.
      Pulmonary microvascular disease in chronic thromboembolic pulmonary hypertension.
      • Bonderman D.
      • Skoro-Sajer N.
      • Jakowitsch J.
      • et al.
      Predictors of outcome in chronic thromboembolic pulmonary hypertension.
      • Mayer E.
      Surgical and post-operative treatment of chronic thromboembolic pulmonary hypertension.
      Historically, medications indicated for use in pulmonary arterial hypertension have been prescribed off-label to select subgroups of chronic thromboembolic pulmonary hypertension patients.
      • Pepke-Zaba J.
      • Delcroix M.
      • Lang I.
      • et al.
      Chronic Thromboembolic Pulmonary Hypertension (CTEPH): results from an international prospective registry.
      • Kim N.H.
      Riociguat: an upcoming therapy in chronic thromboembolic pulmonary hypertension?.
      • Kirson N.Y.
      • Birnbaum H.G.
      • Ivanova J.I.
      • Waldman T.
      • Joish V.
      • Williamson T.
      Excess costs associated with patients with chronic thromboembolic pulmonary hypertension in a US privately insured population.
      Recently, a pharmacotherapy has been approved to treat chronic thromboembolic pulmonary hypertension patients. Riociguat is a soluble guanylate cyclase stimulator indicated for the treatment of adults with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (World Health Organization Group 4) after surgical treatment to improve exercise capacity and World Health Organization functional class.
      • Ghofrani H.A.
      • D'Armini A.M.
      • Grimminger F.
      • et al.
      CHEST-1 Study Group
      Riociguat for the treatment of chronic thromboembolic pulmonary hypertension.
      • Simonneau G.
      • D'Armini A.M.
      • Ghofrani H.A.
      • et al.
      Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2).
      Bayer HealthCare Pharmaceuticals, Inc
      Adempas.
      However, the impact of pharmacotherapy on long-term survival in these patients requires further study.
      The 2014 guidelines on managing pulmonary embolism from the European Society of Cardiology and from the Fifth World Symposium on Pulmonary Hypertension state that a ventilation-perfusion scan should be the first-line imaging modality for diagnosing chronic thromboembolic pulmonary hypertension following pulmonary embolism. A ventilation-perfusion scan suggestive of chronic thromboembolic pulmonary hypertension should be followed by right heart catheterization to confirm pulmonary hypertension and computed tomographic angiography or pulmonary angiography to confirm pulmonary embolism as the cause. Chronic thromboembolic pulmonary hypertension is thus diagnosed, and suitability for surgery can be determined (Figure 1).
      • Konstantinides S.
      • Torbicki A.
      • Agnelli G.
      • et al.
      2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism.
      • Kim N.H.
      • Delcroix M.
      • Jenkins D.P.
      • et al.
      Chronic thromboembolic pulmonary hypertension.
      However, a recent report indicates the underutilization of ventilation-perfusion scans as part of the diagnostic work-up of pulmonary arterial hypertension, which may lead to missing cases or misclassification of pulmonary hypertension.
      • McLaughlin V.V.
      • Langer A.
      • Tan M.
      • et al.
      Pulmonary Arterial Hypertension-Quality Enhancement Research Initiative
      Contemporary trends in the diagnosis and management of pulmonary arterial hypertension: an initiative to close the care gap.
      The report also disclosed that in roughly one-third of the cases without a ventilation-perfusion scan, the provider reported that the scan was not relevant. Therefore, physicians appear to be undereducated with regard to the appropriate evaluation of pulmonary hypertension in general.
      Figure thumbnail gr1
      Figure 1Stepwise process for the diagnosis of chronic thromboembolic pulmonary hypertension. CTA = computed tomographic angiography; CTEPH = chronic thromboembolic pulmonary embolism; MRA = magnetic resonance angiogram.
      Reproduced with permission; Kim et al.
      • Kim N.H.
      • Delcroix M.
      • Jenkins D.P.
      • et al.
      Chronic thromboembolic pulmonary hypertension.
      In this the INvestigating the role oF disease monitORing in incident pulmonary embolism patients using a Managed care claims dataset (INFORM) study, the objectives were 1) to determine the proportion of incident pulmonary embolism patients that show symptoms and signs related to pulmonary hypertension; 2) to determine the proportion of incident pulmonary embolism patients that have a diagnosis of pulmonary hypertension; and 3) to document overall disease monitoring patterns as they relate to ventilation-perfusion scans and other diagnostic tests.

      Methods

      Study Design and Data Source

      We conducted a retrospective claims database analysis of incident pulmonary embolism cases identified from the LifeLink Health Plan Claims Database (PharMetrics; IMS Health, Danbury, Conn.). This database consists of claims from over 80 managed-care organizations in the US and is representative of the commercially insured population with respect to age, sex, and region. The data include fully adjudicated medical and pharmaceutical claims for over 70 million lives. The database includes inpatient and outpatient diagnoses (in International Classification of Disease, Ninth Revision, Clinical Modification [ICD-9-CM] format), procedures (in Current Procedural Terminology-4 and Health Common Procedure Coding System formats), and retail and mail order prescription records.

      Study Cohort

      Figure 2 details the study eligibility criteria. Patients aged 18 years or above, with a claim for pulmonary embolism during the enrollment period (July 1, 2010 to September 30, 2011), a continuous enrollment for at least 1 year prior to pulmonary embolism claim (baseline) and at least 2 years post pulmonary embolism claim (follow-up) were included in the study. The first medical claim for pulmonary embolism (ICD-9-CM codes: 415.1x, 416.2x) served as the index event. Incident pulmonary hypertension patients were also identified based on a medical claim of pulmonary hypertension (ICD-9-CM codes: 416.0 or 416.8) during the follow-up period. Patients with a medical claim for pulmonary embolism or pulmonary hypertension during the baseline period were excluded.
      Figure thumbnail gr2
      Figure 2Selection of patients with incident pulmonary embolism between July 1, 2010 and September 30, 2011. ICD-9-CM = International Classification of Disease, Ninth Revision, Clinical Modification; PE = pulmonary embolism.
      The present study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Patient records used in this study were de-identified and were compliant with all requirements of the Health Insurance Portability and Accountability Act.

      Variables

      The following measures were constructed for each patient in the follow-up period (see Supplementary Table 1, Supplementary Table 2, Supplementary Table 3, Supplementary Table 4, Supplementary Table 5, available online):
      • 1.
        Patients with a medical claim for symptoms/signs related to pulmonary hypertension;
      • 2.
        Patients with a pulmonary hypertension diagnosis on or after index pulmonary embolism;
      • 3.
        Patients with a claim consistent with other heart or lung diseases;
      • 4.
        Patients with a procedure claim for a diagnostic imaging test; and
      • 5.
        Time to first diagnostic imaging test post pulmonary embolism event.
      Claims for 10 prespecified pulmonary hypertension symptoms (Table 1) were identified at least 3 months post pulmonary embolism event. The 3-month washout period served to exclude symptoms arising from the pulmonary embolism index event.
      Table 1ICD-9-CM Diagnoses Codes for Pulmonary Embolism and for Pulmonary Hypertension-Related Symptoms
      DescriptionICD Codes
      Pulmonary embolism
       Pulmonary embolism and infarction415.1
      Iatrogenic pulmonary embolism and infarction415.11
      Septic pulmonary embolism415.12
      Saddle embolus of pulmonary artery415.13
      Other pulmonary embolism and infarction415.19
       Chronic pulmonary embolism416.2
      Pulmonary hypertension symptoms
       Syncope780.2
       Malaise and fatigue780.7
       Dyspnea786.0
       Hemoptysis786.3
       Chest pain, unspecified786.5
       Dizziness/vertigo, not otherwise specified780.4
       Gait abnormality781.2
       Cardiomegaly429.3
       Ascites789.3
       Peripheral edema782.3
      ICD-9-CM = International Classification of Disease, Ninth Revision, Clinical Modification.
      Diagnostic imaging tests assessed in the follow-up period included ventilation-perfusion scans, echocardiograms, chest computed tomographic angiography, right heart catheterizations, and pulmonary angiography. Baseline patient demographic and clinical characteristics assessed included age, sex, geographical region, health plan type, and comorbid conditions.

      Statistical Analyses

      Univariate statistics used to describe the study population included proportion for categorical variables and means and standard deviation for continuous variables.

      Results

      A total of 46,140 patients had a pulmonary embolism event during the index period, of which 7068 patients met the inclusion criteria (Figure 2). The average age at index was 57 (± 14.5) years; 53% (n = 3718) were female (Table 2). The majority of patients were from the Midwest (45%) or South (30%) and were enrolled in a preferred provider organization (66%). About 52% of patients had a co-diagnosis of hypertensive disease (ICD-9-CM code: 401-405) and 30% had acute respiratory infections (ICD-9-CM code: 460-466). Mean Charlson comorbidity score, a predictor of 10-year mortality, was 1.6 ± 2.1.
      Table 2Characteristics of Incident Pulmonary Embolism Patients (N = 7068) Included in the Study Cohort
      VariableMeanSD
      Age (y)5714.5
      Charlson Comorbidity Score1.62.1
      n%
      Female371852.6%
      Health plan type
       Health maintenance organization146820.8%
       Preferred provider organization464265.7%
       Point of service4846.8%
       Other4746.7%
      US Region
       Northeast96613.7%
       Midwest320845.4%
       South212830.1%
       West76610.8%
      Codiagnosis
      Codiagnosis reported for >10% patients.
      (ICD-9 code)
       Hypertensive disease (401-405)371352.5%
       Ischemic heart disease (410-414)118116.7%
       Other heart disease (420-429)214330.3%
       Cerebrovascular disease (430-438)6749.5%
       Disease of arteries/arterioles/capillaries (440-448)79011.2%
       Disease of veins and lymphatic & others (451-459)201228.5%
       Acute respiratory infections (460-466)214830.4%
       Other disease of upper respiratory tract (470-478)110915.7%
       Pneumonia and influenza (480-488)85112.0%
       COPD & allied conditions (490-496)159922.6%
       Other diseases of respiratory system (510-519)165923.5%
      COPD = chronic obstructive pulmonary disease; ICD-9 = International Classification of Disease, Ninth Revision; SD = standard deviation.
      Codiagnosis reported for >10% patients.

      Monitoring Postpulmonary Embolism

      During follow-up, 55% (n = 3909) of patients had diagnostic procedural claim(s), including 47% for echocardiogram, 20% computed tomographic angiography, 6% ventilation-perfusion scan, and <1% right heart catheterization and pulmonary angiography (Figure 3). A majority (87%) of patients had a medical claim for at least one of the 10 pulmonary hypertension-related symptoms, with a majority showing symptoms in the first year (82%) vs the second year (53%). The most common presenting symptoms related to pulmonary hypertension during follow-up were dyspnea (39%) and chest pain (36%) (Table 3). Malaise/fatigue, gait abnormality, and hemoptysis were present in 30%, 8%, and 1% of patients, respectively.
      Figure thumbnail gr3
      Figure 3Disease monitoring in the 2-year period following the incident pulmonary embolism event. CTA = computed tomographic angiography; ECHO = echocardiogram; ICD-9-CM = International Classification of Disease, Ninth Revision, Clinical Modification; PAG = pulmonary angiography; PH = pulmonary hypertension; RHC = right heart catheterization; VQ = ventilation/perfusion scan. *The 10 prespecified PH symptoms (with ICD-9-CM codes in parenthesis) include syncope (780.2), malaise and fatigue (780.7), dyspnea (786.0), hemoptysis (786.3), chest pain (786.5), dizziness/ vertigo (780.4), gait abnormality (781.2), cardiomegaly (429.3), ascites (789.3), and peripheral edema (782.3).
      Table 3Intensity of Disease Monitoring in Patients Showing ‘Suggestive’ Pulmonary Hypertension Symptoms 3 Months After Pulmonary Embolism Diagnosis
      nAny TestVQ ScanEchoCTA ScanRHCPAG
      n%n%n%n%n%n%
      Total Number of Patients7068390955.3%4586.5%330946.8%142720.2%620.9%190.3%
      Probable CTEPH symptoms
       Syncope48439281.0%6613.6%36074.4%14329.6%20.4%00.0%
       Malaise and fatigue2127140366.0%2009.4%123157.9%53825.3%241.1%60.3%
       Dyspnea2725211877.7%32411.9%183567.3%86131.6%411.5%150.6%
       Hemoptysis977981.4%1818.6%6769.1%4849.5%22.1%22.1%
       Chest pain, unspecified2532189574.8%27510.9%161963.9%80531.8%381.5%100.4%
       Dizziness/vertigo, not otherwise specified95669973.1%949.8%62765.6%25626.8%121.3%10.1%
       Gait abnormality55538669.6%549.7%35564.0%13023.4%71.3%00.0%
       Cardiomegaly (429.3)59853489.3%9115.2%51085.3%17929.9%264.4%71.2%
       Ascites (789.3)19013872.6%2613.7%11962.6%5529.0%31.6%00.0%
       Peripheral edema (782.3)138195769.3%14810.7%84661.3%35225.5%211.5%50.36%
      CTA = computed tomographic angiography; CTEPH = chronic thromboembolic pulmonary hypertension; Echo = echocardiogram; PAG = pulmonary angiogram; PE = pulmonary embolism; RHC = right heart catheterization; VQ = ventilation-perfusion.
      Despite 87% of patients having symptoms suggestive of pulmonary hypertension, only 61% of this symptomatic group underwent imaging during the 2-year follow-up, which could be used to screen for or verify a diagnosis of chronic thromboembolic pulmonary hypertension—52% echocardiogram, 23% computed tomographic angiography, 7% ventilation-perfusion scan, 1% right heart catheterization, and 0.3% pulmonary angiography (Figure 3). Only 12% and 11% of patients experiencing dyspnea and chest pain, respectively, had a ventilation-perfusion scan performed post pulmonary embolism index event (Table 3).
      The mean time from pulmonary embolism index event to the first screening test was 131 days (Table 4). The amount of time post event varied by test; eg, computed tomographic angiography scan at a mean of 167 days and right heart catheterization at a mean of 212 days. The mean time for earliest ventilation-perfusion scan was 176 days.
      Table 4Number of Tests and Days to Earliest Diagnostic Test Post Pulmonary Embolism
      nNumber of Tests Post PEDays to the Earliest Test
      Mean (SD)Mean (SD)
      Any test39092.3 (2.06)131.46 (191.85)
      VQ scan4581.25 (0.63)176.11 (219.04)
      Echocardiogram33091.92 (1.72)142.76 (200.23)
      CTA14271.39 (0.89)166.85 (199.65)
      Right heart catheterization621.18 (0.64)212.34 (238.47)
      Pulmonary angiogram191.16 (0.5)157.21 (222.16)
      CTA = computed tomographic angiography; PE = pulmonary embolism; VQ = ventilation-perfusion.

      Disease Monitoring in the Pulmonary Hypertension Subgroup

      In the 2-year follow-up, 7.6% (n = 538) of patients had a medical claim for pulmonary hypertension (ICD codes 416.0 or 416.8). The cumulative incidence of pulmonary hypertension in the first year was 6.2% (n = 439). The mean age of the patients in the pulmonary hypertension subset was 60 years, and 52% were female. About 50% (n = 267) of these patients also had a coexisting medical claim for left heart disease. During the 2-year follow-up, the majority of pulmonary hypertension patients (90%, n = 482) had a procedural claim, with echocardiogram being the most frequent claim (87%, n = 466) (Figure 4). Ventilation-perfusion scan, right heart catheterization, and pulmonary angiography were documented in 16%, 4%, and 2% of the pulmonary hypertension patients, respectively.
      Figure thumbnail gr4
      Figure 4Disease monitoring post index pulmonary embolism in patients with a diagnosis of pulmonary hypertension on or after index event. n = 538 patients with a diagnosis of pulmonary hypertension (ICD-9-CM codes 416.0 or 416.8). CTA = computed tomographic angiography; ECHO = echocardiogram; ICD-9-CM = International Classification of Disease, Ninth Revision, Clinical Modification; PAG = pulmonary angiography; RHC = right heart catheterization; VQ = ventilation perfusion.

      Discussion

      The present study provides insight into the patterns of disease monitoring in a large cohort of medically insured patients diagnosed with pulmonary embolism in the US. The study suggests underutilization of the ventilation-perfusion scan, which is recommended for the diagnosis of chronic thromboembolic pulmonary hypertension, in a cohort of incident pulmonary embolism patients with symptoms suggestive of pulmonary hypertension.
      A growing body of evidence supports the likelihood of acute pulmonary embolism triggering the cascade of events that may eventually result in chronic thromboembolic pulmonary hypertension.
      • Pengo V.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      Thromboembolic Pulmonary Hypertension Study Group
      Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism.
      • Surie S.
      • Gibson N.S.
      • Gerdes V.E.
      • et al.
      Active search for chronic thromboembolic pulmonary hypertension does not appear indicated after acute pulmonary embolism.
      • Dutt T.S.
      • Mohan B.V.
      • Tousheed S.Z.
      • Ramanjenaya R.
      • Shetty D.P.
      Incidence of chronic thrombo-embolic pulmonary hypertension following acute pulmonary thrombo-embolism: an Indian perspective.
      A systematic review of studies of imaging tests in pulmonary embolism patients reported significant residual perfusion defects after acute pulmonary embolism on ventilation-perfusion scan or computed tomographic angiography in 57% of patients at 6 months. This suggests that a considerable proportion of patients with symptomatic acute pulmonary embolism will experience persistent pulmonary vascular sequelae.
      • Nijkeuter M.
      • Hovens M.M.
      • Davidson B.L.
      • Huisman M.V.
      Resolution of thromboemboli in patients with acute pulmonary embolism: a systematic review.
      An early diagnosis of chronic thromboembolic pulmonary hypertension is of paramount importance given the poor prognosis and because pulmonary endarterectomy is a potential curative treatment. Ventilation-perfusion scans are recommended as the first-line test in screening for chronic thromboembolic pulmonary hypertension following pulmonary embolism because of their high sensitivity.
      • Mehta S.
      • Helmersen D.
      • Provencher S.
      • et al.
      Diagnostic evaluation and management of chronic thromboembolic pulmonary hypertension: A clinical practice guideline.
      Guidelines indicate that ventilation-perfusion cans that suggest chronic thromboembolic pulmonary hypertension should be followed up with a right heart catherization and pulmonary angiography for a definitive diagnosis.
      • Galie N.
      • Hoeper M.M.
      • Humbert M.
      • et al.
      Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT).
      • Konstantinides S.
      • Torbicki A.
      • Agnelli G.
      • et al.
      2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism.
      • Galie N.
      • Hoeper M.M.
      • Humbert M.
      • et al.
      Guidelines for the diagnosis and treatment of pulmonary hypertension.
      • Tunariu N.
      • Gibbs S.J.
      • Win Z.
      • et al.
      Ventilation–perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension.
      Figure 1 outlines the recommended steps for the diagnosis of chronic thromboembolic pulmonary hypertension.
      The present study determined the proportion of incident pulmonary embolism patients with symptoms suggestive of pulmonary hypertension and reviewed the use of ventilation-perfusion scans as well as other diagnostic procedures in these patients. Despite 87% of incident pulmonary embolism patients showing possible pulmonary hypertension symptoms, a relatively small segment of this population was evaluated for chronic thromboembolic pulmonary hypertension using a ventilation-perfusion scan, and an even smaller proportion received either right heart catheterization or pulmonary angiography. Nearly 45% of incident pulmonary embolism patients had no follow-up imaging tests performed for the 24 months post pulmonary embolism diagnosis. These findings may suggest significant under-recognition and under-diagnosis of this condition and that further education is needed to communicate the importance of evaluation for chronic thromboembolic pulmonary hypertension in patients who remain symptomatic following an acute pulmonary embolism or are diagnosed with pulmonary hypertension.
      Development of pulmonary hypertension after pulmonary embolism should raise suspicion for chronic thromboembolic pulmonary hypertension. Although there is no unique ICD-9-CM code for chronic thromboembolic pulmonary hypertension, we estimated its incidence by excluding patients with probable concomitant left heart disease (the most common cause of pulmonary hypertension) from the 7.6% of patients with an ICD-9-CM claim for pulmonary hypertension, resulting in an incidence of 3.8%. This incidence is identical to that reported by Pengo et al.
      • Pengo V.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      Thromboembolic Pulmonary Hypertension Study Group
      Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism.
      Because of the limitations of claims data, we cannot confirm a clinical diagnosis of chronic thromboembolic pulmonary hypertension, but nevertheless these patients are suspect and should be closely monitored.
      The true incidence of chronic thromboembolic pulmonary hypertension after a pulmonary embolism is not known. In one prospective study, the incidence of chronic thromboembolic pulmonary hypertension was estimated to be 2.7% at 1 year in 110 acute pulmonary embolism patients who were experiencing persistent dyspnea.
      • Surie S.
      • Gibson N.S.
      • Gerdes V.E.
      • et al.
      Active search for chronic thromboembolic pulmonary hypertension does not appear indicated after acute pulmonary embolism.
      In another single-center study with 223 patients with first episode of symptomatic pulmonary embolism, the cumulative incidence of symptomatic chronic thromboembolic pulmonary hypertension was found to be 1.0% at 6 months, 3.1% at 1 year, and 3.8% at 2 years.
      • Pengo V.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      Thromboembolic Pulmonary Hypertension Study Group
      Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism.
      Regardless of the precise incidence, given that over 300,000 patients suffer an acute pulmonary embolism per year in the US, and only approximately 350 pulmonary endarterectomy procedures are performed per year, there exists a large gap in the appropriate diagnosis and treatment of chronic thromboembolic pulmonary hypertension.
      • White R.H.
      The epidemiology of venous thromboembolism.

      Fedullo P. From Acute to Chronic, or Not? The Epidemiology and Pathophysiology of CTEPH. Oral Presentation. American College of Cardiology. San Diego, California: March 16, 2015.

      Persistent dyspnea and chest pain are common symptoms in patients with acute symptomatic pulmonary embolism, and may identify patients at risk for chronic thromboembolic pulmonary hypertension.
      • Mehta S.
      • Helmersen D.
      • Provencher S.
      • et al.
      Diagnostic evaluation and management of chronic thromboembolic pulmonary hypertension: A clinical practice guideline.
      In our study, dyspnea and chest pain were the most frequently reported pulmonary hypertension-related symptoms in incident pulmonary embolism patients, about 39% and 36%, respectively. Chest pain is less common than progressive dyspnea, but it can be an accompanying symptom. In our study, only 12% and 11% of patients with dyspnea or chest pain, respectively, had a ventilation-perfusion scan performed during follow-up. Furthermore, right heart catheterization and pulmonary angiography, the guideline-recommended tests for establishing a confirmed diagnosis of chronic thromboembolic pulmonary hypertension, were performed in only 4% and 2% of incident pulmonary hypertension patients, respectively. Even in patients coded for pulmonary hypertension, a ventilation-perfusion scan was infrequently performed. These data again highlight that this disease remains substantially underrecognized and that there are gaps between the guideline recommendations and real-world clinical practice in the management of pulmonary embolism patients with signs or symptoms suggestive of pulmonary hypertension.
      This study has limitations inherent in medical claim database analyses. The PharMetrics database may not be fully representative of the incident pulmonary embolism and chronic thromboembolic pulmonary hypertension patients. Due to the nature of a claims database, the clinical reasons to recommend or not recommend screening procedures are unknown. The miscoding, overcoding, or undercoding of medical diagnosis and procedures in claims databases are common, and the validity of the codes used in this study to define patients and variables can be argued to have not been established. Progressive dyspnea is by far the most common presentation for chronic thromboembolic pulmonary hypertension; other symptoms we included, such as gait abnormality, and malaise and fatigue, may be more likely due to disorders other than chronic thromboembolic pulmonary hypertension. Furthermore, chest pain can be caused by a number of disorders much more common than chronic thromboembolic pulmonary hypertension, even in a patient with previous pulmonary embolism. Thus, the presence of one of these symptoms in a patient with previous pulmonary embolism does not necessarily prove that chronic thromboembolic pulmonary hypertension was present and not evaluated properly.
      Furthermore, ICD-9-CM codes are nonspecific for the different categories of pulmonary hypertension, potentially leading to inaccurate characterization of chronic thromboembolic pulmonary hypertension. In this study, we used claims data to identify patient populations that may be at risk of developing chronic thromboembolic pulmonary hypertension. Because the objective was to identify suspect patients and to identify diagnostic testing patterns, confirmed diagnoses were not necessary for the integrity of the study. Another potential limitation is that there is only a 2-year followup. It is feasible that with a 5-year follow-up, more patients would be diagnosed.

      Conclusion

      To our knowledge this is the first real-world study that documents the use of diagnostic imaging scans in incident pulmonary embolism patients in a commercially insured US population. The low usage of diagnostic imaging scans in this population suggests a potential need for efforts to improve physician education about the risk of chronic thromboembolic pulmonary hypertension after pulmonary embolism, the symptoms and signs of this condition, the available diagnostic tools, and the treatment guidelines. There are no evidence-based guidelines that dictate exactly what imaging studies should be performed in the months or years after acute pulmonary embolism diagnosis and when to do them. Future studies need to investigate how pulmonary embolism patients, both with and without pulmonary hypertension, may differ in the way they are treated and managed in order to gain additional insights into prevalence, treatment patterns, and costs associated with chronic thromboembolic pulmonary hypertension.

      Acknowledgment

      Editorial and writing support was provided by Rohini Sharma and Cristina Phillips from Communication Symmetry (North Andover, MA) and was funded by Bayer HealthCare Pharmaceuticals.

      Supplementary Data

      Supplementary Table 1CPT Procedure Codes for Ventilation/Perfusion Scan
      Procedure DescriptionCPT Codes
      Pulmonary perfusion imaging78580
      Pulmonary ventilation (eg, aerosol or gas) and perfusion imaging78582
      Pulmonary perfusion with vent single breath78584
      Pulmonary perfusion w/ washout, w or w/o single breath78585
      Pulmonary ventilation imaging78586
      Pulmonary ventilation multiple projections78587
      Pulmonary perfusion imaging, particulate, with ventilation imaging, aerosol, 1 or multiple projection7858
      CPT = current procedure terminology.
      Supplementary Table 2ICD-9-CM Diagnoses Codes for Co-existing Respiratory Diseases
      Co-existing diseases were grouped in broad categories for reporting purposes. However, individual diagnostic level medical claim were captured for future sub-group analyses.
      Diagnoses DescriptionICD Codes
      Acute respiratory infections460-466
      Other diseases of the upper respiratory tract470-478
      Pneumonia and influenza480-488
      COPD and allied conditions490-496
      Pneumoconioses and other lung diseases due to external agents500-508
      Other diseases of respiratory system510-519
      COPD = chronic obstructive pulmonary disease; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification.
      Co-existing diseases were grouped in broad categories for reporting purposes. However, individual diagnostic level medical claim were captured for future sub-group analyses.
      Supplementary Table 3ICD-9-CM Diagnoses Codes for Co-existing Cardiovascular Diseases
      Co-existing diseases were grouped in broad categories for reporting purposes. However, individual diagnostic level medical claim were captured for future sub-group analyses.
      Diagnoses DescriptionICD Codes
      Acute rheumatic fever390-392
      Chronic rheumatic heart disease393-398
      Hypertensive disease401-405
      Ischemic heart disease410-414
      Other forms of heart disease420-429
      Cerebrovascular disease430-438
      Diseases of arteries, arterioles, and capillaries440-448
      Diseases of veins and lymphatics, and other diseases of circulatory system451-459
      ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification.
      Co-existing diseases were grouped in broad categories for reporting purposes. However, individual diagnostic level medical claim were captured for future sub-group analyses.
      Supplementary Table 4CPT and ICD-9-CM Procedure Codes for Other Diagnostic Tests
      Diagnostic TestCPT/ICD CodeCode Descriptor
      Echocardiogram93306ECHO TTHRC R-T 2D W/WOM-MODE COMPL SPEC&COLR D
      93307ECHO TRANSTHORAC R-T 2D W/WO M-MODE REC COMP
      93308ECHO TRANSTHORC R-T 2D W/WO M-MODE REC F-UP/LMTD
      93320DOPPLER ECHOCARD PULSE WAVE W/SPECTRAL DISPLAY
      93325DOP ECHOCARD COLOR FLOW VELOCITY MAPPING
      8872 (ICD code)DIAGNOSTIC ULTRASOUND OF HEART
      93321DOP ECHOCARD PULSE WAVE W/SPECTRAL F-UP/LMTD STD
      CT scan71275CT ANGIOGRAPHY CHEST W/CONTRAST/NONCONTRAST
      Right heart catheterization93501RIGHT HEART CATHETERIZATION
      3723 (ICD code)COMBINED RIGHT AND LEFT HEART CARDIAC CATHETERIZATION
      3721 (ICD code)RIGHT HEART CARDIAC CATHETERIZATION
      93503INSERTION FLOW DIRECTED CATHETER FOR MONITORING
      Pulmonary angiogram75741ANGIOGRAPHY PULMONARY UNILATERAL SLCTV RS&I
      75743ANGIOGRAPHY PULMONARY BILATERAL SLCTV RS&I
      75746ANGRPH PULMONARY NONSLCTV CATH/VEN NJX RS&I
      CPT = current procedure terminology; CT = computed tomography; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification.
      Supplementary Table 5Group 2 and 5 PH Conditions Mapped to ICD-9 Codes
      WHO PH Group ClassificationICD CodesCode Description
      Group 2. Pulmonary hypertension with left heart disease
       2.1 Left ventricular systolic dysfunction414.10Aneurysm of heart (wall)
       2.2 Left ventricular diastolic dysfunction425.3Endocardial fibroelastosis
      428.1Left heart failure
      428.2Systolic heart failure
      428.3Diastolic heart failure
       2.3 Valvular disease394, 424.0Disease/disorders of the mitral valve
      395, 424.1Disease/disorders of the aortic valve
      396Disease of mitral and aortic valve
      746.3-7, 746.81Congenital anomalies of mitral/aortic valves
       2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies425.1Hypertrophic obstructive cardiomyopathy
      425.8Cardiomyopathy in other diseases classified elsewhere
      746.8Other specified congenital anomalies of heart
      Group 5. Pulmonary hypertension with unclear multifactorial mechanisms
       5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy282Hereditary hemolytic anemias
      283Acquired hemolytic anemias
      238.4Polycythemia vera
      238.79Other lymphatic and hematopoietic tissues
       5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis135Sarcoidosis
      277.89, 202.5Histiocytosis X
      228.1Lymphangioma any site
       5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders271Disorders of carbohydrate transport and metabolism
      272.7Gaucher disease
      240-246Disorders of thyroid gland
       5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH519.2Mediastinitis
      585Chronic renal failure
      415.19Pulmonary emboli
      746Other congenital anomalies of heart
      ICD-9 = International Classification of Diseases, Ninth Revision; PH = pulmonary hypertension; WHO = World Health Organization.

      References

      1. Centers for Disease Control and Prevention (CDC). CDC figure: Venous thromboembolism (blood clots). Available at: http://www.cdc.gov/ncbddd/dvt/data.html. Accessed June 6, 2015.

        • Tapson V.F.
        • Humbert M.
        Incidence and prevalence of chronic thromboembolic pulmonary hypertension.
        Proc Am Thorac Soc. 2006; 3: 564-567
        • Pengo V.
        • Lensing A.W.
        • Prins M.H.
        • et al.
        • Thromboembolic Pulmonary Hypertension Study Group
        Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism.
        N Engl J Med. 2004; 350: 2257-2264
        • Becattini C.
        • Agnelli G.
        • Pesavento R.
        • et al.
        Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism.
        Chest. 2006; 130: 172-175
        • Lang I.M.
        Chronic thromboembolic pulmonary hypertension—not so rare after all.
        N Engl J Med. 2004; 350: 2236-2238
        • Nijkeuter M.
        • Hovens M.M.
        • Davidson B.L.
        • Huisman M.V.
        Resolution of thromboemboli in patients with acute pulmonary embolism: a systematic review.
        Chest. 2006; 129: 192-197
        • Galie N.
        • Hoeper M.M.
        • Humbert M.
        • et al.
        Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT).
        Eur Heart J. 2009; 30: 2493-2537
        • McLaughlin V.V.
        • Archer S.L.
        • Badesch D.B.
        • et al.
        ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association.
        J Am Coll Cardiol. 2009; 53: 1573-1619
        • Ali J.M.
        • Hardman G.
        • Page A.
        • Jenkins D.P.
        Chronic thromboembolic pulmonary hypertension: an underdiagnosed entity?.
        Hosp Pract (1995). 2012; 40: 71-79
        • Pepke-Zaba J.
        • Delcroix M.
        • Lang I.
        • et al.
        Chronic Thromboembolic Pulmonary Hypertension (CTEPH): results from an international prospective registry.
        Circulation. 2011; 124: 1973-1981
        • Escribano-Subias P.
        • Blanco I.
        • Lopez-Meseguer M.
        • et al.
        Survival in pulmonary hypertension in Spain: insights from the Spanish registry.
        Eur Respir J. 2012; 40: 596-603
        • Mayer E.
        • Jenkins D.
        • Lindner J.
        • et al.
        Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry.
        J Thorac Cardiovasc Surg. 2011; 141: 702-710
        • Jaff M.R.
        • McMurtry M.S.
        • Archer S.L.
        • et al.
        Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association.
        Circulation. 2011; 123: 1788-1830
        • Mehta S.
        • Helmersen D.
        • Provencher S.
        • et al.
        Diagnostic evaluation and management of chronic thromboembolic pulmonary hypertension: A clinical practice guideline.
        Can Respir J. 2010; 17: 301-334
        • Kim N.H.
        Riociguat: an upcoming therapy in chronic thromboembolic pulmonary hypertension?.
        Eur Respir Rev. 2010; 19: 68-71
        • Galie N.
        • Kim N.H.
        Pulmonary microvascular disease in chronic thromboembolic pulmonary hypertension.
        Proc Am Thorac Soc. 2006; 3: 571-576
        • Bonderman D.
        • Skoro-Sajer N.
        • Jakowitsch J.
        • et al.
        Predictors of outcome in chronic thromboembolic pulmonary hypertension.
        Circulation. 2007; 115: 2153-2158
        • Mayer E.
        Surgical and post-operative treatment of chronic thromboembolic pulmonary hypertension.
        Eur Respir Rev. 2010; 19: 64-67
        • Kirson N.Y.
        • Birnbaum H.G.
        • Ivanova J.I.
        • Waldman T.
        • Joish V.
        • Williamson T.
        Excess costs associated with patients with chronic thromboembolic pulmonary hypertension in a US privately insured population.
        Appl Health Econ Health Policy. 2011; 9: 377-387
        • Ghofrani H.A.
        • D'Armini A.M.
        • Grimminger F.
        • et al.
        • CHEST-1 Study Group
        Riociguat for the treatment of chronic thromboembolic pulmonary hypertension.
        N Engl J Med. 2013; 369: 319-329
        • Simonneau G.
        • D'Armini A.M.
        • Ghofrani H.A.
        • et al.
        Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2).
        Eur Respir J. 2015; 45: 1293-1302
        • Bayer HealthCare Pharmaceuticals, Inc
        Adempas.
        ([highlights of prescribing information]) Bayer HealthCare Pharmaceuticals, Inc, Whippany, NJ2014
        • Konstantinides S.
        • Torbicki A.
        • Agnelli G.
        • et al.
        2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism.
        Eur Heart J. 2014; 35: 3033-3069
        • Kim N.H.
        • Delcroix M.
        • Jenkins D.P.
        • et al.
        Chronic thromboembolic pulmonary hypertension.
        J Am Coll Cardiol. 2013; 62: D92-D99
        • McLaughlin V.V.
        • Langer A.
        • Tan M.
        • et al.
        • Pulmonary Arterial Hypertension-Quality Enhancement Research Initiative
        Contemporary trends in the diagnosis and management of pulmonary arterial hypertension: an initiative to close the care gap.
        Chest. 2013; 143: 324-332
        • Surie S.
        • Gibson N.S.
        • Gerdes V.E.
        • et al.
        Active search for chronic thromboembolic pulmonary hypertension does not appear indicated after acute pulmonary embolism.
        Thromb Res. 2010; 125: e202-e205
        • Dutt T.S.
        • Mohan B.V.
        • Tousheed S.Z.
        • Ramanjenaya R.
        • Shetty D.P.
        Incidence of chronic thrombo-embolic pulmonary hypertension following acute pulmonary thrombo-embolism: an Indian perspective.
        Indian J Chest Dis Allied Sci. 2013; 55: 205-207
        • Galie N.
        • Hoeper M.M.
        • Humbert M.
        • et al.
        Guidelines for the diagnosis and treatment of pulmonary hypertension.
        Eur Respir J. 2009; 34: 1219-1263
        • Tunariu N.
        • Gibbs S.J.
        • Win Z.
        • et al.
        Ventilation–perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension.
        J Nucl Med. 2007; 48: 680-684
        • White R.H.
        The epidemiology of venous thromboembolism.
        Circulation. 2003; 107: I4-I8
      2. Fedullo P. From Acute to Chronic, or Not? The Epidemiology and Pathophysiology of CTEPH. Oral Presentation. American College of Cardiology. San Diego, California: March 16, 2015.