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Eur J Cardiothorac Surg 2000;17:331-335
© 2000 Elsevier Science NL

Effect of high dose platelet inhibitor treatment on thromboembolism in Novacor patients

Christof Schmida, Markus Wilhelma, Markus Rothenburgera, Darius Nabavib, Mario C. Denga, Dieter Hammela, Hans H. Schelda

a Department of Cardiothoracic Surgery, Westfälische Wilhelms-University Münster, Münster, Germany
b Department of Neurology, Westfälische Wilhelms-University Münster, Münster, Germany

Corresponding author. Klinik und Poliklinik für Thorax-, Herz- & Gefäßchirurgie, Westfälische Wilhelms-Universität, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany. Tel.: +49-251-834-7401; fax: +49-251-834-8316
e-mail: schmid{at}uni-muenster.de


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
Background: Thromboembolism and bleeding are among the most hazardous complications following implantation of long-term left ventricular support systems. This report focuses on the effect of high dose platelet inhibitor treatment in patients with the Novacor system to prevent thromboembolic events. Methods: Thirty-eight (out of 58) Novacor patients (43±11 years old) were studied in a non-randomized manner. Postimplantation: 20 patients were treated with heparin only (control group), whereas in the other 18 patients aspirin (3x330 mg/day) and dipyridamol (3x75 mg/day) were added to the treatment protocol (aspirin group). Results: Age, body size, underlying heart disease and support interval were comparable among both groups, however, patients in the aspirin group were much sicker with regard to urgency status, postoperative right heart failure and hematologic disorders. Cerebral thromboembolic complications were lower in the aspirin group (33% of patients, 0.4±0.7 events) as compared to the control group (55% (P=0.18), 1.4±2.3 events (P=0.048)). Non-cerebral thromboembolism of surgical relevance was rare. The incidence of bleeding complications was mildly increased in the aspirin group. Conclusion: The addition of high dose platelet inhibitors seems to lower the incidence of thromboembolism in Novacor patients.

Key Words: Ventricular assist system • Aspirin • Stroke


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
Thromboembolism and bleeding are among the most hazardous complications following implantation of long-term left ventricular assist systems (LVAS). The incidence of thromboembolism varies among devices and institutions, from less than 5 to more than 40% [1]. The main target of the emboli is the brain, and hemiplegic as well as ocular symptoms predominate [2]. Fortunately, prognosis is excellent as most patients recover without neurologic residues [3]. Clinically evident thromboembolic involvement of intestinal and peripheral arteries is less common, however, it occasionally requires surgical intervention on an emergency basis [4]. Therefore, all long-term ventricular support systems require an appropriate level of anticoagulation, except for the devices with heparin-coated blood-contacting surfaces and those with textured surfaces to allow endothelialization [5].

Early bleeding complications result from extensive surgical procedures and perioperative anticoagulant disorders in mortally ill patients; late bleeding problems are usually a consequence of overanticoagulation and may involve any part of the body [6]. In general, prognosis of bleeding complications is less favorable as single or multiple surgical reinterventions are often necessary. Surgery not only burdens the patient but also promotes further complications, particularly thromboembolism and device infection [2,7]. Principally severe is intracerebral bleeding as it usually results in permanent neurologic deficits and may preclude subsequent heart transplantation.

This report focuses on the effect of a high dose platelet inhibitor treatment protocol in patients with the Novacor LVAS to prevent thromboembolic events.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
In our institution, all patients supported with the portable Novacor N100 device (Baxter Healthcare Corp., Oakland, CA) are followed in a prospective non-randomized manner. The additional treatment of the patients with left ventricular assist devices with a high dose of platelet inhibitors was introduced in October 1996. To assess its impact on thromboembolic complications, we retrospectively compared the two consecutive patients groups receiving additional platelet inhibitor treatment (aspirin group) or not (control group).

2.1. Demographic data
Thirty-eight out of our 58 patients were included in the study. The patients being part of the initial learning curve, where anticoagulation was not standardized, were excluded. There were 30 male and eight female patients with their age ranging from 23 to 61 years, mean age was 43±11 years. The underlying heart disease was dilative cardiomyopathy in 19 and end-stage ischemic heart disease in 13 cases. Four patients suffered from acute myocarditis, and one patient each from heart failure after correction of Fallot's tetralogy during childhood and postpartum cardiomyopathy. All patients were listed for heart transplantation at Eurotransplant/Leiden. Device implantation was elective in 16 patients, and non-elective in 22 patients [8].

Demographic data between the two groups revealed no major differences with regard to age, body size, underlying heart disease, postcardiotomy failure, redo surgery and pre-LVAS mechanical support interval (control vs. aspirin group: 112±74 days vs. 160±136 days, n.s.). However, the patients in the aspirin group were much sicker with regard to the preoperative urgency status [9]. In that group, device implantation was elective in only 17% of patients, in contrast to 65% in the control group (Table 1).


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  		Table 1. Preoperative patient data

 
2.2. Surgery
The electrically driven portable Novacor N 100 system was implanted on the beating heart with the patient connected to extracorporeal circulation as reported previously [10]. The pump chamber was placed into the posterior sheath of the left abdominal rectus muscle avoiding entrance of the abdominal cavity. The left-sided diaphragm was partially detached to allow the inflow cannula to be connected to the left ventricular apex. The outflow cannula was anastomosed to the ascending aorta. If a cardioverter/defibrillator (ICD) had been placed previously into the left abdominal wall, it was transposed to the opposite side. After a few single beats and meticulous deairing, LVAS support was initiated in a fixed-rate mode and switched to the fill-rate mode at the end of the procedure. A pump output of 5–6 l/min was aspired and the central venous pressure allowed to rise up to 25 mmHg. In the case of imminent right heart failure, prostaglandin derivates were administered intravenously or via the endotracheal tube during artificial respiration to lower pulmonary vascular resistance.

2.3. Anticoagulation
Anticoagulation was initiated immediately after surgery with administration of 1000 cm3 of dextran solution. At 2–6 h postoperatively or with cessation of major drainage losses, heparin was started, aiming at a partial thromboplastin time of 60–80 s. If drainage losses were above normal levels but did not warrant surgical revision, heparin was temporarily lowered or stopped. In three patients, heparin-induced thrombocytopenia type II (HIT II) was diagnosed, in two patients prior to surgery, and in another patient after device implantation. In the former cases, heparin was immediately discontinued after diagnosis. One patient underwent device implantation using danaparoid-sodium (Orgaran, Org 10172, N.V. Organon, BH Oss, The Netherlands) with anti-factor Xa serum concentrations from 0.2 to 0.6 U/ml being considered therapeutic. A second patient being treated with the hirudin derivate lepirudin (Refludan, Hoechst Marion Russel, Bad Soden; Germany) prior to surgery underwent device placement with heparin and was switched to danaparoid-sodium postoperatively. Oral anticoagulation with phenprocoumon was started with removal of all drains with an INR of 3.0–4.0 being the assumed optimum.

The first consecutive 20 patients of that patient series received no platelet inhibitors and were assigned to the control group. The following 18 cases were additionally treated with aspirin (330 mg) and dipyridamol (75 mg) three times a day (aspirin group) and constituted the aspirin group (Table 2).


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  		Table 2. Postoperative anticoagulation

 
2.4. Statistical analysis
In both study groups, demographic data were analyzed by calculating means and standard deviations. Statistical analysis was performed with Statview 4.0®, an Apple-Macintosh based computer program (Abacus Concepts, Inc.). Comparison between the two study groups was achieved using the {chi}2-test (nominal variables) and the Mann–Whitney test (continuous and ordinal variables), P<0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Appendix A. Conference...
 References
 
3.1. Thromboembolism and bleeding complications
Cerebral thromboembolic complications occurred in a total of 17 patients (45%), involving 11 patients in the control group (55%), but only six in the aspirin group (33%) (P=0.18). The mean number of events was also higher in the control group with 1.4±2.3 events per patient (0.012±0.022 events per day of mechanical support, 2.5±2.6 events per patient affected) as compared to 0.4±0.7 in patients treated with platelet inhibitors (0.003±0.007 events per day of mechanical support, 1.3±0.5 events per patient affected) (P=0.048) (Fig. 1).



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  		Fig. 1. Cerebral thromboembolic events (TE).

 
Non-cerebral thromboembolism of surgical relevance was rare and developed only in two patients of the control group and in one of the aspirin-treated patients. The latter developed consecutive infectious thromboembolic occlusion of both femoral arteries due to Aspergillus contamination of the device.

The incidence of diffuse bleeding necessitating redo sternotomy after the first postoperative day was similar in both groups. In the aspirin group, three patients had to undergo surgical revision between day 4 and day 32, which is comparable to the findings in the control group, where four patients had to undergo redo sternotomy between day 5 and day 156. In the aspirin group, however, further significant bleeding complications occurred. Two more patients, both with an alternative anticoagulation following diagnosis of heparin-induced thrombocytopenia type II, experienced multiple bleeding complications including cerebral hemorrhage and ultimately died awaiting heart transplantation as special urgency candidates, and another two patients developed pericardial tamponade which made a subxiphoid relief necessary.

3.2. Outcome
Significantly more complications following device implantation developed in the aspirin group, the patient cohort containing much more critically ill patients. In this group, three patients required temporary right ventricular assist by either an implantable paracorporeal system (Medos, Helmholtz Institut Aachen) or by extracorporeal membrane oxygenation. One patient experienced patient-related device failure and required exchange of the pump chamber. Occurrence of heparin-induced thrombocytopenia type II necessitated non-standardized anticoagulation with danaparoid and lepirudin in three patients as mentioned above. None of these complications occurred in the control group.

Mortality was 35% in the control and 44% in the aspirin group. In the control group, causes of death were multiorgan failure in five and of cerebral origin in two patients, whereas in the aspirin group six patients expired from multi-organ failure and one for cerebral reasons. One more patient experienced ventricular fibrillation while at home.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Appendix A. Conference...
 References
 
Thromboemboli can form in any part of the artificial circulation. In the Novacor system, thrombus formation was frequently found on the silicone-flanged, bovine pericardial valves, especially on the inflow valve concave side, and also within the conduits, whereas the pump chamber was usually not involved [11]. If the patient's aortic valve does not open regularly or if atrial fibrillation is present, thrombi may also form in the patient's own heart due to an inadequate wash-out of the left ventricle.

The key question regarding anticoagulation after LVAS implantation is and still remains ‘when to start and what is the best’. The early protocols from the manufacturer proposed a strong anticoagulation with heparin only followed by oral anticoagulants when the patients recovered sufficiently. Some patients did quite well with this regimen. However, with increasing success and more patients being supported for longer intervals, the number of thromboembolic events increased despite an apparently appropriate treatment. This was also true in our early experience. At that time (November 1996), we adopted the treatment strategy from our patients operated upon for cerebrovascular disorders, who were treated postoperatively with a combination of aspirin and dipyridamol.

When comparing both study groups, less thromboembolic events occurred in the patient group treated with platelet inhibitors, even if it has to be admitted that significance levels were hardly reached. The interpretation of data was further complicated by the fact that both study groups exhibit some important differences. In the control groups, most patients underwent LVAS implantation in an elective manner. There were no coagulation disorders. In contrast, in the aspirin group, surgery was most often performed on an urgent or emergency basis, i.e. patients were much sicker and this, of course, has had a negative impact on outcome [8]. Considering the worse average condition of the patients in the aspirin group, the better outcome in that group is even more important. However statistically seen, the significance levels for thromboembolism would remain unchanged if the early deaths as well as the three patients with HIT type II, who received the much more difficult to control anticoagulant (danaparoid, lepirudin) therapy are excluded from statistical analysis. In contrast, the incidence of bleeding complications in the aspirin group would be considerably lower.

In parallel with the initiation of our study, the so-called ‘Chicago protocol’ was devised, which also includes the use of aspirin and dipyridamol, although at a lower dosage [12]. It is still a matter of discussion whether a low or a high dose of the platelet inhibitors is better, as thromboembolism could not be completely abolished in the high dose aspirin group. One may argue, that (1) a lower dose of aspirin has been equally successfully used by others, and (2) that other pathophysiologic mechanisms are critically involved in thrombogenesis, and platelet inhibition per se is ineffective or not effective enough in some patients. One possibility may be device contamination which occurs in 25–40% of all patients on long-term mechanical support [13,14]. It is well known, that device infection is associated with a procoagulant state since leukocytes activate coagulation via the extrinsic pathway of coagulation [15]. Although cases of successful eradication of systemic infections have been reported, control of microorganisms adhering to damaged tissue and artificial material via surface receptors such as staphylococci, pseudomonas and candida is difficult. Not infrequently, bacteria persist despite clinical improvement of the patient's condition rendering long-lasting antibiotic treatment necessary. A growing body of evidence even suggests that circulatory shock treated with left ventricular assist device placement is already associated with a proinflammatory cytokine response similar to that seen in septic shock [16]. In our patients, we did not see a close correlation between infection and thromboembolism or bleeding within the study groups so far. The efficacy of lowering the platelet inhibitor dose which has recently been reemphasized by the manufacturer is matter of ongoing research in our institution.

The study is limited by the relative low number of patients and by the great variability within the groups. High standard deviations and the lack of clear-cut significance levels are the consequence. Large patient numbers would probably much better emphasize the importance of platelet inhibitors with regard to outcome. However, it is rather difficult to create appropriate patient cohorts within a single institution and thereby maintaining most of the other influencing parameters constant in an ever changing time.

In conclusion, treatment of Novacor patients with a high dose of platelet inhibitors seems to reduce the incidence of thromboembolic complications. It is still unclear whether a high dose or a low dose therapy is more favorable. If the initiation of antiplatelet therapy is adjusted to the patient's hematologic condition, bleeding complications remain acceptably low.


   Footnotes
 
Presented at the 13th Annual Meeting of the European Association for Cardio-thoracic Surgery, Glasgow, Scotland, UK, September 5–8, 1999.


   Appendix A. Conference discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
References
 
Mr T.R. Graham (Birmingham, UK): Can I ask what your current anti-thromboembolic regime is with this device?

Dr Schmid: Basically we give the patients heparin with a PTT in the range of 60–80. We add, as early as possible, aspirin at a dosage of 100 mg and we follow this with a platelet function analyzer to look whether we should increase the dosage, which sometimes could be up to 250 mg. When the drains are removed and the patients are quite well, we switch to oral anticoagulation additionally to the aspirin.

Mr Graham: Do you think the newer agents, such as clopidogrel may be useful in this arena?

Dr Schmid: Maybe. We didn't discuss it so far.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 

  1. Goldstein D.J., Oz M.C., Rose E.A. Implantable left ventricular assist devices. N. Engl J Med 1998;339:1522-1533.[Free Full Text]
  2. Schmid C., Weyand M., Nabavi D.G., Hammel D., Deng M., Ringelstein E., Scheld H.H. Cerebral and systemic embolization during left ventricular support with the Novacor N100 device. Ann Thorac Surg 1998;65:1703-1710.[Abstract/Free Full Text]
  3. Nabavi D.G., Georgiadis D., Mumme T., Schmid C., Mackay T.G., Scheld H.H., Ringelstein E.B. Clinical relevance of intracranial microembolic signals in patients with left ventricular assist devices. A prospective study. Stroke 1996;27:891-896.[Abstract/Free Full Text]
  4. Schmid C., Hammel D., Deng M.C., Weyand M., Baba H., Tjan T.D.T., Drees G., Roeder N., Schmidt C., Scheld H.H. Ambulatory care of patients with left ventricular assist devices. Circulation 1999;100(Suppl II):II224-II228.
  5. Spanier T., Oz M., Levin H., Weinberg A., Stamatis K., Stern D., Rose E., Schmidt A.M. Activation of coagulation and fibrinolytic pathways in patients with left ventricular assist devices. J Thorac Cardiovasc Surg 1996;112:1090-1097.[Abstract/Free Full Text]
  6. Kormos R.L., Borovetz H.S., Gasior T., Antaki J.F., Armitage J.M., Pristas J.M., Hardesty R.L., Griffith R.P. Experience with univentricular support in mortally ill cardiac transplant candidates. Ann Thorac Surg 1990;49:261-272.[Abstract]
  7. Herrmann M., Weyand M., Greshake B., von Eiff C., Proctor R.A., Scheld H.H., Peters G. Left ventricular assist device infection is associated with increased mortality but is not a contraindication to transplantation. Circulation 1997;95:814-817.[Abstract/Free Full Text]
  8. Schmid C., Deng M.C., Hammel D., Weyand M., Loick H.M., Scheld H.H. Emergency versus elective/urgent LVAD implantation. J Heart Lung Transplant 1998;17:1024-1028.[Medline]
  9. Deng M.C., Weyand M., Hammel D., Schmid C., Kerber S., Schmidt C., Breithardt G., Scheld H.H. Selection and outcome of ventricular assist device patients: the Muenster experience. J Heart Lung Transplant 1998;17:817-825.[Medline]
  10. Scheld H.H., Hammel D., Schmid C., Weyand M., Deng M., Möllhoff T., Kerber S. Beating heart implantation of a wearable NOVACOR left-ventricular assist device. Thorac Cardiovasc Surg 1996;44:62-66.[Medline]
  11. Wagner W.R., Johnson P.C., Kormos R.L., Griffith B.P. Evaluation of bioprosthetic valve-associated thrombus in ventricular assist device patients. Circulation 1993;88:2023-2029.[Abstract/Free Full Text]
  12. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events. Lancet 1996;348:1329–1339.
  13. Hunt S.A., Frazier O.H. Mechanical circulatory support and cardiac transplantation. Circulation 1998;97:2079-2090.[Free Full Text]
  14. Mehta M.S., Aufiero T.X., Pae W.E., Miller C.A., Pierce W.S. Combined registry for the clinical use of mechanical ventricular assist pumps and the total artificial heart in conjunction with heart transplantation: sixth official report – 1994. J Heart Lung Transplant 1995;14:585-593.[Medline]
  15. Addonizio V.P. Insights into thromboembolism and bleeding. Ann Thorac Surg 1996;61:374-375.[Free Full Text]
  16. Goldstein D.J., Moazami N., Seldomridge J.A., Laio H., Ashton R.C., Naka Y., Pinsky D.J., Oz M.C. Circulatory resuscitation with left ventricular assist device support reduces interleukin 6 and 8 levels. Ann Thorac Surg 1997;63:971-974.[Abstract/Free Full Text]
Received September 6, 1999; received in revised form December 28, 1999; accepted January 11, 2000.




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