Life expectancy after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension: a Swedish single-center study

Abstract

Pulmonary endarterectomy is the guideline recommended treatment for chronic thromboembolic pulmonary hypertension, in addition to life-long anticoagulation therapy. The aim was to analyze long-term relative survival after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. We included all patients who underwent pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension at Karolinska University Hospital between 1997 and 2018 (n = 100). We obtained baseline characteristics and vital status from patient charts and national health-data registers. The expected survival from the general Swedish population matched by age, sex, and year of surgery was obtained from the Human Mortality Database. The relative survival was used as an estimate of cause-specific mortality. The mean age of the patients was 62 years and 39% were women. Most patients were severely symptomatic (95% in New York Heart Association functional class III–IV), and mean preoperative systolic/diastolic (mean) pulmonary artery pressure was 78/27 (45) mmHg. The mean and maximum follow-up time was 7.2 and 22.1 years, respectively. Early (30-day) mortality was 7%. The 15-year observed, expected, and relative survival was 55% (95% confidence interval, 40%–68%), 71%, and 77% (95% confidence interval, 56%–95%), respectively. The 15-year relative survival conditional on 30-day survival was 83% (95% confidence interval, 60%–100%). Although the life expectancy following pulmonary endarterectomy was shorter compared to the general population, the difference was small in those who survived the operation and the early postoperative period. Patients with chronic thromboembolic pulmonary hypertension who are surgical candidates should undergo pulmonary endarterectomy to improve prognosis.

Keywords

pulmonary endarterectomy chronic thromboembolic pulmonary hypertension survival life expectancy

Introduction

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare medical condition affecting about 0.5%–4% of patients surviving pulmonary embolism (PE).^1–4 In Sweden, the four-year mortality for inoperable CTEPH was 55%–60% according to the Annual Report of 2018 from the Swedish Arterial Pulmonary Hypertension Registry.⁵ Patients with coagulopathies are overrepresented in the group of patients diagnosed with CTEPH^6,7 and many of the patients have a history of venous thromboembolism. The exact cellular mechanisms leading from acute PE to CTEPH are still unclear, but vascular remodeling with intimal hyperplasia in the pulmonary arteries serves an important role.⁸ Mechanical obstruction of the pulmonary arteries with unresorbed thrombi leads to fibrosis and stenosis, with complete or partial occlusions of the pulmonary arteries. Via the bronchial circulation, the pulmonary vascular bed receives circulating blood to the non-obstructed parts of the lungs. According to Dorfmuller et al., this bronchopulmonary venous shunting may contribute to microvascular changes and even more vasoconstriction.⁹ This results in an increase in pulmonary vascular resistance and elevated blood pressure in the pulmonary arteries causing right heart failure. Patients seek care for vague symptoms such as dyspnea and fatigue. Different imaging tools are needed in order to diagnose CTEPH. Echocardiography is commonly used as the first screening tool to study pulmonary artery pressures (PAPs) and signs of right heart failure. Lung perfusion defects are evaluated with scintigraphy, and right heart catheterization is used to verify and precisely measure PAPs, pulmonary vascular resistance, and cardiac output. Pulmonary angiography is then used to evaluate the operability with respect to central or distal pathology in the vessels.¹⁰ There are three main treatment modalities for CTEPH. Pulmonary endarterectomy (PEA) is the primary treatment of operable CTEPH.¹¹ Targeted therapy with riociguat offers inoperable patients or patients with residual or recurrent pulmonary hypertension (PH) after PEA relief in symptoms with higher exercise capacity and improved hemodynamics.^12,13 During the last decade, balloon pulmonary angioplasty (BPA) has evolved as a possible treatment for inoperable CTEPH or for patients with residual or recurrent PH after PEA. BPA has been shown to result in a reduction of PAP.¹⁴ As a complement to these therapeutic options, pharmacological treatment with life-long anticoagulation is of great importance. PEA is performed via median sternotomy using cardiopulmonary bypass with deep hypothermia and circulatory arrest. The endarterectomies are then performed through incisions in the pulmonary arteries.^15–17 PEA is the only curative treatment for CTEPH, but little is known about survival in this patient group compared to the general population. The aim of this study was to analyze long-term relative survival in patients undergoing PEA surgery for CTEPH compared to the general population.

Methods

Study design

This observational cohort study was approved by the regional Human Ethics Committee in Stockholm, Sweden (2018/1296-31). No informed consent was required. We included all patients who underwent PEA for CTEPH at Karolinska University Hospital between 1997 and 2018 (n = 100). We obtained baseline characteristics and vital status from patient charts and national health-data registries. Surgery was performed according to established techniques through a median sternotomy, and a complete bilateral endarterectomy was done during one or more episodes of circulatory arrest at a body temperature of 18℃.

The expected survival from the general Swedish population matched by age, sex, and year of surgery was obtained from the Human Mortality Database (www.mortality.org). In the Human Mortality Database, researchers can find detailed open access information about population and mortality in 41 countries. Information about birth rates, population size, exposure to risk, death rates, and life tables is also available.

Statistical methods

Baseline characteristics were described with frequencies and percentages for categorical variables and means and standard deviations (SDs) for continuous variables. Person-time in days was calculated from the date of surgery until the date of death or end of follow-up (April 1, 2019). The Kaplan−Meier method was used to calculate cumulative survival. The expected survival from the general population in Sweden matched by age, sex, and year of surgery was obtained from the Human Mortality Database. The expected and observed survival curves were constructed with the strs¹⁸ Stata command. Data management and statistical analyses were performed using Stata 16.0 (Stata Corp LP, College Station, TX, USA) and included the use of the strs¹⁸ program.

Results

A total of 100 patients were included (Fig. 1). The mean age of the patients was 62 (range 23–81) years and 39% were women. The mean body mass index for the patients was 26.6 (SD 5.0), 19% of the patients had concomitant chronic obstructive pulmonary disease, 5% had suffered a prior stroke, and 73% of the patients had normal kidney function. Most patients were severely symptomatic (95% in New York Heart Association functional class III–IV), and preoperative mean systolic/diastolic PAP was 78/27 mmHg. Mean PAP in the patients was 45 mmHg (SD 11). The majority, 86% of the patients, had normal left ventricular ejection fraction and none of the patients had severely depressed left ventricular ejection fraction (Table 1).

Fig. 1.

Number of patients who underwent pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension per year at Karolinska University Hospital from 1997 to 2018.

Table 1.

Baseline characteristics in 100 patients who underwent pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension in Stockholm between 1997 and 2018.

Variable	Total study population (n = 100)
N	100
Age, years, mean (SD), median (Q1/Q3)	62 (13), 64 (54/72)
Men	61 (61%)
Women	39 (39%)
Body mass index, kg/m², mean (SD), median (Q1/Q3)	26.9 (5.0), 25.7 (23.5/29.1)
Hypertension	8 (8%)
Atrial fibrillation	19 (19%)
Diabetes	1 (1%)
Chronic obstructive pulmonary disease	19 (19%)
Prior PCI	2 (2%)
Peripheral artery disease	0
Prior stroke	5 (5%)
eGFR
>60 mL/min/1.73 m²	73 (73%)
<60 mL/min/1.73 m²	27 (27%)
Left ventricular ejection fraction
>50%	86 (86%)
30%–50%	14 (14%)
<30%	0
NYHA class
I	0
II	5 (5%)
III	76 (76%)
IV	19 (19%)
Systolic PAP, mmHg, mean (SD), median (Q1/Q3)	78 (19), 77 (66/89)
Diastolic PAP, mmHg, mean (SD), median (Q1/Q3)	27 (9.3), 28 (22/33)
Mean PAP, mmHg, mean (SD), median (Q1/Q3)	45 (11), 47 (39/52)

Note: Numbers are n (%) unless otherwise noted. SD: standard deviation; Q1/Q3: 25th/75th percentile; eGFR: estimated glomerular filtration rate; NYHA: New York Heart Association; PAP: pulmonary artery pressure; PCI: percutaneous coronary intervention.

The mean and maximum follow-up time was 7.2 and 22.1 years, respectively. Early (30-day) mortality was 7%.

As shown in Table 2, at five years, the observed survival was 80% (95% confidence interval (CI), 70%–87%), whereas the expected five-year survival in a sex, age, and year-of-surgery matched population was 92%. The relative survival at five years was 87% (95% CI, 77%–94%). Conditional on 30-day survival, the observed, expected, and relative survival was 86% (95% CI, 77%–92%), 92%, and 94% (95% CI, 83%–100%), respectively.

Table 2.

Observed, expected, and relative survival in patients who underwent pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension in Stockholm between 1997 and 2018.

	Number of patients	Observed mean survival (95% CI), %	Expected mean survival, %	Relative survival (95% CI), %
Total study population	100	53 (40–64)	80	66 (51–80)
At 1 year	89	91 (83–95)	99	92 (85–97)
At 5 years	64	80 (70–87)	92	87 (77–94)
At 10 years	29	69 (57–78)	82	84 (69–96)
At 15 years	8	55 (40–68)	71	77 (56–95)
At 19 years	4	40 (20–59)	60	67 (34–100)
Sex
Women	39	46 (28–63)	87	53 (32–73)
Men	61	58 (41–71)	76	76 (54–94)
Conditional on 30-day survival	93	59 (46–70)	80	74 (57–87)
At 1 year	89	98 (92–100)	99	99 (93–100)
At 5 years	64	86 (77–92)	92	94 (83–100)
At 10 years	29	74 (61–83)	82	91 (75–100)
At 15 years	8	59 (43–72)	71	83 (60–100)
At 19 years	4	43 (21–63)	60	72 (36–100)

CI: confidence interval.

At 10 years, the observed survival was 69% (95% CI, 57%–78%), the expected survival was 82%, and the relative survival was 84% (95% CI, 69%–96%). Conditional on 30-day survival, the observed, expected, and relative survival at 10 years was 74% (95% CI, 61%–83%), 82%, and 91% (95% CI, 75%–100%), respectively.

The 15-year observed, expected, and relative survival was 55% (95% CI, 40%–68%), 71%, and 77% (95% CI, 56%–95%), respectively. Conditional on 30-day survival, observed, expected, and relative survival was 59% (95% CI, 43%–72%), 71%, and 83% (95% CI, 60%–100%), respectively.

The Kaplan–Meier estimated survival is shown in Fig. 2, and the observed and expected survival is shown in Fig. 3. As shown in Fig. 4, the female relative survival was 53% (95% CI, 32%–73%) for the cohort, whereas for men 76% (54%–94%).

Fig. 2.

Kaplan–Meier estimated survival in patients who underwent pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension from 1997 to 2018. The upper panel shows the survival in the total study population, and the bottom panel shows the survival conditional on patient survival beyond 30 days after pulmonary endarterectomy.

Fig. 3.

The observed survival (95% confidence interval) in patients after pulmonary endarterectomy (red solid line and red dashed lines) compared to the expected survival of an age-, sex-, and calendar-year matched Swedish population (black line). The upper panel shows the survival in the total study population (n = 100), and the bottom panel shows the survival conditional on patient survival beyond 30 days after pulmonary endarterectomy (n = 93).

Fig. 4.

The relative survival (95% CI) in men and women after pulmonary endarterectomy. A relative survival of 100% signifies that patients with chronic thromboembolic pulmonary hypertension who underwent pulmonary endarterectomy have the same survival as people of the same age in the general Swedish population. As shown in the graph, the relative survival was less than 100%, particularly in women. CI: confidence interval.

Discussion

The main finding of our study was that life expectancy following PEA was shorter compared to the general population, but the difference was relatively small. In patients who survived the operation and early postoperative phase, survival at 15 years was 59% compared to 71% in the matched general population, and the relative survival was 83% (95% CI, 60%–100%). Of note, the relative survival was worse in women compared to men.

In comparison, the prognosis for inoperable CTEPH is discouraging with a 3-year survival of 70% according to the European CTEPH registry,¹⁹ a 5-year survival in Sweden of about 50%,⁵ and a 10-year survival at only 40% in a Korean population.²⁰ Similar results were published by Quadery et al., who reported a five-year survival between 53% and 59% in inoperable patients.²¹

Patients undergoing PEA at dedicated high-volume centers have excellent long-term survival with 5-year survival between 79% and 82% and 10-year survival between 72% and 75%.^22–25 These PEA populations have not been compared to a general age, sex, and year of surgery matched population, and therefore, our study complements prior findings and adds information about the prognosis after PEA in patients with CTEPH.

Delcroix et al. performed a multicenter, prospective registry study with data obtained from the CTEPH registry from 27 centers in Europe and Canada. They included newly diagnosed CTEPH patients who underwent PEA between 2007 and 2009 (n = 404) and found a three-year survival of 89% and an in-hospital mortality rate of 4.4%.¹⁹ Mean age for the patients at the time of surgery was 60 years.

Results from the world's largest PEA cohort from the University of California, San Diego, by Madani et al., demonstrated a 10-year survival of 75% for patients who underwent PEA surgery.²⁴ In their study, 1410 patients were included between 1999 and 2010,²⁴ and the mean age at time of surgery was 52 years.

Papworth Hospital in Cambridge is the national center for PEA in the UK. Cannon et al. reported a 10-year survival of 72% for 880 consecutive patients who underwent PEA between 1997 and 2012.²⁵ Mean age at the time of surgery was 57 years. Conditional on three-month survival, the five-year survival at Papworth Hospital was 92.5% for a cohort who underwent PEA between 1997 and 2006.²⁶ In comparison, the five-year survival conditional on 30-day survival was 86% in our study.

Korsholm et al. at Aarhus University Hospital, the national center for PEA in Denmark, recently reported excellent results in 239 patients who underwent PEA between 1994 and 2016. In their study, the 10-year survival rate was 62%.²⁷ The in-hospital mortality was 8.4% for the entire cohort and interestingly, it decreased from 22.6% in the early era to 4.3% in the later part of the study period. The majority of patients had an improvement in functional class and 6-min walk test postoperatively. Median follow-up time was 4.4 years, and the mean age at the time of surgery was 60 years. Based on available data, the patient baseline characteristics in the Danish study appear similar to the patient population that were operated at Karolinska University Hospital.

Interestingly, we found that women had worse relative survival compared to men. This observation needs further investigation, and the reason for this trend is unclear. Possible explanations could be gender differences related to severity of disease at the time of diagnosis or higher burden of comorbidity at the time of surgery. It has been shown that preoperative higher mean PAP confers higher mortality and worse prognosis.²⁸ It is also possible that females are more prone to peripheral disease and therefore have worse surgical outcome with, for example, signs of residual elevation in mean PAP. Additionally, mean expected survival in females in Sweden is generally high with 84.25 years, according to Statistics Sweden,²⁹ which also impacts relative survival. This finding warrants further investigations, preferably in a larger patient cohort to better understand possible gender differences. A recent study from Barco et al. from the CTEPH registry demonstrated better long-term survival for women than for men³⁰ over a three-year period (83% for females vs. 79.3% for men). Their study was limited by a small study population and only reported a single-center experience. Their cohort also stretches over a long period of time, 11 years. During this time, perioperative management of the patients has improved and treatment with specific pulmonary hypertension drugs has been refined.

Study limitations

Our findings should be interpreted in light of the fact that patients were included from a single center, and the findings may therefore not be generalizable to other centers or countries. It is possible that changes in diagnosis, referral, and care of patients with CTEPH during the study period could have affected our results. A limitation of our study is the lack of information regarding post-PEA treatment, such as targeted medication and/or BPA.

Conclusions

Although the life expectancy following PEA was shorter compared to the general population, the difference was small. Our results suggest worse relative survival in women compared to men, a finding that needs further investigation. Given the dismal prognosis without effective treatment, patients with CTEPH who are surgical candidates should undergo PEA to improve survival.

Footnotes

Conflict of interest

The author(s) declare that there is no conflict of interest.

Funding

This work was supported by the Swedish Heart-Lung Foundation (grant numbers 20160522, 20160525, and 20180400 to U.S.), Åke Wiberg Foundation (grant number: M18-0016 to U.S.), Karolinska Institutet Foundations and Funds (grant number 2018-01784 to U.S.), and grants provided by Region Stockholm (ALF project, grant number 20180114 to U.S.).

ORCID iD

Ulrik Sartipy

References

Becattini

Agnelli

Pesavento

, et al. Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism. Chest 2006; 130: 172–175.

Pengo

Lensing

Prins

, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350: 2257–2264.

Ende-Verhaar

Cannegieter

Vonk Noordegraaf

, et al. Incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: a contemporary view of the published literature. Eur Respir J 2017; 49: 1601792.

Gall

Hoeper

Richter

, et al. An epidemiological analysis of the burden of chronic thromboembolic pulmonary hypertension in the USA, Europe and Japan. Eur Respir Rev 2017; 26: 160121.

Svensk Förening för Pulmonell Hypertension. Svenska Pulmonell Arteriell Hypertension Registret – Årsrapport 2018, www.ucr.uu.se/spahr/arsrapporter/arsrapport-spahr-2018 (2019, accessed 30 March 2020).

Jiang

Cheng

, et al. Antiphospholipid syndrome in chronic thromboembolic pulmonary hypertension: a well-defined subgroup of patients. Thromb Haemost 2019; 119: 1403–1408.

Wolf

Boyer-Neumann

Parent

, et al. Thrombotic risk factors in pulmonary hypertension. Eur Respir J 2000; 15: 395–399.

Yan

Liu

, et al. Research progress on the pathogenesis of CTEPH. Heart Fail Rev 2019; 24: 1031–1040.

Dorfmuller

Gunther

Ghigna

, et al. Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature. Eur Respir J 2014; 44: 1275–1288.

10.

Kharat

Hachulla

Noble

, et al. Modern diagnosis of chronic thromboembolic pulmonary hypertension. Thromb Res 2018; 163: 260–265.

11.

Konstantinides

Meyer

Becattini

, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41: 543–603.

12.

Ghofrani

Galie

Grimminger

, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369: 330–340.

13.

Wiedenroth

Ghofrani

Adameit

MSD

, et al. Sequential treatment with riociguat and balloon pulmonary angioplasty for patients with inoperable chronic thromboembolic pulmonary hypertension. Pulm Circ 2018; 8: 2045894018783996.

14.

Ogawa

Satoh

Fukuda

, et al. Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: results of a multicenter registry. Circ Cardiovasc Qual Outcomes 2017; 10: e004029.

15.

Jenkins

. Pulmonary endarterectomy: the potentially curative treatment for patients with chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2015; 24: 263–271.

16.

Madani

Mayer

Fadel

, et al. Pulmonary endarterectomy. Patient selection, technical challenges, and outcomes. Ann Am Thorac Soc 2016; 13: S240–S247.

17.

Madani

. Surgical treatment of chronic thromboembolic pulmonary hypertension: pulmonary thromboendarterectomy. Methodist Debakey Cardiovasc J 2016; 12: 213–218.

18.

Dickman

Coviello

. Estimating and modeling relative survival. Stata J 2015; 15: 186–215.

19.

Delcroix

Lang

Pepke-Zaba

, et al. Long-term outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. Circulation 2016; 133: 859–871.

20.

Kim

Lee

Ahn

, et al. Long-term outcomes of surgery for chronic thromboembolic pulmonary hypertension compared with medical therapy at a single Korean center. Korean J Intern Med 2017; 32: 855–864.

21.

Quadery

Swift

Billings

, et al. The impact of patient choice on survival in chronic thromboembolic pulmonary hypertension. Eur Respir J 2018; 52: 1800589.

22.

Jenkins

Madani

Fadel

, et al. Pulmonary endarterectomy in the management of chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2017; 26: 160111.

23.

Mahmud

Madani

Kim

, et al. Chronic thromboembolic pulmonary hypertension: evolving therapeutic approaches for operable and inoperable disease. J Am Coll Cardiol 2018; 71: 2468–2486.

24.

Madani

Auger

Pretorius

, et al. Pulmonary endarterectomy: recent changes in a single institution’s experience of more than 2,700 patients. Ann Thorac Surg 2012; 94: 97–103. discussion 103.

25.

Cannon

Kiely

, et al. Dynamic risk stratification of patient long-term outcome after pulmonary endarterectomy: results from the United Kingdom National Cohort. Circulation 2016; 133: 1761–1771.

26.

Freed

Thomson

Tsui

, et al. Functional and haemodynamic outcome 1 year after pulmonary thromboendarterectomy. Eur J Cardiothorac Surg 2008; 34: 525–529. discussion 529–530.

27.

Korsholm

Andersen

Mellemkjaer

, et al. Results from more than 20 years of surgical pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension in Denmark. Eur J Cardiothorac Surg 2017; 52: 704–709.

28.

Klok

Barco

Konstantinides

, et al. Determinants of diagnostic delay in chronic thromboembolic pulmonary hypertension: results from the European CTEPH Registry. Eur Respir J 2018; 52: 1801687.

29.

Statistics Sweden. Mean survival in Sweden 2018, www.scb.se/hitta-statistik/sverige-i-siffror/manniskorna-i-sverige/medellivslangd-i-sverige (2019, accessed 30 March 2020).

30.

Barco

Klok

Konstantinides

, et al. Sex-specific differences in chronic thromboembolic pulmonary hypertension. Results from the European CTEPH registry. J Thromb Haemost 2019; 18: 151–161.