Decrease of Vascular and Bleeding Complications After Balloon Aortic Valvuloplasty Performed Without Heparin

Abstract: Objectives. To determine whether vascular and bleeding complications may be reduced with balloon aortic valvuloplasty (BAV) performed without heparin. Background. Vascular and bleeding complications are currently the main adverse events occurring after BAV. Methods. This registry included 162 consecutive patients with severe aortic stenosis who underwent BAV by femoral approach in our center between 2008 and 2012. Eighty-five patients had unfractionated heparin (UH) 50 IU/kg bolus IV during the procedure, whereas 77 patients did not have heparin. Our primary combined endpoint included severe vascular or bleeding complications (BARC score ≥3), severe ischemic events (acute limb ischemia or systemic embolism) or death at 1-month follow-up. Results. The primary composite endpoint was achieved in 27 patients overall (16.7%) and was significantly lower in the heparin-free group (9.1% vs 23.5%; P=.01). Vascular, bleeding, or ischemic events were dramatically lower in the heparin-free group (5.2%) compared with the heparin group (22.4%; P=.01). UH use was associated with an increased risk of vascular and bleeding complications (relative risk [RR], 3.85; 95% CI, 1.35-10.94), but not with a decreased risk of ischemic events (RR, 1.81; 95% CI, 0.34-9.62). After adjustment for patient and procedure characteristics, including the sheath size, heparin use was the only significant predictor of either ischemic, bleeding or vascular complications (adjusted odds ratio, 6.64; 95% CI, 1.86-23.76). Conclusion. BAV performed without heparin is associated with a reduction of severe vascular events or death without increased ischemic risk. This marked difference is difficult to explain by confounding factors, but should be confirmed in a randomized controlled trial. 

J INVASIVE CARDIOL 2014;26(10):528-533

Key words: balloon aortic valvuloplasty, vascular complications, heparin

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Percutaneous balloon aortic valvuloplasty (BAV) was originally proposed by Cribier et al¹ in the late 1980s as an alternative to cardiac surgery for aortic stenosis (AS) treatment in patients who were considered to be poor candidates for aortic valve replacement. After an initial enthusiasm, the technique was rapidly abandoned due to high restenosis rates and no benefit on survival.^2-5 An increased use of BAV was observed since 1997, first because a substantial population of comorbid and elderly patients derives a significant palliative benefit from the technique, and second because BAV has been increasingly used in poor surgical risk groups as a bridge before transcatheter aortic valve implantation (TAVI) or surgery.^6-9 The BAV complications were markedly reduced by technique and material improvements, including the use of lower-size sheaths related to better balloon profile and stiff wires that allow easier crossing of tortuous aortoiliac vessels. Uncommon major complications currently include valve perforation or rupture, development of aortic regurgitation, cardiac perforation, complete heart block, and stroke. In the most recent reports, the risk of death was less than 1%.^9-14 The main risks of the procedure remain complications at the femoral entry site, with a high risk of bleeding and need for blood transfusion that can affect up to 17% of patients.^9,10,13 The decrease in vascular and bleeding events has become an important goal in interventional cardiology. This question is of major concern after BAV or TAVI performed in elderly patients, who often have advanced lower-limb atherosclerosis, increasing the risk of these complications.^15,16 Heparin is used in routine practice during the BAV procedure, but may contribute to increased femoral access complications. However, unlike coronary angioplasty, its benefit to decrease ischemic events is questionable and not supported by rational data. Since 2010, we therefore abandoned the use of heparin bolus during BAV at our center. In this registry, which was conducted in all consecutive patients who underwent BAV between 2008 and 2012 in our hospital, we evaluated the effect of heparin use or not on a 1-month combined endpoint encompassing all severe vascular complications, bleeding, ischemic events, or death.  

Methods  

Patient population. All patients referred for BAV to the Department of Cardiology, University Hospital of Montpellier, France between May 2008 and August 2012 were included in this registry. All had severe, symptomatic AS secondary to degenerative disease confirmed by transthoracic echocardiography (mean gradient >40 mm Hg and/or surface <1 cm²) and were not candidates for aortic valve replacement after internal discussions on the therapeutic options. The logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) was calculated for all patients.¹⁷ Patients with significant (grade >2 on echocardiography) aortic regurgitation and lack of femoral vascular access were not included, as they did not qualify for BAV. We considered two groups: patients who received systematic injection of unfractionated heparin (UH) bolus (50 IU/kg) after introduction of the sheath (heparin group) and patients without UH bolus (heparin-free group).  

Balloon aortic valvuloplasty procedure. BAV procedure was performed according to standard technique via the retrograde femoral approach in all patients and by the same operating team of three experienced interventional cardiologists. Heparin bolus, administrated to all patients between 2008 and 2009 immediately after insertion of the sheath, was progressively abandoned since 2010. Our experience with the technique, coupled with the objective to decrease vascular and bleeding complications in this elderly population, encouraged us to progressively abandon heparin. All patients initially underwent diagnostic left heart catheterization by unique femoral approach with measurement of left ventricular and central aortic pressures and measuring aortic gradient. Selective coronary angiography was systematically done and when coronary angioplasty was considered, it was performed at least 48 hours before BAV.  Left ventricular ejection fraction (LVEF) was determined before valvuloplasty by contrast left ventriculography. 

The aortic valve was crossed under fluoroscopic guidance with a 0.034˝ straight guidewire through an Amplatz catheter AL1 or AL2. The aortic valve gradient was measured from simultaneous pressure recordings from the left ventricle and the descending aorta through the sheath. An Amplatz 0.038˝ stiff guidewire (Boston Scientific) shaped to have a curved tip was advanced into the left ventricle through the Amplatz catheter, and left in place while the LV catheter was removed under fluoroscopic guidance. Then, the valvuloplasty balloon was advanced and placed at the mid-level of the calcified aortic valve. We used non-compliant dilatation balloons catheters (Z-MED, PFM Medical; NuMED NuCLEUS and Tyshak, B Braun Interventional Systems). Large sheaths (9-10 Fr) were used in patients treated between 2008 and 2009, whereas smaller sheaths (8 or 9 Fr only possible with low-profile Tyshak balloon catheters) were used in patients included after 2009. In the two patient groups, the same sheath flushing technique was used, ie, multiple flushings according to the procedure length (usually 1 or 2 times) with a small amount (5 mL) of heparinized saline serum. We did not use continuous flushing. 

To stabilize the balloon position across the valve, rapid pacing (180-200 beats/min) was used in all patients, with a temporary pacemaker positioned in the right ventricle through the femoral vein. The goal is to obtain a mean pressure gradient <20 mm Hg or to decrease the initial gradient by 50%. If this goal has not been achieved and no procedural complications have occurred, the procedure may be repeated using a larger balloon catheter, but without exceeding a balloon/ring ratio >1.2. Changes in aortic regurgitation were assessed after valvuloplasty by supravalvular aortography.  

Arterial puncture sites were closed either with a collagen-plug based closure device (8 Fr Angio-Seal, St Jude Medical) or by manual compression (whether or not aided by compression devices such as the FemoStop device), depending on the choice of the interventional cardiologist and the size of the sheath used. 

Clinical endpoints. Clinical events were evaluated during hospital stay and at 1-month follow-up and were compared between the two groups of patients. Our primary combined endpoint included death, vascular and bleeding complications, and adverse ischemic events. Vascular complications included femoral pseudoaneurysm and arteriovenous fistulae requiring surgery or endovascular intervention. Severe bleeding events were defined as a score ≥3 according to the Bleeding Academic Research Consortium (BARC) classification.¹⁸ Ischemic complications included acute limb ischemia, myocardial infarction (defined as a rise in troponin >3-fold the 99th percentile of the upper reference limit), stroke, mesenteric ischemia, or systemic embolism. 

 We also evaluated all serious adverse events including moderate-to-severe aortic regurgitation and permanent pacemaker requirement.

Statistical analysis. Patient characteristics are presented using median and 25%-75% interquartile range (IQR) or mean ± standard deviations for continuous variables and frequencies and proportions for categorical variables. Heparin and heparin-free groups were compared using Kruskall Wallis test for continuous variables and Chi-square or Fisher’s test for categorical ones. Relative risk (RR) and corresponding 95% confidence interval (CI) were calculated between the two groups. A multivariate analysis of the factors associated with severe complications was carried out using logistic regression, using a backward selection of the variables. The α-to-enter and α-to-exit were set at 0.20 and 0.15, respectively. Odds ratio (OR) and corresponding 95% CIs were calculated. Statistical bilateral significance threshold was set at 5%. Statistical analyses were performed using SAS version 9.1 (SAS Institute).

Results

Patient population. Between 2008 and 2012, a total of 162 consecutive patients underwent BAV (6 repeat procedures, 4 second repeat procedure), including 85 patients (52.5%) on heparin and 77 patients (47.5%) without heparin. Bridge to TAVI (n=78; 48%), palliative therapy (n=73; 45%), and in a lesser extent bridge to surgery (n=10; 6%) or cardiogenic shock (n=1; 0.6%) were the main indications of BAV.

The baseline characteristics of the patients are summarized in Table 1. The study included elderly patients (median age, 85 years; IQR, 80-88 years) with baseline LVEF <35% in 41 patients (25.5%) and New York Heart Association class 3 or 4 in 130 patients (80.7%). The mean EuroSCORE was 22. Except in emergency procedures, all patients had lower-limb Doppler before BAV to evaluate quality of peripheral vasculature. The median hospital duration was 7 days (IQR, 4-12 days). The two groups had similar baseline clinical characteristics and in particular similar median age (P=.37), prevalence of peripheral vascular disease (overall 30.4%; P=.46), and body mass index (P=.42). We used 20, 22, or 23 mm Tyshak balloons. The 20 and 22 mm balloons (n=90) require 8 Fr sheaths, whereas 23 mm balloons (n=72) require 9 Fr sheaths. Balloon size was not statistically different in the two groups (P=.50). Smaller sheaths (8 or 9 Fr) were used in all patients after 2009, representing 63 patients (75.0%) and 75 patients (97.4%) in the heparin and heparin-free groups, respectively (P<.001). Vascular closure devices were used in 48 patients (57.1%) of the heparin-free group and in 45 patients (58.4%) of the heparin group (P=.81).

Severe vascular, bleeding, and ischemic complications (Table 2). The primary composite endpoint, which includes vascular bleeding complications, adverse ischemic events, or death, was achieved in 27 patients overall (16.7%). Bleeding, vascular, or ischemic complications concerned 23 patients overall (14.2%). Bleeding was the most common adverse event, occurring in 19 patients (11.7%), whereas severe vascular complications occurred in 7 patients (4.3%). Ischemic events were observed in 6 patients (3.7%), including 1 cerebral ischemic attack in the heparin group and 5 patients with acute limb ischemia.

The use of heparin was associated with a significant risk of severe vascular, bleeding and ischemic complications or death (RR, 2.59; 95% CI, 1.16-5.78). This excess risk was driven by an increased risk of vascular and bleeding complications (RR, 3.85; 95% CI, 1.35-10.94), while ischemic complications were not reduced (RR, 1.81; 95% CI, 0.34-9.62). Adverse effect of heparin concerned mainly the risk of bleeding complications (RR, 4.83; 95% CI, 1.46-15.94). We never observed major bleeding during the procedure requiring reversal with protamine. Indeed, the majority of bleeding or vascular events occurred during the hours after the procedure when the effect of unfractionated heparin was completed. Overall, 6 patients (3.7%) died during follow-up: 1 patient (1.2%) in the heparin group and 5 patients (6.6%) in the heparin-free group; P=.10. Death was caused by cardiogenic shock related to severe left ventricular dysfunction in 4 cases and to annular rupture during the procedure in 1 patient. The last death was related to severe pulmonary infection. Two deaths concerned patients who suffered from bleeding complications.

One patient in the heparin group had an atrioventricular block requiring pacemaker implantation. In 2 patients (1 in each group), we observed a mild aortic regurgitation after the procedure.
Predictive factors of vascular, bleeding, and ischemic complications. The use of heparin during BAV was associated with a crude five-fold increased risk of vascular, bleeding, or ischemic events (OR, 5.25; 95% CI, 1.70-16.24; P=.01), age (P=.12), low body mass index (P=.18), sheath size (P=.10), LVEF (P=.03), New York Heart Association class (P=.16), history of peripheral vascular disease (P=.14), and manual compression versus the use of vascular closure device (P=.11) tended to be associated with the primary outcome. New York Heart Association class was introduced in the multivariate models rather than LVEF because it is the most relevant and reliable marker of heart failure used in routine practice. Age was not further considered in the models because median age tended to be lower in patients who had complications: 80 years (IQR, 76-88 years) vs 85 years (IQR, 80-88 years); P=.14. All other potential confounding factors, including patient characteristics, the type of puncture site closure (manual compression versus vascular closure device), and the size of the used sheath were therefore introduced in the multivariate models.

After adjustment for the above factors, heparin use remained highly associated with the occurrence of severe complications (adjusted OR, 6.64; 95% CI, 1.86-23.76).

Only manual compression tended also to be associated with the primary outcome (adjusted OR, 2.15; 95% CI, 0.82-5.63). All other potential confounding factors including patient characteristics and the size of the sheath used, corresponding to the inclusion period, did not impact significantly on the rate of complications and were dropped from the final model.

Discussion 

In this single-center registry including 162 consecutive patients, not using heparin during BAV was associated with two-fold reduction of a combined endpoint of death or serious vascular and bleeding complications without increasing ischemic risk of the procedure. To our knowledge, this is the first report in the literature of a BAV procedure without use of heparin. 

BAV: an old technique with new developments. Resurgence of BAV was observed with the development of TAVI and the increasing number of poor surgical candidates in the expanding elderly population, which mandates less invasive methods such as BAV to improve quality of life.^6,9 

Recent studies showed interest in BAV as a bridge to aortic valve replacement,^7,8 with a decreased of operative risk and an improved postoperative course. Recent guidelines from the European Society of Cardiology (ESC) state that BAV is class IIb, level of evidence C in patients who are in an unstable state as a bridge to surgery or TAVI or in patients with severe symptomatic AS who require urgent major non-cardiac surgery. The guidelines also indicate that the procedure could be considered in non-surgical candidates as a palliative measure.¹⁹ Similar guidelines exist from the American College of Cardiology/American Heart Association (ACC/AHA), but TAVI was not considered to be a therapeutic option in 2006.^20,21 In our study, valvuloplasty was indicated mainly because patients had unstable hemodynamic condition not compatible with surgery or TAVI. Eventually, a majority of them (n=88; 54.3%) had surgery or TAVI a few months later. However, an important part of our population underwent BAV only as a palliative therapy (n=73; 45.1%).

Vascular and bleeding complications: the Achilles’ heel of BAV. Although BAV complications decreased over the last 20 years, vascular and bleeding complications remain the main risk of the technique, with subsequent increased hospital duration, extracardiac complications, and cost^{15, 16} in this elderly and frail population. 

The first two main registries evaluating BAV were the National Heart Lung and Blood Institute (NHLBI) and the Mansfield Scientific,^22,23 reporting adverse events in 25% of patients within 24 hours of the procedure and documenting death in 3%. The most common complication reported was transfusion (20%), related predominantly to vascular entry-site complications. Cumulative cardiovascular mortality before discharge was 8% in the NHLBI registry.²² Less common complications included stroke, emboli, and ventricular perforation.

In more recent series, the rate of serious adverse events was lower, ranging from 15.6%-22% according to different criteria considered.^5,12,13 Vascular complications were reported in 6.9%-9% of patients and up to 17.6% required blood transfusion.^12,13 

The rate of either vascular, bleeding, or ischemic complications among the patients from the heparin group (18.8%) is in accordance with previous data and concerned mainly the bleeding risk. The use of heparin greatly increased this risk, independent of patient characteristics and materials used, and conversely we did not find more ischemic events in the heparin-free group. These results are of particular interest since bleeding related to invasive cardiovascular coronary or TAVI procedures is associated with significant mid-term morbidity and mortality.^15,16

How to decrease BAV complication rates. Improvements in techniques and materials are key to decreasing complications rates in BAV. The retrograde approach is the main approach used for BAV, involving the femoral artery and the positioning of a guidewire across the valve from the aorta and inflation of the balloon afterward. With recent advances in the interventional hardwire, BAV can be done more easily and safely.^7,9,11,12 Lower sheath sizes (8 and 9 Fr) can be used in the majority of cases with the new generation of balloons. Extra-stiff wires allow progression into calcified and tortuous aorta with minimal risk. However, we did not find clinical benefits of smaller sheaths on vascular and bleeding complications. It is likely that the benefit was mainly obtained between 10 Fr and larger sheaths (14 to 16 Fr) used in the beginning experience of BAV.^1,22,23 Conversely, the size of the “larger” sheath (10 Fr) compared to the  “smaller” sheath (8 Fr) in our study did not result in difference in vascular or bleeding complications. Considering our experience with Angio-Seal, we do not use preclosure devices at our center (Proglide or Prostar) to obtain hemostasis of the femoral puncture site.

Interestingly, the adjustment performed for the sheath size in our analyses corresponds to an adjustment for the inclusion period. This allowed us to take into account potential time-related confounding factors that were not collected in our study.  Use of a vascular closure device (Angio-Seal ) did not seem to reduce the occurrence of vascular, bleeding, or ischemic complications compared to manual compression. However, there was a trend toward an increase in vascular complications observed after manual compression compared to vascular closure devices. Although we cannot exclude the possibility that the non-significance of the odds ratio was due to a lack of power, these results are in accordance with previous data.^24,25 

Use of heparin: questionable. In all studies reported in the literature, UH bolus was administered during the BAV procedure after sheath insertion. The dose was highly variable and ranged from 2500-7500 IU, usually according to patient weight.^12,13,22,23 There are, however, no specific guidelines on the dose of heparin during BAV.  

Thromboembolism may occur during any interventional procedure. Atheroembolism may be a consequence of traumatic passage of wires and catheters around an atheromatous aortic arch. Calcific embolism might be observed when the endothelial covering of a degenerated aortic valve is disrupted. Retrograde catheterization of the aortic valve itself has a risk of neurological complications. Therefore, in a prospective study, Omran et al²⁶ showed that passage through the aortic valve was associated with a substantial risk of silent ischemic brain lesions as assessed by magnetic resonance imaging. Case reports described calcific non-thrombotic cerebral emboli on computed tomography in AS after retrograde catheterization.²⁷ Last, a recent report of transcranial Doppler recorded during TAVI procedures showed that Doppler signals (HITS) corresponding to embolic events were recorded almost entirely during the valve implantation and not during valvuloplasty.²⁷

Unlike coronary angioplasty, in which thrombosis is an obligatory event, the BAV procedure is probably poorly thrombogenic. The most common mechanisms involved in valve opening are intraleaflet fractures within calcified nodular deposits, which may increase flexibility within the calcified aortic root, separation of fused leaflets, leaflet hyperextension, and annular stretching of the calcified aortic root.^9,28,29 These mechanisms do not lead to thrombosis. Cerebral emboli originating from the aortic valve and proximal aorta are likely the major mechanism of stroke in the setting of aortic valve intervention and could probably not be prevented by heparin.²⁸ 

In all recent reports, like ours, BAV has been associated with a stroke rate of 1% or less.^11-14 The main complications of BAV concerned femoral access site and bleeding, all adverse events that may be increased by the systematic use of heparin. Therefore, considering the risk to benefit ratio, use of anticoagulation with heparin during BAV is really questionable. Our results argue in favor of an important benefit in reducing vascular and bleeding complications when heparin is not used, whereas absence of heparin did not increase ischemic events. 

Study limitations. Limits of the study concern its non-randomized, single-center, and retrospective nature, which can lead to potential bias, particularly concerning the choice of heparin use or not. Patients from the two groups, however, had very similar baseline characteristics, and the period of enrollment (using sheath size as a proxy) did not change the results. Therefore, the marked increase in vascular and bleeding complications when heparin was used is unlikely explained by confounding factors, although residual confounding is always possible. With the increased use of BAV as a bridge to TAVI at our center since 2009, operator experience likely increased, leading to a decrease in complication rate. Considering the low incidence of cerebral ischemic events, the power of the study is probably too low to definitely exclude an increased risk of such events without use of heparin during BAV. Last, since this is a retrospective, observational study, the findings are hypothesis generating and cannot change our current practice. 

Conclusion

This registry suggests that not using heparin during BAV is both safe and associated with a dramatic reduction in vascular and bleeding complications without increasing ischemic events. The impact of not using heparin during BAV on severe complications should be confirmed in a randomized, controlled trial.

References 

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From the ¹Department of Cardiology, ²Department of Medical Information, University of Montpellier, Arnaud de Villeneuve hospital, Montpellier, France.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted September 20, 2013, provisional acceptance given November 18, 2013, final version accepted January 29, 2014.

Address for correspondence: Florence Leclercq, Department of Cardiology, Arnaud de Villeneuve University Hospital, 295 avenue du doyen Giraud, 34295 Montpellier cedex 5, France. Email: f-leclercq@chu-montpellier.fr