Embolization for Pulmonary Arteriovenous Malformation in Hereditary Hemorrhagic Telangiectasia

CHEST

Original Research PULMONARY ARTERIOVENOUS MALFORMATION

Embolization for Pulmonary Arteriovenous Malformation in Hereditary Hemorrhagic Telangiectasia A Decision Analysis Samir Gupta, MD, MSc; Marie E. Faughnan, MD, MSc; and Ahmed M. Bayoumi, MD, MSc

Background: Although experts recommend presymptomatic coil embolotherapy for patients with hereditary hemorrhagic telangiectasia (HHT) who have pulmonary arteriovenous malformations (PAVMs), this approach has not been studied prospectively and is not applied universally. We used decision analysis to evaluate the optimal treatment strategy for HHT patients with asymptomatic PAVMs. Methods: We developed a Markov model to evaluate the following three strategies: no embolotherapy; embolotherapy only in the event of a PAVM complication; and immediate embolotherapy. Our model incorporated PAVM complications, embolotherapy effectiveness and complications, and the possibility of PAVM growth or reperfusion of successfully embolized PAVMs. The base case was a 40-year-old man with HHT and an asymptomatic PAVM with a 3-mm feeding artery. We modeled the natural history of HHT and the clinical course of embolotherapy based on review of the medical literature. We incorporated quality-of-life weights derived from the direct assessment of patient preferences (n ⴝ 45) and a literature review. Results: No embolotherapy, embolotherapy only in the event of a PAVM complication, and immediate embolotherapy were associated with expected survival times of 37.2, 37.6, and 39.0 years, respectively. After adjusting for quality of life, the corresponding estimates were 32.6, 34.1, and 37.2 quality-adjusted life-years. The outcome of the model was robust to changing model parameters within plausible ranges. Conclusions: Patients with HHT and a PAVM with a feeding artery of > 3 mm have improved life expectancy and quality-adjusted survival with immediate embolotherapy. Embolotherapy should be the standard of care in such circumstances. (CHEST 2009; 136:849 – 858) Abbreviations: DVT ⫽ deep venous thrombosis; HHT ⫽ hereditary hemorrhagic telangiectasia; PAVM ⫽ pulmonary arteriovenous malformation; QALY ⫽ quality-adjusted life-year; TIA ⫽ transient ischemic attack

hemorrhagic telangiectasia (HHT) is a H ereditary rare autosomal-dominant disorder characterized by recurrent epistaxis, mucocutaneous telangiectasias, and visceral arteriovenous communications, including pulmonary arteriovenous malformations (PAVMs) in 15 to 35% of patients.1–3 PAVMs with feeding arteries of ⱖ 3 mm in diameter are associated with stroke, brain abscess, hemothorax, and life-threatening hemoptysis.3– 6 Some experts have recommended3,5–10 preventive occlusion of such PAVMs with transcatheter embolotherapy, in which thrombogenic metal coils are inserted via an endovascular approach. However, embolization is not www.chestjournal.org

always successful and has its own set of complications, including stroke, coil migration through PAVMs to another vascular bed, pleurisy, and deep venous thrombosis (DVT).3,11 Embolization may be required several times over a patient’s lifetime because PAVMs may reperfuse, and small PAVMs (with feeding arteries ⬍ 3 mm in diameter) may grow over time.3,6,12,13 Embolotherapy might be acceptable if the associated risks and benefits could be quantified. However, given the rarity of HHT and the infrequency of associated PAVM complications, a randomized, controlled trial of embolotherapy would require a proCHEST / 136 / 3 / SEPTEMBER, 2009

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hibitively large number of patients and prolonged follow-up. Without evidence for benefit, some nonexpert physicians are reluctant to recommend embolotherapy and some third-party health-care payers refuse to reimburse procedural costs.14 We examined the optimal management strategy for PAVMs in patients with HHT by using decision analysis, a rigorous method for guiding decisions under conditions of uncertainty, such as when insufficient experimental evidence exists. Our approach integrates reasonable assumptions about risks and benefits into a simulation model to yield a measure of net health benefit. If the estimate of net benefit is robust to varying assumptions over reasonable ranges, such an approach may convince skeptics that knowledge is sufficient to adopt embolotherapy as the standard of care.

Materials and Methods Online Poll To ascertain whether there was uncertainty around the use of embolotherapy, we conducted a poll of current practice and experience among HHT experts worldwide, through the HHT Foundation International. We designed a Web-based survey requiring approximately 5 min to complete; a request and link to this survey were sent on our behalf by the HHT Foundation International by personal e-mail to HHT expert pulmonologists practicing at HHT centers of excellence and to the directors of each Center (n ⫽ 91). Manuscript received February 8, 2009; revision accepted March 24, 2009. Affiliations: From the Departments of Medicine (Drs. Gupta, Faughnan, and Bayoumi), and Health Policy, Management, and Evaluation (Dr. Bayoumi), University of Toronto, Toronto, ON, Canada; and the Division of Respirology (Drs. Gupta and Faughnan), Department of Medicine, the Centre for Research on Inner City Health, Keenan Research Centre (Dr. Bayoumi), Li Ka Shing Knowledge Institute (Drs. Gupta, Faughnan, and Bayoumi), and the Division of General Internal Medicine (Dr. Bayoumi), St. Michael’s Hospital, Toronto, ON, Canada. Funding/Support: This research was supported by the Li Ka Shing Knowledge Institute of St. Michael’s Hospital and the St. Michael’s Hospital Research Institute (Dr. Gupta). During this research, Dr. Gupta was also supported by the Canadian Lung Association and the University of Toronto Clinician Scientist Program. Dr. Faughnan is supported by the Nelson Arthur Hyland Foundation and the Li Ka Shing Knowledge Institute of St. Michael’s Hospital. Dr. Bayoumi is supported by Canadian Institutes of Health Research/Ministry of Health and Long Term Care Applied Chair in Health Services Research. The Centre for Research on Inner City Health is supported in part by a grant from the Ontario Ministry of Health and Long-Term Care. © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). Correspondence to: Samir Gupta, MD, MSc, 30 Bond St, Suite 6045, Bond Wing, Toronto, ON, Canada, M5B 1W8; e-mail [email protected] DOI: 10.1378/chest.09-0334

Markov Model We built a Markov computer simulation model in which we followed a hypothetical cohort of patients over the course of a lifetime. The base case patient was a 40-year-old man with HHT2 who was otherwise healthy and had a single, simple PAVM with a 3-mm feeding artery and no prior PAVM-related complications (which we designated as asymptomatic). The model defined possible health states and associated quality of life as well as possible transitions between states, which occurred at 1-month intervals. In each cycle, patients faced a mortality risk equal to that of the population as well as additional risks associated with PAVM complications.15 We measured outcomes as both survival and qualityadjusted life-years (QALYs). We constructed and analyzed the model by using appropriate software (Decision Maker for Windows, version 2006). Further details and supplementary results are described in the online data supplement. Strategies We evaluated three possible strategies (Fig 1). In the first strategy, “treat-none,” patients were observed and treated for any complications of the PAVM but received no embolotherapy. In the second strategy, “treat-only-if-complication,” patients received embolotherapy only after a PAVM-related complication. Finally, we evaluated a strategy of “treat-all,” in which all patients received immediate embolotherapy (for the complete state transition diagram, please see the figure in the online data supplement). Data Sources Our primary sources of data were the English language medical literature for transition probabilities. We searched the Medline database up to week 2 of September 2008, using the search term “hereditary hemorrhagic telangiectasia.” All titles and citations were reviewed, and all abstracts excluding basic science study abstracts were reviewed by two independent reviewers regarding relevance for full review. We reviewed full-text articles for any studies that were thought to contain data regarding transitional probabilities. We hand searched bibliographic lists for additional articles from the full-text articles obtained and from any reviews. We performed direct interviews for quality-of-life weights (Table 1). When the literature reported several estimates for an event probability, we pooled these data (see the online data supplement). For probability estimates and quality-of-life decrements that were unavailable in the literature, we used our judgment and the opinion of an additional HHT expert, and incorporated a wide range in sensitivity analyses (J.R. Gossage; personal communication; June 2006). PAVM Complications The model incorporated PAVM complications, which we classified as either transient or permanent. Transient complications included transient ischemic attack (TIA), hemothorax, and massive hemoptysis; permanent complications included ischemic stroke and brain abscess. We assumed that stroke and brain abscesses were associated with either minor or major neurologic deficits and that patients with brain abscesses would require antiseizure medication. With the exception of TIA, each complication was associated with a risk of death. We assumed that all patients who experienced two major strokes would die after the second stroke. Embolization Complications The model incorporated the following embolization complications: death; stroke; nonserious coil migration (ie, migration not

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Treat None PAVM

PAVM with minor stroke

Treat only if complication PAVM

Hemothorax, Hemoptysis, or TIA

Treat ± major deficit

PAVM with minor abscess

PAVM with major deficit

Treat All

PAVM

Treat

Figure 1. Decision tree. The square node represents the decision between the three strategies in the model. Possible transitions between the initial state (PAVM) and embolization (Treat) are modeled. In the treat-none strategy, no patients received embolization. In the treat-only-if-complication strategy, patients received embolization only after a PAVM-related complication. In the treat-all strategy, patients proceeded immediately to embolization.

resulting in organ ischemia); pleurisy; and DVT. We assumed that all postembolization strokes were associated with major neurologic deficits (based on reports in the literature), that all patients with DVT or pleurisy experienced consequences for no longer than one cycle length (1 month), and that nonserious coil migration was to a vascular bed from which the coil was either removable or could be left in place with no sequelae. We made the simplifying assumption that each patient would experience only one embolization complication with each procedure, given the rarity of these events. Because not all embolizations are successful, we allowed for up to three repeat procedures, after which the PAVM was considered not to be amenable to embolization. Retreatment After Successful Embolization After successful embolization, patients experienced a small but ongoing risk of PAVM-related complications because of the presence of one or more remaining PAVMs with feeding arteries of ⬍ 3 mm. In addition, PAVM reperfusion (defined as undetected residual PAVM perfusion, PAVM recanalization, or reperfusion of an embolized PAVM by an accessory feeding artery or small bronchial artery collaterals)16 or a new PAVM with a ⱖ 3 mm feeding artery (from the growth of a previously smaller PAVM) could subsequently develop. After either of these events, patients underwent repeat embolization in the next cycle. State Transitions All patients in the model start with an asymptomatic PAVM (Fig 1). In the treat-none strategy, patients can experience PAVM complications. In the treat-only-if-complication strategy, patients who experience any PAVM complication and survive are treated, but www.chestjournal.org

asymptomatic patients receive no therapy. In the treat-all strategy, all patients are treated immediately after entry into the model. Transition Probabilities: PAVMs We estimated the rates of PAVM complications on the basis of pooled data from the literature (Table 1). We used both incidence and prevalence data to estimate these rates, although evidence from prevalence studies was generally stronger. We based mortality estimates for PAVM complications on corresponding mortality estimates for similar complications from other conditions. We varied the plausible limits widely, according to clinical judgment, to account for differences between populations in the literature and in the model. Transition Probabilities: Embolization We estimated the probability of success and the risks of embolization to determine the probabilities of each transition between relevant health states. In calculating the probability of embolization-related major stroke (0.50%), we only included studies that explicitly reported looking for this complication, resulting in a possible overestimation. However, the lower limit considered plausible in sensitivity analyses was zero. Death from embolization has not been reported but was included as a potential complication, albeit with very low risk. There are limited data on the annual rates of PAVM complications after a successful embolization.7,10,16,17 To estimate TIA and stroke rates, we applied the hazard ratio for ischemic stroke after embolization provided in a single study.17 CHEST / 136 / 3 / SEPTEMBER, 2009

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Table 1—PAVM and Embolization Complications, Quality-of-Life Weights Parameters PAVM complications* Stroke TIA Abscess Hemothorax Massive hemoptysis PAVM complications after successful embolization* Stroke TIA Abscess Hemothorax Massive hemoptysis PAVM natural history after successful embolization* Reperfusion or new PAVM growth Sequelae of PAVM complications, % Major neurologic deficit from a stroke Major neurologic deficit from an abscess Death from a stroke Death from an abscess Death from a hemothorax Death from massive hemoptysis Embolization complications, % Successful coil embolization Death from coil embolization Stroke with a major neurologic deficit from coil embolization Pleurisy from coil embolization DVT from coil embolization Nonserious migration of coil Quality–of–life weights† PAVM PAVM plus minor stroke PAVM plus minor abscess PAVM plus major deficit Treat Treat plus major deficit Postembolization Postembolization plus major deficit Quality-of-life decrements‡ PAVM complications Stroke with a minor neurologic deficit TIA Abscess with a minor neurologic deficit Hemothorax Massive hemoptysis Embolization complications Pleurisy DVT Nonserious migration

Baseline Value 0.65 0.84 0.43 0.18 0.39 0.00011 0.00014 0.03 0.02 0.04

2.40

Range

References

0–2.5 0.075–3 0.20–3 0.10–0.60 0.03–0.82

4, 5, 7, 13, 16, 17, 32, 35–40 5, 7, 13, 16, 32, 35, 37–41 4, 5, 7, 10, 13, 16, 17, 32, 35, 37–43 5, 7, 10, 32, 37, 44 5, 7, 10, 13, 16, 32, 35–37, 42–45

0–0.65 0.–0.5 0.0032–0.4 0.002–0.10 0.0028–0.20

7, 16, 17 10, 16, 17 10, 16, Expert opinion Expert opinion 16, Expert opinion

0.62–16

7, 10, 16, 31, 42, 46, 47

9.88 9.71 10.0 12.63 1.36 13.17

4.5–13.5 5–25 5–20 0–19 1–10 5–20

97.33 0.01 0.50

96–100 0.00–0.01 0–1.3

5, 7, 35, 42, 63 Expert opinion 10, 17, 31, 32, 35

12.08 0.97 1.22

3.0–32.0 0–20.0 0.30–3.3

5, 7, 10, 16, 31, 32, 35, 41, 42 5, 10, 31, 32, 64 5, 7, 10, 31, 32, 41, 42

0.882 0.880 0.840 0.575 0.882 0.575 0.956 0.623

0.5096–1 0.584–1 0.544–1 0.007–1 0.5096–1 0.007–1 0.802–1 0.011–1

48 40, 49–51 52–55 17, 40, 49–51, 56, 57 58 59–62

Measured Measured Measured, 65 Measured Measured Measured Measured Measured

0.12 0.1 0.16 0.3 0.12

0.1–0.4 0.05–0.2 0.1–0.4 0.05–0.5 0.05–0.3

Measured 66 Measured, 65 66 66

0.0375 0.05 0.025

0.01–0.1 0.01–0.3 0.01–0.1

Expert opinion 66 Expert opinion

Values are given as the No. of events per 100 patient-years, unless otherwise indicated. *Rates were converted to monthly probabilities in the Markov tree by using the formula p ⫽ 1 ⫺ e⫺rate/12. †We measured several quality-of-life weights in 45 patients by using the standard gamble method. Ranges for quality-of-life weights were based on mean ⫾ 2 SDs with an upper limit of ⱕ 1. ‡Event quality-of-life decrements were subtracted from a patient’s overall quality of life during the cycle in which the patient experienced the event.67

Quality-of-Life Weights

Sensitivity Analysis

We assessed quality-of-life weights for HHT-related health states from 45 patients who attended a tertiary HHT referral center in Toronto, ON, Canada. An institutional research ethics board approved the study. Participants were recruited consecutively from a preestablished database, provided informed consent, and rated health states by using the standard gamble method.18,19

We assessed the robustness of our model to the baseline values of each input parameter by intentionally varying these values over ranges that exceeded clinically plausible ranges. We also performed selected two-way sensitivity analyses, in which we varied the values of two parameters simultaneously.

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0.020

Treat None Treat All Treat Only If Complication

Proportion With Major Stroke

0.015

0.010

0.005

0.000 0

2

4

6

8

10

12

14

16

18

20

Years

Figure 2. Proportion of patients with a stroke with a major neurologic deficit over time, by strategy. The proportion of patients with major stroke in the treat-none group exceeded that in the treat-all group after 10.2 years. The corresponding threshold between the treat-only-if-complication group and the treat-all group occurred at 9.2 years.

Results Online Poll We received responses to our online poll from 21 of 92 pulmonologists and/or HHT center directors (23%) in nine countries. Fourteen respondents (67%) estimated that fewer than one-half of physicians practicing outside of HHT centers recommend embolization for an asymptomatic PAVM (feeding artery ⱖ 3 mm). Furthermore, 16 respondents (76%) had encountered a patient who had experienced a major complication as a result of a physician’s failure to recommend embolization. Four of 15 participants (27%) from centers in which healthcare coverage was not universal reported that thirdparty health-care payers sometimes or often refuse to reimburse the costs of embolization, which in some cases resulted in a major patient complication. The results of this poll have been posted on the HHT Foundation International Web site.14 Markov Model Our model predicts that a cohort of 1,000 patients would experience 24 strokes with a major neurologic deficit with the treat-none approach, 20 strokes with the treat-only-if-complication approach, and 10 strokes with the treat-all approach. This corresponds to a number-needed-to-treat of 100 patients to prevent a single stroke with a major neurologic deficit over a patient’s lifetime, by treating all patients immediately rather than by waiting to treat patients until complications developed. However, the timing www.chestjournal.org

of major strokes varied between strategies, with high initial rates from treatment (Fig 2). Not treating patients with PAVMs was associated with a life expectancy of 37.2 years. Waiting to treat patients until complications developed resulted in an expected survival time of 37.6 years, whereas treating all patients resulted in the greatest expected survival time of 39.0 years. The ranking of these strategies was the same after quality adjustment, with expected outcomes of 32.6, 34.1, and 37.2 QALYs, respectively (Table 2). Sensitivity Analysis The finding that the treat-all strategy was preferred was robust in sensitivity analyses, with only three and four parameters indicating model sensitivity when outcomes were measured in QALYs and life-years, respectively, and none of these in the prespecified plausible range (Table 3). Simultaneously varying the probability of a stroke with a major neurologic deficit from coil embolization and the probability of successful coil embolization demonstrated that the optimal strategy

Table 2—Results Life Expectancy, Quality-Adjusted Life yr Expectancy, QALYs

Strategies Treat all Treat only if complication Treat none

39.0 37.6 37.2

37.2 34.1 32.6

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Table 3—Sensitive Parameters in One-Way Sensitivity Analyses Life Expectancy Baseline Value

Parameters Rate of reperfusion or new PAVM growth, No. of events/100 patient-yr

Successful coil embolization, %

2.40

97.33

Range 0–52.3 52.3–52.4 52.4–100 0–11.9 11.9–100

Quality-Adjusted Life Expectancy, QALYs

Preferred Strategy Treat all Treat only if complication Treat none Treat none Treat all

Not sensitive

0–2.4 2.4–6.1

Death from coil embolization, %

0.01

0–3.1 3.1–100

Treat all Treat none

6.1–100 0–8.2 8.1–8.6

Stroke with a major neurologic deficit from coil embolization, %

0.50

0–3.9 3.9–100

Treat all Treat none

8.6–100 0–9.1 9.1–9.9 9.9–100

was treat-only-if-complication at unlikely values for either parameter, when outcomes were measured in QALYs (Fig 3). Discussion We evaluated the optimal treatment strategy for patients with HHT having a PAVM with a feeding artery of at least 3 mm in diameter. Our analysis

Preferred Strategy

Range

Treat none Treat only if complication Treat all Treat all Treat only if complication Treat none Treat all Treat only if complication Treat none

strongly suggests that immediate coil embolization is the preferred strategy, with expected gains of 1.4 years and 3.1 QALYs when compared with a strategy of treating patients only if complications develop. These gains are considered large by decision analysis standards.20,21 Our findings were robust throughout sensitivity analyses. Indeed, the threshold for efficacy of embolization below which immediate treatment is not preferred is so low (6.1% in the QALY

Coil Embolization (%)

Probability of Major Stroke from

10 9

Treat Only If

8

Complication

7 6 5 4

Treat All

3 2 1 0 50

60

70

80

90

100

Probability of Successful Coil Embolization (%)

Figure 3. Two-way sensitivity analysis of the probability of a stroke with a major neurologic deficit from coil embolization and the probability of successful coil embolization with outcomes measured as QALYs. Any combination of values above the solid line favors the treat-only-if-complication strategy, and any combination below the solid line favors the treat-all strategy. The “X” marks the baseline values for these probabilities, and the shaded area represents the range of parameter values that are considered plausible. 854

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analysis) as to be clinically implausible. Thus, our model suggests that embolization should become the standard of care for these patients. Although embolotherapy for patients having a PAVM with a feeding artery of at least 3 mm in diameter has been adopted in HHT Centers of Excellence, authors have noted17 that it is not routinely recommended for all asymptomatic patients. Our poll confirms these reports, suggesting that less than one-half of physicians in non-HHT centers have adopted this practice, frequently resulting in major PAVM complications. The poll also suggests that PAVM embolization in asymptomatic patients is not always considered a necessary and thus reimbursable therapy by third-party health-care payers, also resulting in major complications. The failure of this recommendation to emerge as a universal standard of care may be due to the fact that it is based on expert opinion with limited supporting data. The practice was initially suggested by Hewes et al22 in 1985, on the basis of a case series documenting embolic cerebral artery occlusion in four of five patients with asymptomatic PAVMs who presented with stroke. Subsequently, when helical CT scanning was established as a reliable modality to determine the angioarchitecture of PAVMs,23 experts recommended24 embolization of all PAVMs with feeding arteries of ⱖ 3 mm in diameter seen on CT scan. This cutoff was based on unpublished retrospective data describing clinical stroke resulting from paradoxical embolization in 4 of 17 patients with PAVMs, in which these four patients had PAVM feeding artery diameters of between 2.9 and 4.6 mm.24 Given that definitive evidence for this practice in the form of a randomized, controlled trial will not be attainable, the robust conclusions of this decision analysis may serve to demonstrate the validity of this practice to all parties. In our model, the advantage of the treat-all strategy is largely due to the ongoing risk of stroke for patients with an untreated PAVM of 0.65 events per 100 patient-years, which is in turn associated with a high immediate and ongoing mortality risk. Additional, but less significant, mortality risks are attributable to abscess, massive hemoptysis, and hemothorax. In contrast, patients in the treat-all group face small, one-time, procedure-related risks of death and major stroke. The difference in quality-adjusted life expectancy is even greater than that for unadjusted survival because the majority of patients in the treat-none group remain in the PAVM state, which has a lower quality of life than the postembolization state. The overall outcome of each strategy is based on the cumulative occurrence of complications over patients’ lifetimes, but the timing of events varies between strategies, with relatively high immediate www.chestjournal.org

risks of major stroke in the treat-all strategy traded off against an ongoing lifetime risk in the other strategies. This distinction may be important for individual-level decision making. For example, patients who value time in the near future much more highly than time in the distant future might opt to delay or avoid embolization.25 Our estimates of the efficacy of embolization, the risk of complications, and the rates of reperfusion or new PAVM growth were based mainly on large series reported by HHT centers. Actual complication and reperfusion rates may exceed literature estimates for three reasons. First, most studies were retrospective and did not adjust for temporal trends. Second, many studies failed to report which complications they monitored and recorded, leading to concerns about underreporting. Third, publication bias may favor publication of reports by centers with good outcomes. Apart from study accuracy, an additional concern is that the effectiveness and risks of embolization in practice are dependent on operator skill. Previous studies26,27 have demonstrated important volume-outcome relationships for similar interventional procedures, such as percutaneous coronary intervention. Our model suggests that establishing volume and performance thresholds for embolization is an important objective for future research and quality assurance studies.11,28 Our model did not account for expected increases in PAVM complication rates with advancing patient age or gender-related differences in complication rates.17 Also, our base case model had a single PAVM with a simple anatomy, but reality is somewhat more complicated. PAVM complication rates in the literature have mostly been reported for mixed cohorts, with up to 36% of patients having multiple PAVMs, which are associated with a higher rate of PAVM complications,4 and 10 to 20% of PAVMs having a complex anatomy.3,8,23,29 Similarly mixed cohorts have been included in reports of embolization complication rates. Also, embolization success, complication, and reperfusion rates were calculated from heterogeneous data that included the use of detachable balloons, multiple types of coils, or both. Because embolization of a single, simple PAVM is technically easier and less time consuming than that of multiple PAVMs or a complex PAVM,3,9,29,30 we may have overestimated complication rates. A number of studies included in the analysis reported no major strokes from embolization17,31,32; however, the use of lower embolization complication rates would only render a strategy of immediate coil embolization even more favorable. Overall, our assumptions of efficacy and safety are likely to be conservative and would not change our conclusions. CHEST / 136 / 3 / SEPTEMBER, 2009

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An important additional consideration before adopting embolization is the associated cost. While we did not carryout a formal cost-effectiveness analysis, it is instructive to compare the costs of embolization with the costs of major stroke, the most serious and costly complication of both PAVM and embolization. We compared the literature-based costs of stroke in 2008 Canadian dollars ($155,000 per patient with major stroke33,34) to the cost of a single-vessel coil embolization procedure at our institution ($992.20). Incorporating model-predicted estimates of stroke, the treat-all strategy was less expensive per patient than the treat-none and treat-only-if-complication strategies by $1,156 and $574, respectively. Furthermore, if we were to incorporate the cost of other PAVM complications (minor stroke, TIA, abscess, hemothorax, and massive hemoptysis), cost savings with the treat-all approach would be even greater. In summary, our analysis has demonstrated that coil embolization for patients with PAVMs with a feeding artery of ⱖ 3 mm offers a significant life expectancy and quality-adjusted life expectancy benefit over other strategies. Although this recommendation is congruent with expert opinion and existing standards of care in specialized HHT centers, embolotherapy is not routinely recommended for all asymptomatic patients.17 Less than one-half of physicians practicing at non-HHT centers recommend embolization, and third-party health-care payers often refuse to reimburse procedural costs.14 Our model indicates that only under implausible conditions would other strategies be preferred to immediate embolization. Because additional evidence from controlled trials or observational studies with appropriate comparators is unlikely, our analysis likely represents the best available evidence to make this decision. Accordingly, we believe that there is a strong argument for a universal strategy of immediate embolization for these patients. Acknowledgments Author contributions: Drs. Gupta and Faughnan conducted the literature search and determined the basic contents of the decision tree. Drs. Gupta and Bayoumi designed and tested the Markov decision analytic model and determined its outcomes. Dr. Gupta prepared the manuscript with the help of the other two authors. Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The views expressed in this article are those of the authors, and no official endorsement by supporting agencies is intended or should be inferred. Other contributions: We thank Dr. James R. Gossage for his expert opinion, Dr. Michael Miletin for conducting patient preference assessments, and Dr. Justine H. Cohen for assisting in the literature search.

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