Low-Molecular-Weight Heparin for the Treatment of Patients with Mechanical Heart Valves

Transcription

1 Clin. Cardiol. 25, (2002) Low-Molecular-Weight Heparin for the Treatment of Patients with Mechanical Heart Valves YARON SHAPIRA, M.D., ALEX SAGIE, M.D., ALEXANDER BATTLER, M.D. Department of Cardiology, Rabin Medical Center, Beilinson Campus, Petah Tiqva and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Summary Background: The interruption of oral anticoagulant (OAC) administration is sometimes indicated in patients with mechanical heart valves, mainly before noncardiac surgery, nonsurgical interventions, and pregnancy. Unfractionated heparin (UH) is currently the substitute for selected patients. Lowmolecular-weight heparin (LMWH) offers theoretical advantages over UH, but is not currently considered in clinical guidelines as an alternative to UH in patients with prosthetic valves. Hypothesis: The aim of the present study was to review the data accumulated so far on the use of LMWH in this patient population and to discuss its applicability in common practice. Methods: For this paper, the current medical literature on LMWH in patients with mechanical heart valves was extensively reviewed. Results: There were eight series and six case reports. None of the studies was randomized, and only one was prospective. Data to establish the thromboembolic risk were incomplete. After excluding case reports, the following groups were constructed: (a) short-term administration, after valve insertion (n = 212); (b) short-term, perioperative (noncardiac)/periprocedural (n = 114); (c) long-term, due to intolerance to OAC (n = 16); (d) long-term, in pregnancy (n = 10). The incidence rate of thromboembolism was 0.9% for all the studies and 0.5, 0, 20, and 0% in groups a, b, c, and d, respectively; for hemorrhage, the overall rate was 3.4% (3.8, 2.6, 10, and 0% for the respective groups). Address for reprints: Yaron Shapira, M.D. Department of Cardiology Rabin Medical Center, Beilinson Campus Petah Tikva, 49100, Israel shapira_yaron@hotmail.com Received: May 16, 2001 Accepted: October 1, 2001 Conclusions: In patients with mechanical heart valves, short-term LMWH therapy compares favorably with UH. Data on mid- and long-term LMWH administration in these patients are sparse. Further randomized studies are needed to confirm the safety and precise indications for the use of LMWH in patients with mechanical heart valves. Key words: prosthesis, heart, valves, mechanical, low-molecular-weight heparin Introduction Mechanical prosthetic heart valves carry a substantial thromboembolic risk, which may reach 8.6% without anticoagulants. 1 This rate can be lowered to 1.8% with anticoagulant therapy. The yearly rates of major embolism are 1 and 4% with and without anticoagulants, respectively, and the corresponding rates of valve thrombosis are 0.2 and 1.8%. 1 Therefore, it is recommended that patients with mechanical prosthetic heart valves receive life-long anticoagulant therapy; however, there are some situations in which oral anticoagulant therapy should be interrupted. These include the following: need to minimize bleeding during surgery and any invasive procedures with moderate to severe bleeding risk; risk of embryopathy, especially in gestational Weeks 6 12; and occurrence of side effects of anticoagulant agents or extreme difficulties in the management of anticoagulation. In these cases, anticoagulation is either stopped for the short term or administered parenterally, depending on the appreciated thromboembolic risk in the specific patient. Until recently, the only parenteral alternative to oral anticoagulant therapy in patients scheduled for noncardiac surgery was unfractionated heparin (UH). This approach was highly recommended in the 1995 guidelines of the European Society of Cardiology. 2 In 1998, the American College of Cardiology/ American Heart Association (ACC/AHA) Task Force recommended parenteral administration of UH to patients at high risk of thrombosis off warfarin (recent thrombosis, Bjork-Shiley valve, or three risk factors). 3 However, the guidelines of the American College of Chest Physicians 4 refer to an article by

2 324 Clin. Cardiol. Vol. 25, July 2002 Kearon and Hirsh, 5 wherein they objected to any replacement anticoagulant therapy unless the patient experienced an arterial embolism within 1 month from the scheduled procedure. The low-molecular-weight heparins (LMWH) are a group of antithrombotic compounds, in clinical use for the last two decades. They exert an antifactor Xa activity, that is two- to four-fold higher than its antifactor IIa activity. The emerging role of LMWH in cardiovascular medicine has been extensively reviewed and it has been found to have several advantages over UH. 6 8 Low-molecular-weight heparin has been shown to be effective both in the treatment of arterial 9 and venous 10 thrombotic disorders. Both the European and American guidelines, as well as the recent recommendations from the Mayo Clinic group, suggest that LMWH is a good potential alternative to UH, although more evidence is needed before definitive conclusions can be reached. 5, 6, 11 Reports on the utility of LMWH in patients with prosthetic mechanical heart valves began to emerge in the mid 1990s The aim of the present study was to review the data accumulated so far on the use of LMWH in this patient population and to discuss its applicability in common practice. Methods A computerized PubMed search was conducted using the terms low molecular weight heparin, and the specific preparations, ardeparin, dalteparin, enoxaparin, nadroparin, reviparin, and tinzaparin. These were matched with the terms heart valve prosthesis and mechanical heart valves. Data were gathered up to December The Related Articles section in PubMed and the Science Citation Index were used to find related articles. We also sought abstracts from congresses of the American College of Cardiology, American Heart Association, and European Society of Cardiology containing the same key words, starting from Data were gathered on the clinical set-up, type, and position of the valve, therapeutic regimen, anticoagulation achieved, thromboembolic complications, and hemorrhagic phenomena. The complication rate was calculated only for series of 5 patients to avoid the inherent bias of case reports. Results Fourteen articles were identified, including eight series 14, 16 19, 22, 23, 25 and six case reports. 12, 13, 15, 20, 21, 24 Three articles appeared as abstracts in international congresses. 16, 23, 25 The total number of patients receiving LMWH in these studies was 360, including 352 in series and 8 in case reports. None of the studies was randomized. Only one study was prospective, 18 and the remainder was retrospective. Clinical Set-Up There were four indications for the administration of LMWH: (1) immediately following prosthetic valve insertion until therapeutic international normalized ratio (INR) was achieved (n = 213); 12, 16, 22 (2) scheduled noncardiac surgery or a procedure with moderate (+) bleeding risk (n = 115); 15, 18, 19, 23, 25 (3) to replace warfarin in cases of intolerance (n = 19); 14, 20, 21, 24 (4) during pregnancy (n = 13). 13, 17, 24 Low-Molecular-Weight Heparin Preparations The most frequently used preparation was enoxaparin (n = 183), followed by nadroparin (n = 104), dalteparin (n = 34), and tedelparin (n = 1). Data were insufficient or unavailable in the remaining cases. Low-Molecular-Weight Heparin Dosage The most frequently used dose was 1 mg/kg twice daily, 12 16, 18, 21, 22 with dose adjustment according to the measured anti-xa activity in patients receiving long-term LMWH therapy. Some authors used a fixed lower dose 23, 24 or a fixed unadjusted dose. 17 Treatment Duration Low-molecular-weight heparin was usually administered for a few days, except in 13 pregnant patients who received the medication for variable periods, 13, 17, 24 and in 17 patients who were unable to receive OAC for various reasons. 14, 24 Target Anti-Xa Concentration Three studies reported anti-xa levels in patients receiving long-term LMWH Harenberg et al. aimed at achieving IU/CC in samples drawn 3 4 h after LMWH injection. 14 Lee et al. 13 aimed at achieving IU/CC, and Manley et al., IU/CC. Neither of the latter reports specified the time at which the samples were withdrawn. A single short-term study (immediately following valve replacement) reported anti-xa levels of 0.8 ± 0.05 IU/CC. 22 Valve Position Precise data on valve position were available in 232 cases: 12, 13, 15, 16, 18, 20 22, mitral, 96 aortic, and 37 double valve (mitral and aortic). Valve Models The exact valve types were detailed in only 117 patients: 13, 16, 20, 21, 24 bileaflet (mostly St. Jude) in 115 patients and Starr-Edwards in 2. Partial information on the valve model was provided by another study, 22 but the precise allocation of the patients to the study groups was not noted. Endpoints (Table I) The following endpoints apply to 352 patients in series (case reports were excluded): Thromboembolism: There were three episodes of thromboembolism (0.9% of all patients). Two occurred among 26 patients on long-term LMWH, both pregnant, 17 and one case

3 Y. Shapira et al.: LMWH for mechanical heart valves 325 TABLE I Outcome of low-molecular-weight heparin therapy a Indication Long term, OAC Long term, Short term, perioperative Short term, after intolerance pregnancy (noncardiac) / periprocedural valve insertion Total No. of patients Thromboembolism (%) 0 2 (20) 0 1 (0.5) 3 (0.9) Hemorrhage (%) 0 1 (10) 3 (2.6) 8 (3.8) 12 (3.4) a In a series of 5 patients. Abbreviation: OAC = oral anticoagulants. of transient neurologic deficit occurred during short-term LMWH administration after prosthetic valve insertion. 16 Thus, the incidence of thromboembolism during short-term LMWH was 1 of 326 (0.3%). No case of thromboembolism was reported in patients switched to short-term heparin before noncardiac surgery or procedure. In addition to the larger series, there were three case reports of obstructive valve thrombosis during long-term LMWH therapy. 20, 24 However, the authors did not provide data on the total number of patients who received LMWH for similar indications, and therefore the complication rate could not be calculated. Hemorrhage: There were 12 episodes of hemorrhage (3.4%), 11 in patients undergoing procedures with hemorrhagic risk. A single case of vaginal bleeding was reported in a pregnant woman. 17 Pregnancy Thirteen patients received LMWH during pregnancy. It was interesting to note that in the two patients with Starr- Edwards mitral prostheses, who were treated for almost the entire duration of their pregnancies, the gestational course was uneventful. 13 In another study, 10 patients received nadroparine in the second half of the first trimester. 17 Two of them experienced thrombosis-related valve malfunction. The cumulative percentage of adverse events (neonatal death, premature deliveries, intrauterine fetal death, and spontaneous abortion) in these patients was 20%. The rates of adverse events were 66.6% in patients who continued coumadin throughout pregnancy, 12.5% in those who switched temporarily to subcutaneous heparin, and 20% in those who received porcine prostheses. 17 One patient experienced valve thrombosis in gestational Week 35 after being treated with a fixed low dose of LMWH (40 mg enoxaparin). 24 Comparison with Unfractionated Heparin Only two studies have compared LMWH with UH 17, 22 in a retrospective, nonrandomized fashion. One was conducted in pregnant women (see paragraph above); 17 the other compared subcutaneous UH injection (500 IU/kg 3 per day, target activated partial thromboplastin time [aptt] of control) with LMWH (enoxaparine 1 mg/kg twice daily or nadroparin 87 anti-xa units twice daily; target anti-xa activity IU/cc) in the period immediately following valve implantation. 22 The proportion of patients who received mitral prostheses (alone or with an additional aortic prosthesis) was 32% in the UH group and only 17% in the LMWH group (p = 0.01 by chi-square). There were no statistically significant differences between these two groups for other risk factors of increased thromboembolic rate (left ventricular dysfunction, atrial fibrillation, prior ischemic stroke, left-sided thrombus, etc.). The complication rate was very low and similar in both groups. No study has compared LMWH with UH in patients scheduled for noncardiac surgery or nonsurgical intervention. Miscellaneous There is a single report on the use of LMWH (tedelparin) as an alternative to UH for the purpose of cardiopulmonary bypass. 12 The intraoperative course was uneventful. Discussion Despite its favorable characteristics, LMWH is not included in the guidelines for the management of patients with prosthetic heart valves, and physicians are currently reluctant to use it. According to a recent Canadian survey of physicians preferences in patients with prosthetic valves scheduled for elective noncardiac surgery, only % opted for outpatient subcutaneous heparin or LMWH. 26 Indeed, most of the experience with LMWH in patients with prosthetic mechanical heart valves was gained in Europe; only two of the studies published were conducted in North America. 18, 23 Why should we be interested in changing the anticoagulant policy at all? There are several arguments in favor of LMWH over UH. 6 8 First, LMWH is associated with a more reproducible response to a fixed dose (unlike UH, LMWH does not show marked fluctuations in aptt control); second, its bioavailability is three- to four-fold higher; third, its pharmacologic properties enable its subcutaneous administration twice daily, and this can be done on an outpatient basis; fourth, it does not require blood monitoring when administered for short time; and finally, it has less propensity to induce thrombocytopenia. Moreover, when given periprocedurally for a short period on an outpatient basis, LMWH can markedly reduce costs compared with inpatient care and monitoring, as required for UH. 18, 21 Patients, too, apparently strongly prefer

4 326 Clin. Cardiol. Vol. 25, July 2002 LMWH over UH. 18 Another possible argument in support of LMWH is the avoidance of infectious complications related to continuous intravenous infusion. The diversity among the published series in clinical set-up, valve model, valve position, and other confounding factors, as well as the absence of important data in many of them, precludes integration of the data by means of a meta-analysis. The present paper is, therefore, an overview of the current status of LMWH in this patient population. Short-Term Administration of Low-Molecular-Weight Heparin The data on the safety of the short-term administration of LMWH in patients with prosthetic mechanical heart valves are encouraging: 0.3% thromboembolism, 3.6% hemorrhage. Are they sufficient to recommend routine LMWH when short- or even long-term cessation of oral anticoagulation is indicated? Direct Comparison of Low-Molecular-Weight and Unfractionated Heparin Only three studies have compared LMWH and UH in patients with prosthetic heart valves, 17, 19, 22 and they were all retrospective and did not adjust for baseline characteristics. Although in one study many risk factors were evenly balanced between the two groups, the proportion of patients receiving only aortic prostheses (and therefore are less prone to thromboembolism) was significantly higher in the LMWH group. 22 With these drawbacks, LMWH seemed at least as effective as UH in the main outcome measures (thromboembolism or hemorrhage). Indirect Comparison of Low-Molecular-Weight and Unfractionated Heparin We analyzed outcome in the studies of UH administration in patients with prosthetic heart valves scheduled for major noncardiac surgery. 19, The patients with aortic valve prostheses (either caged-ball and bileaflet) did not experience thromboembolic events whether or not they received UH. Patients with tilting disc prostheses, reported in only one study, had a 8.6% thromboembolic rate (3/35), but their perioperative anticoagulation protocol was not fully detailed. 19 In patients with mitral prostheses, the thromboembolic rate was quite higher, reaching 17.6% (9/51) in one recent study: 7/14 (50%) with tilting disc valves and 2/37 (5.4%) with bileaflet valves. 19 These events occurred despite replacement anticoagulant therapy and seemingly proper International Normalized Ratio levels in nearly half of the cases. The findings on the safety of LMWH administration to patients with newly implanted prosthetic mitral valves are promising, with no case of thromboembolism in 135 patients on short-term therapy (99 mitral prosthesis, 37 mitral and aortic prostheses). The majority of these reports concerned the immediate course following valve insertion; only two cases were derived from a study of patients undergoing noncardiac surgery. 18 In view of the high incidence of prosthetic valve thrombosis (18%, mostly nonobstructive) in newly implanted mitral prostheses, 30 these data are encouraging, although in none of the studies was a transesophageal echocardiographic evaluation included. The lack of thromboembolic phenomena in patients receiving LMWH before noncardiac surgery can be attributed to a selection bias of low-risk patients, that is, those with aortic prostheses, sinus rhythm, good left ventricular function, no previous embolism, no atrial fibrillation, no hypercoagulable state. We suggest that when designing a future comparative study between UH and LMWH, researchers should include a UH arm for nonbileaflet valve models in the aortic valve replacement group. It is questionable whether such a study is justified in patients with a bileaflet aortic prosthesis who are in sinus rhythm and did not experience a thromboembolic event. It should be borne in mind that sample size needed to prove that LMWH is at least as good as UH in the prevention of thromboembolic phenomena in patients with prosthetic heart valves is quite large. For example, if the expected rate of thromboembolic events during UH therapy is 2.5%, 19 it would take 1,808 patients to construct a negative study, provided that a 5% thromboembolic event rate during LMWH would still be acceptable. 31 This number rises exponentially as the acceptable event rate lowers. This calls for a multicenter study to overcome the statistical power limitations. Safety during Long-Term Therapy Data on this issue in patients with mechanical heart valves are sparse 32 patients, including 13 during pregnancy. Two cases of valve thrombosis occurred in nonpregnant patients, 20, 24 both described in case reports. Three cases occurred in pregnant women, 17, 24 one of whom was described in a case report. 24 These data are insufficient to draw any conclusions on the safety of long-term LMWH, but they do raise some concern. As for the use of LMWH during pregnancy, additional outcome measures should also be taken into account (neonatal death, premature deliveries, intrauterine fetal death, and spontaneous abortion). In the small study cited, adverse obstetric outcomes were more frequent in the coumadin group. 17 However, other studies show less marked difference between oral anticoagulation throughout pregnancy and UH in the first trimester. 32 Conclusions Short-term LMWH therapy in patients with prosthetic mechanical heart valves is an attractive alternative to UH. It is associated with a very low thromboembolic rate and an acceptable bleeding rate. It is also more convenient to the patient, saves unnecessary hospitalization with its inherent complications, and is more cost effective. However, in the absence of randomized studies and lack of stratification of patients according to thromboembolic risk, the possibility of selection bias of low-risk patients cannot be excluded. Data on mid- and long-term LMWH administration in this set-up are sparse, but there is some concern regarding its use in pregnancy. Although

5 Y. Shapira et al.: LMWH for mechanical heart valves 327 the data on the short-term use are encouraging, further randomized studies are needed to confirm the safety of the drug and its precise indications. Such studies should include a UH arm. In studies of low-risk patients (e.g., aortic valves and no additional risk factors), a third arm (no treatment) should be considered. Aside from the common clinical endpoints (thromboembolism and hemorrhage), there is a place for assessment of valve function (transvalvular gradients, leaflet motion) and for ruling out silent nonobstructive thrombosis. Hospital-acquired complications (e.g., septicemia, hospitalacquired pneumonia) should be recorded for the UH arm. Any further study should address and analyze the thromboembolic risk according to valve position, valve model, left ventricular function, atrial fibrillation, previous embolism, and procoagulant state (i.e., surgery for cancer). References 1. 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