This is the protocol for a review and there is no abstract. The objectives are as follows:
To evaluate the effectiveness of and potential adverse events with the use of anticoagulation in the management of pulmonary hypertension (PH).
To evaluate the effective therapeutic INR in pulmonary hypertensive patients receiving anticoagulants (North America 1.5 to 2.5, European centres 2.0 to 3.0).
Description of the condition
Pulmonary hypertension (PH) is defined as an increase in pulmonary arterial pressure (PAP) greater than or equal to 25 mmHg at rest as assessed by right heart catheterization (D'Alonzo 1991). It is a progressive disease and can be fatal if untreated, although the rate of progression is highly variable. Available data show that the normal mean PAP at rest is 14 ± 3 mmHg with an upper limit of normal of approximately 20 mmHg (Badesch 2009; Kovasc 2009).
PH was previously classified as primary pulmonary hypertension, now called idiopathic pulmonary arterial hypertension (IPAH), or secondary PH (Rich 1998). The World Health Organization (WHO) classified PH into five groups based on the etiopathogenesis (Simoneau 2009).
Group 1 PAH is pulmonary arterial hypertension (PAH). This group consists of sporadic IPAH, heritable IPAH, and PAH due to diseases that localize to small pulmonary muscular arterioles. These diseases include connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, chronic haemolytic anaemia, persistent pulmonary hypertension of the newborn, pulmonary veno-occlusive disease, and pulmonary capillary haemangiomatosis. Drug (including anorexigens) and toxin-induced PAH are also considered group 1 PAH.
Group 2 PH is pulmonary hypertension due to left heart diseases. PH due to systolic dysfunction, diastolic dysfunction, or valvular heart disease is included in this group. Group 3 PH is pulmonary hypertension due to lung diseases or hypoxaemia. This group includes PH caused by chronic obstructive pulmonary disease, interstitial lung disease, pulmonary diseases with a mixed restrictive and obstructive pattern, sleep-disordered breathing, and alveolar hypoventilation disorders. Group 4 PH is chronic thromboembolic pulmonary hypertension. This group includes patients with PH due to thromboembolic occlusion of the proximal or distal pulmonary vasculature. Group 5 PH is pulmonary hypertension with unclear, multifactorial mechanisms.
While the prevalence of group 1 PAH in the general population is estimated to be five to 15 cases per one million adults (Humbert 2006; Ling 2012), there is a paucity of data on the prevalence among other groups of PH.
The prognosis of PH depends on various factors. The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) registry risk score is used to predict the disease progression. Poor prognostic indicators include age at initial presentation > 50 years (Peacock 2007), male sex and ≥ 60 years (Marcus 2008), persistent (WHO) functional class III or IV, pericardial effusion, and elevated right atrial pressure, (Paulus 2007; Torbicki 2007). The one, three, and five year survival rates are 84%, 67%, and 58% respectively with a median survival of 3.6 years (Thenappan 2007). Pregnancy is noted to be associated with 30% to 50% mortality in patients with PAH (Bedard 2009) and consequently PAH is a contra-indication to pregnancy.
Description of the intervention
Recently, the treatment of PH has undergone extraordinary evolution. Management of PH is multifaceted and includes rehabilitation, psychosocial support, surgical and medical treatment. Balloon atrial septostomy, septal defect closure, and lung transplantation or heart-lung transplantation are the available surgical interventions. Medical management is comprised of calcium channel blockers, for example nifedipine, diltiazem; endothelin receptor antagonists, for example ambrisentan, bosentan; phosphodiesterase-5 inhibitor, for example sildenafil; prostanoids, for example epoprostenol; diuretics; oxygen; and anticoagulants.
It is generally accepted that anticoagulation is indicated in patients with IPAH (Barst 2009; Galie 2009; McLaughlin 2009), hereditary PAH, drug-induced PAH (Barst 2009; Galie 2009), and chronic thromboembolic PH. Anticoagulants include warfarin, heparin, fondaparinux, argatroban, dabigatran, apixaban, and rivaroxaban but the anticoagulant of choice is warfarin. The target international normalized ratio (INR) in patients with IPAH varies from 1.5 to 2.5 (in most North American centres) to 2.0 to 3.0 (in European centres) (Galie 2009). The starting dose of warfarin is 2 to 5 mg daily, which can be increased until the target INR is achieved. The half life is 20 to 60 hours, which is highly variable depending on the rate of clotting factor catabolism. Warfarin is usually taken once a day by mouth, with or without food, at around the same time every day. It is metabolised in the liver and excreted by the kidneys. Warfarin is also prescribed for people with certain types of irregular heartbeat, people with prosthetic (replacement or mechanical) heart valves, and people who have suffered a heart attack. However, the purpose of this review is to evaluate the effects of warfarin and other anticoagulants in the treatment of PH.
Some medications also used in the treatment of PH have a significant interaction with warfarin. Concomitant use of epoprostenol (Ogawa 2005) or sitaxsentan (Widlitz 2005) and warfarin increases the risk of bleeding, while bosentan decreases the anticoagulant effect of warfarin (Murphey 2003).
How the intervention might work
PAH is a proliferative vasculopathy characterized by vasoconstriction, cell proliferation, fibrosis, and thrombosis. Pathologic findings include intimal hyperplasia and fibrosis, medial hypertrophy, and in situ thrombi of the small pulmonary arteries and arterioles (Humbert 2004; Pietra 2004). The pathologic appearance of the small pulmonary arteries and arterioles is qualitatively similar in all patients with group 1 PAH. It is unclear how applicable these mechanisms are to most other types of PH. Current evidence suggests that abnormalities of blood coagulation factors, antithrombotic factors, and the fibrinolytic system contribute to a pro-thrombotic state in patients with IPAH (Johnson 2006). Patients with PH are at increased risk for intrapulmonary thrombosis and thromboembolism due to sluggish pulmonary blood flow, dilated right heart chambers, venous stasis, and immobility. Even a small thrombus can produce haemodynamic deterioration in a patient with a compromised pulmonary vascular bed. There is a high prevalence of vascular thrombotic lesions at postmortem in patients with IPAH (Fuster 1984) and histological evidence of microvascular thrombosis (Bjornsson 1985; Wagenvoort 1980). A previous pathophysiological review identified several lines of evidence to suggest a relationship between thrombotic arteriopathy and PAH (Johnson 2006). The use of anticoagulant is believed to reduce the risk of thrombus formation and embolization. Anticoagulants like warfarin act by inhibiting the gamma-carboxylation of clotting factors II, V, VII, IX, and endogenous anticoagulants protein C and protein S. Other anticoagulants function by different mechanisms, for example argatroban directly inhibits thrombin whereas faundaparinaux directly inhibits activated factor X. The interruption of this coagulation cascade by anticoagulants theoretically should improve survival in patients with PH. This presents a plausible rationale for oral anticoagulation in PAH.
Why it is important to do this review
The justification for the use of anticoagulation therapy, its effectiveness and survival benefits, in patients with PAH remains uncertain. The current guidelines for anticoagulation with warfarin are based on non-controlled, observational studies along with expert opinion. A recent study found that treatment with warfarin has a low probability of improving survival in either systemic sclerosis-associated PAH or IPAH (Johnson 2012). In a systematic review of seven observational studies that evaluated the effect of warfarin in patients with group 1 PAH, five studies found a mortality benefit while two studies did not support its effectiveness in IPAH (Johnson 2006B). Anticoagulation therapy is not without risk, and the risk of major haemorrhage is of greatest concern. The situation is even graver in patients with increased risk of bleeding, such as with advanced age; concomitant renal, cardiac, or hepatic disease; diabetes (DiMarco 2005); scleroderma (Duchini 1998), and portopulmonary hypertension with severe oesophageal varices (Galie 2009). It is therefore pertinent that we evaluate the effectiveness and potential adverse events associated with anticoagulation in patients with PH.
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs). We will include studies reported in full text, those published as abstracts only, and unpublished data. We will exclude non-RCTs.
Types of participants
We will include all individuals with PH including Group 1 through Group 5 irrespective of their WHO functional class. PH will be defined as an increase in pulmonary arterial pressure (PAP) greater than or equal to 25 mmHg at rest as assessed by right heart catheterization. Patients with PH with other co-morbidities including medical conditions requiring chronic anticoagulation will also be included. There will be no exclusions based on age, sex, and the cause of PH.
Types of interventions
We will include trials comparing warfarin with placebo, heparin with placebo, argatroban with placebo, fondaparinux with placebo, and any other anticoagulant compared with placebo.
Types of outcome measures
Six-minute walk test
Haemorrage from anticoagulant use (number of people experiencing one or more events): bleeding requiring significant intervention will be regarded as a major bleed
Cardio-pulmonary exercise testing
Thromboembolism (number of people experiencing one or more events)
Pulmonary arterial pressure (PAH)
Pulmonary vascular resistance
WHO functional class
Adverse events other than haemorrhage: soft tissue necrosis, gangrene, tracheobronchial calcification
Search methods for identification of studies
We will identify trials from searches of the following databases:
Cochrane Airways Group Trials Register;
Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library;
The proposed MEDLINE strategy is listed in Appendix 1. This will be adapted for use in the other databases. We will also conduct a search of ClinicalTrials.gov (http://clinicaltrials.gov) and the WHO trials portal (www.who.int/ictrp/en/). We will search all databases from their inception to the present, and we will not impose any restriction on language of publication.
Searching other resources
We will check reference lists of all primary studies and review articles for additional references. We will search relevant manufacturers' websites for trial information.
We will search for errata or retractions from the included studies, published in PubMed (www.ncbi.nlm.nih.gov/pubmed), and report the date this was done within the review.
Data collection and analysis
Review authors (IE and HE) will independently appraise all identified citations to establish their relevance for inclusion into the review. Studies will be reviewed for relevance based on study design, types of participants, interventions, and outcome measures. Any disagreement will be resolved by discussion. We will give reasons for excluding potentially relevant trials in the table 'Characteristics of excluded studies'.
Selection of studies
Two review authors (IE and HE) will independently screen the titles and abstracts of all the potential studies for inclusion we identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible or unclear) or 'do not retrieve'. We will retrieve the full-text study reports and two review authors (JN and CE) will independently screen the full text and identify studies for inclusion; and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third author (IE). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram.
Data extraction and management
We will use a data collection form for study characteristics and outcome data which has been piloted on at least one study in the review. One review author (IE) will extract study characteristics from included studies. We will extract the following study characteristics.
Methods: study design, total duration of study, details of any 'run in' period, number of study centres and locations, study setting, withdrawals, and date of study.
Participants: total number (N), mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking history, inclusion criteria, and exclusion criteria.
Interventions: intervention, comparison, concomitant medications, and excluded medications.
Outcomes: primary and secondary outcomes specified and collected, and time points reported.
Notes: funding for trial, and notable conflicts of interest of trial authors.
Two review authors (IE and HE) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third author (JN). One review author (CE) will transfer data into the Review Manager (RevMan) 2012 file. We will double-check that data are entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (HE) will spot-check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
Two review authors (CE and JN) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (HE). We will assess the risk of bias according to the following domains.
Random sequence generation.
Blinding of participants and personnel.
Blinding of outcome assessment.
Incomplete outcome data.
Selective outcome reporting.
We will grade each potential source of bias as high, low, or unclear and provide a quote from the study report together with a justification for our judgment in the 'Risk of bias' table. We will summarise the risk of bias judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes, where necessary. Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.
When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.
Assesment of bias in conducting the systematic review
We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.
Measures of treatment effect
We will analyse dichotomous data as odds ratios and continuous data as mean difference or standardised mean difference. We will enter presented data as a scale with a consistent direction of effect.
We will undertake meta-analysis only where this is meaningful that is. if the treatments, participants, and the underlying clinical question are similar enough (homogeneous) for pooling to make sense.
We will describe skewed data reported as medians and interquartile ranges.
Where multiple trial arms are reported in a single trial, we will include only the relevant arms. If two comparisons (for example warfarin versus placebo and heparin versus placebo) are combined in the same meta-analysis, we will halve the control group to avoid double-counting.
Unit of analysis issues
Studies with similar units of analysis will be grouped together for the purposes of analysis. Studies with different units of analysis will not be pooled for analysis.
Dealing with missing data
We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data, where possible (for example when a study is identified as abstract only). Where this is not possible and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity among the trials in each analysis. If we identify substantial heterogeneity we will report it and explore possible causes by prespecified subgroup analyses. We will consider an I² value of 50% to 90% as substantial heterogeneity.
Assessment of reporting biases
If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible small study biases.
All eligible studies will be summarised in RevMan. The authors will extract the data and enter all data into RevMan, and all the entries will be rechecked by the authors. Disagreements will be resolved by discussion. If no consensus is reached, the Cochrane Airways Review Group will be contacted. We will use a fixed-effect model and perform a sensitivity analysis with the random effects model.
Summary of findings table
We will create a 'Summary of findings' table using the following outcomes: mortality, six-minute walk test, risk of haemorrhage from anticoagulant use, cardio-pulmonary exercise testing, decreased risk of thromboembolism, decrease in the pulmonary arterial pressure, and effect on the WHO functional class. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of the body of evidence as it relates to the studies which contribute data to the meta-analyses for the prespecified outcomes. We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro software. We will justify all decisions to down- or up-grade the quality of studies using footnotes and we will make comments to aid readers' understanding of the review where necessary.
Subgroup analysis and investigation of heterogeneity
Possible sources of heterogeneity in this review will include the type of intervention for example various anticoagulant preparations, gender, and age of program recipients.
We plan to carry out the following subgroup analyses:
type of anticoagulant (warfarin, heparin, argatroban, fondaparinux, dabigatran, apixaban, rivaroxaban);
anticoagulant use in relation to the different groups of PH (Groups 1 to 5).
We will use the following outcomes in subgroup analyses.
Decreased risk of intrapulmonary thrombosis.
Serious adverse events (haemorrhage).
We will use the formal test for subgroup interactions in Review Manager (RevMan) 2012.
If the number of studies and data available allow for sensitivity analysis, we shall perform a sensitivity analysis by using one or all of the following strategies.
Removing studies with high risk of bias to see if there is any effect on the results of the meta-analysis.
Studies with missing data may be re-analysed using a reasonable range of missing values.
Data may be re-analysed using different statistical approaches.
We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice and our implications for research will suggest priorities for future research and outline what the remaining uncertainties are in the area.
We are grateful to the Cochane Airways Group Managing Editor, Emma Welsh, and Liz Stovold, Trials Search Co-ordinator and Information Specialist of the Cochrane Airways Group.
Appendix 1. MEDLINE search strategy
1. exp Hypertension, Pulmonary/
2. Pulmonary Heart Disease/
3. (pulmonary adj5 hypertensi$).tw.
5. exp Anticoagulants/
17. "Ethyl biscoumacetate".tw.
26. 4 and 25
27. (clinical trial or controlled clinical trial or randomized controlled trial).pt.
28. (randomized or randomised).ab,ti.
37. 35 not (35 and 36)
38. 34 not 37
39. 26 and 38
Contributions of authors
All authors contributed to drafting this protocol.