EN HISTORIA DEL ARTE
2. UNA PROPUESTA DIDÁCTICA DE UTILIZACIÓN DE LA
(Refer to Updated Sections 3.2.2 and 3.2.3)
A number of drugs are available to clinicians for manage- ment of patients with UA/NSTEMI. Although the medical literature sometimes refers to such drugs as “antithrombins,” the 2007 Writing Committee has chosen to refer to them as anticoagulants because they often inhibit 1 or more proteins in the coagulation cascade before thrombin. Evaluation of anticoagulant strategies is an active area of investigation. It is difficult to draw conclusions that 1 anticoagulant strategy is to be preferred over another given the uncertainty of whether equipotent doses were administered, the different durations of treatment studied across the trials, and the fact that many patients were already receiving 1 open-label anticoagulant before they were randomized in a trial to another anticoagu- lant (which makes it uncertain what residual effect the open- label anticoagulant had in the trial). Other aspects of the data set that confound interpretation of the impact of specific anti- coagulant strategies include a range of antiplatelet strategies administered concomitantly with the anticoagulant and the addition of a second anticoagulant, either because of clinician preference or as part of protocol design400,422,424 as patients
moved from the medical management phase to the interven- tional management phase of treatment for UA/NSTEMI.
The 2007 Writing Committee also wishes to draw atten- tion to the fact that active-control noninferiority trials are being performed with increasing frequency as it becomes ethically increasingly difficult to perform placebo-controlled trials. In this update, for example, noninferiority (“equiva- lence”) comparisons on primary or major secondary end points were important in the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY),424 Organization to
Assess Strategies for Ischaemic Syndromes (OASIS-5),422
and Randomized Evaluation of PCI Linking Angiomax to reduced Clinical Events (REPLACE-2)527 studies. Although
practically useful, noninferiority analyses depend on assump- tions not inherent in classic superiority analytical designs and thus present additional limitations and interpretative chal- lenges.528–530 Noninferiority trials require an a priori choice
of a “noninferiority margin,” typically defined in terms of a fraction of standard treatment effect to be preserved compared with a putative placebo (eg, 0.5) and which rests on clinical judgment and statistical issues.529 Because noninferiority tri-
als do not have a placebo control, these assumptions cannot be easily verified. Thus, whether the new therapy indeed is ther- apeutically “equivalent” is less certain than in a superiority
trial. Hence, additional caution in weighing and applying the results of noninferiority trials is appropriate.
The 2007 Writing Committee believes that a number of acceptable anticoagulant strategies can be recommended with a Class I status but emphasizes the fact that a preference for a particular strategy is far from clear (Figures 7, 8, and 9; and Appendix 9 for updated algorithm incorporating newer P2Y12 receptor inhibitors). It is suggested that each institu- tion agree on a consistent approach to minimize the chance of medication errors and double anticoagulation when personal preferences are superimposed on an already-initiated treat- ment plan. Factors that should be weighed when one consid- ers an anticoagulant strategy (or set of strategies to cover the range of patient scenarios) include established efficacy, risk of bleeding in a given patient, cost, local familiarity with dosing regimens (particularly if PCI is planned), anticipated need for surgery, and the desire to promptly reverse the anticoagulant effect if bleeding occurs.
Unfractionated heparin exerts its anticoagulant effect by accelerating the action of circulating antithrombin, a proteolytic enzyme that inactivates factor IIa (thrombin), factor IXa, and factor Xa. It prevents thrombus propagation but does not lyse existing thrombi.531 Unfractionated heparin is a heterogeneous
mixture of polysaccharide chains of molecular weights that range from 5000 to 30 000 Daltons and have varying effects on anticoagulant activity. Unfractionated heparin binds to a number of plasma proteins, blood cells, and endothelial cells. The LMWHs are obtained through chemical or enzymatic depolymerization of the polysaccharide chains of heparin to provide chains with different molecular weight distributions. Approximately 25% to 50% of the pentasaccharide- containing chains of LMWH preparations contain more than 18 saccharide units, and these are able to inactivate both thrombin and factor Xa. Low-molecular-weight heparin chains that are fewer than 18 saccharide units retain their ability to inactivate factor Xa but not thrombin. Therefore, LMWHs are relatively more potent in facilitating inhibition of factor Xa than in the inactivation of thrombin. Distinct advantages of LMWH over UFH include decreased binding to plasma proteins and endothelial cells and dose-independent clearance, with a longer half-life that results in more predictable and sustained anticoagulation with once- or twice- a-day subcutaneous administration. An advantage of LMWHs is that they do not usually require laboratory monitoring of activity. The pharmacodynamic and pharmacokinetic profiles of the different commercial preparations of LMWHs vary, with their mean molecular weights ranging from 4200 to 6000 Daltons. Accordingly, their ratios of anti–factor Xa to anti– factor IIa vary, ranging from 1.9 to 3.8.532 By contrast, the
direct thrombin inhibitors specifically block thrombin without the need for a cofactor. Hirudin binds directly to the anion binding site and the catalytic sites of thrombin to produce potent and predictable anticoagulation.533
Bivalirudin is a synthetic analog of hirudin that binds reversibly to thrombin and inhibits clot-bound thrombin. More upstream in the coagulation cascade are factor Xa inhibitors, such as the synthetic pentasaccharide fondaparinux, that act proximally to inhibit the multiplier effects of the downstream coagulation reactions and thereby reduce the amount of
thrombin that is generated. Advantages of fondaparinux com- pared with UFH include decreased binding to plasma proteins and endothelial cells and dose-independent clearance, with a longer half-life that results in more predictable and sustained anticoagulation with fixed-dose, once-a-day subcutaneous administration. An advantage of these agents over UFH is that like the LMWHs, fondaparinux does not require laboratory monitoring of activity. Fondaparinux is cleared renally, as is the anti–Xa activity of enoxaparin. The factor Xa inhibitors do not have any action against thrombin that is already formed or that is generated despite their administration, which possibly contributes to the observation of an increased rate of catheter thrombosis when factor Xa inhibitors such as fondaparinux are used alone to support PCI procedures. In the case of both the direct thrombin inhibitors and fondaparinux, it is not pos- sible to reverse the effect with protamine because they lack a protamine-binding domain; reversal of their action in the event of bleeding requires discontinuation of their adminis- tration and, if needed, transfusion of coagulation factors (eg, fresh-frozen plasma).
In summary, whereas anticoagulant therapy forms a basic element of UA/NSTEMI therapy, recommendation of an anti- coagulant regimen has become more complicated by a num- ber of new choices suggested by contemporary trials, some of which do not provide adequate comparative information for common practice settings. The 2007 Writing Committee believes that inadequate unconfounded comparative informa- tion is available to recommend a preferred regimen when an early, invasive strategy is used for UA/NSTEMI, and physi- cian and health care system preference, together with individ- ualized patient application, is advised. Additional experience may change this viewpoint in the future. On the other hand, these available trials are less confounded for the large num- ber of patients treated with an initial noninvasive or delayed invasive strategy: they suggest an anticoagulant preference for these patients treated with a noninvasive strategy in the order of fondaparinux, enoxaparin, and UFH (least preferred), using the specific regimens tested in these trials. Bivalirudin has not been tested in a noninvasive strategy and hence cannot be recommended currently. Even in this group, the order of preference often depends on a single, albeit large, trial, so that additional clinical trial information will be welcomed.
The optimal duration of anticoagulation therapy remains undefined. Evidence for recurrence of events after cessation of short-duration intravenous UFH and results of studies in STEMI patients demonstrating superiority of anticoagulant agents that are administered for the duration of the hospital stay suggest that anticoagulation duration of more than 2 d for those who are managed with a conservative strategy may be beneficial, but this requires further study.534,535
3.2.5.1. Unfractionated Heparin
Six relatively small randomized, placebo-controlled trials with UFH have been reported.536–541 The results of studies that com-
pared the combination of ASA and heparin with ASA alone are shown in Figure 10. In the trials that used UFH, the reduc- tion in the rate of death or MI during the first week was 54% (P=0.016), and in the trials that used either UFH or LMWH, the reduction was 63%. Two published meta-analyses have
included different studies. In 1 meta-analysis, which involved 3 randomized trials and an early end point (less than 5 d),373 the
risk of death or MI with the combination of ASA and heparin was reduced by 56% (P=0.03). In the second meta-analysis, which involved 6 trials and end points that ranged from 2 to 12 weeks, the RR was reduced by 33% (P=0.06).542 Most of
the benefits of the various anticoagulants are short term, how- ever, and are not maintained on a long-term basis. Reactivation of the disease process after the discontinuation of anticoagu- lants may contribute to this loss of early gain among medically treated patients that has been described with UFH,543 daltepa-
rin,406 and hirudin.544,545 The combination of UFH and ASA
appears to mitigate this reactivation in part,543,546 although there
is hematologic evidence of increased thrombin activity after the cessation of intravenous UFH (“rebound”) even in the pres- ence of ASA.547 Uncontrolled observations suggested a reduc-
tion in the “heparin rebound” by switching from intravenous to subcutaneous UFH for several days before the drug is stopped.
Unfractionated heparin has important pharmacokinetic limitations that are related to its nonspecific binding to proteins and cells. These pharmacokinetic limitations of UFH translate into poor bioavailability, especially at low doses, and marked variability in anticoagulant response among patients.548 As
a consequence of these pharmacokinetic limitations, the anticoagulant effect of heparin requires monitoring with the activated partial thromboplastin time (aPTT), a test that is sensitive to the inhibitory effects of UFH on thrombin (factor IIa), factor Xa, and factor IXa. Many clinicians have traditionally prescribed a fixed initial dose of UFH (eg, 5000 U bolus, 1000 U per h initial infusion); clinical trials have indicated that a weight-adjusted dosing regimen can provide more predictable anticoagulation than the fixed-dose regimen.549–551 The weight-adjusted regimen recommended
is an initial bolus of 60 U per kg (maximum 4000 U) and an initial infusion of 12 U per kg per h (maximum 1000 U per h). The therapeutic range of the various nomograms differs due to variation in the laboratory methods used to determine aPTT. The American College of Chest Physicians consensus conference552 has therefore recommended dosage
adjustments of the nomograms to correspond to a therapeutic range equivalent to heparin levels of 0.3 to 0.7 U per mL by anti–factor Xa determinations, which correlates with aPTT values between 60 and 80 s. In addition to body weight, other clinical factors that affect the response to UFH include age and sex, which are associated with higher aPTT values, and smoking history and diabetes mellitus, which are associated with lower aPTT values.548,551 At high doses, heparin is
cleared renally.552
Even though weight-based UFH dosing regimens are used, the aPTT should be monitored for adjustment of UFH dos- ing. Because of variation among hospitals in the control aPTT values, nomograms should be established at each insti- tution that are designed to achieve aPTT values in the target range (eg, for a control aPTT of 30 s, the target range [1.5 to 2.5 times control] would be 45 to 75 s). Delays in labora- tory turnaround time for aPPT results also can be a source of variability in care, resulting in over- or under-anticoag- ulation for prolonged time periods, and should be avoided. Measurements should be made 6 h after any dosage change
and used to adjust UFH infusion until the aPTT exhibits a therapeutic level. When 2 consecutive aPTT values are thera- peutic, the measurements may be made every 24 h and, if necessary, dose adjustment performed. In addition, a signifi- cant change in the patient's clinical condition (eg, recurrent ischemia, bleeding, or hypotension) should prompt an imme- diate aPTT determination, followed by dose adjustment, if necessary.
Serial hemoglobin/hematocrit and platelet measurements are recommended at least daily during UFH therapy. In addi- tion, any clinically significant bleeding, recurrent symptoms, or hemodynamic instability should prompt their immediate determination. Serial platelet counts are necessary to monitor for heparin-induced thrombocytopenia. Mild thrombocytope- nia may occur in 10% to 20% of patients who are receiving heparin, whereas significant thrombocytopenia (platelet count less than 100 000) occurs in 1% to 5% of patients and typically appears after 4 to 14 d of therapy.553–557 A rare but dangerous
complication (less than 0.2% incidence) is autoimmune UFH- induced thrombocytopenia with thrombosis, which can occur both shortly after initiation of UFH or, rarely, in a delayed (ie, after 5 to 19 d or more), often unrecognized form.558–560 A
high clinical suspicion mandates the immediate cessation of all heparin therapy (including that used to flush intravenous lines).
Most of the trials that evaluated the use of UFH in UA/ NSTEMI have continued therapy for 2 to 5 d. The optimal duration of therapy remains undefined.
3.2.5.2. Low-Molecular-Weight Heparin
In a pilot open-label study, 219 patients with UA were random- ized to receive ASA (200 mg per d), ASA plus UFH, or ASA plus nadroparin (an LMWH).486 The combination of ASA and
LMWH significantly reduced the total ischemic event rate, the rate of recurrent angina, and the number of patients requiring interventional procedures.
The FRISC study406 randomized 1506 patients with UA or
non–Q-wave MI to receive subcutaneous administration of the LMWH dalteparin (120 IU per kg twice daily) or placebo for 6 d and then once a day for the next 35 to 45 d. Dalteparin was associated with a 63% risk reduction in death or MI during the first 6 d (4.8% vs 1.8%, P=0.001), which matched the favorable experience observed with UFH. Although an excess of events was observed after the dose reduction to once daily after 6 d, a significant decrease was observed at 40 d with dalteparin in the composite outcome of death, MI, or revascularization (23.7% vs 18.0%, P=0.005), and a trend was noted toward a reduction in rates of death or MI (10.7% vs 8.0%, P=0.07).
Because the level of anticoagulant activity cannot be eas- ily measured in patients receiving LMWH (eg, aPTT or acti- vated clotting time [ACT]), interventional cardiologists have expressed concern about the substitution of LMWH for UFH in patients scheduled for catheterization with possible PCI. However, in a study involving 293 patients with UA/NSTEMI who received the usual dose of enoxaparin, Collett et al561
showed that PCI can be performed safely.
An alternative approach is to use LMWH during the period of initial stabilization. The dose can be withheld on the
morning of the procedure, and if an intervention is required and more than 8 h has elapsed since the last dose of LMWH, UFH can be used for PCI according to usual practice patterns. Because the anticoagulant effect of UFH can be more readily reversed than that of LMWH, UFH is preferred in patients likely to undergo CABG within 24 h.
3.2.5.3. LMWH Versus UFH
Nine randomized trials have directly compared LMWH with UFH (Table 17). Two trials evaluated dalteparin, another eval- uated nadroparin, and 6 evaluated enoxaparin. Heterogeneity of trial results has been observed. Trials with dalteparin and nadroparin reported similar rates of death or nonfatal MI com- pared with UFH, whereas 5 of 6 trials of enoxaparin found point estimates for death or nonfatal MI that favored enoxapa- rin over UFH; the pooled OR was 0.91 (95% CI 0.83 to 0.99). The benefit of enoxaparin appeared to be driven largely by a reduction in nonfatal MI, especially in the cohort of patients who had not received any open-label anticoagulant therapy before randomization.
There are few data to assess whether the heterogeneous results are explained by different populations, study designs, various heparin dose regimens, properties of the various LMWHs (more specifically, different molecular weights and anti–factor Xa/anti–factor IIa ratios), concomitant therapies, or other unrecognized influences. Although it is tempting to compare the relative treatment effects of the different LMWH compounds, the limitations of such indirect comparisons must be recognized. The only reliable method of comparing 2 treatments is through a direct comparison in a well-designed clinical trial or series of trials. The comparison of different therapies (eg, different LMWHs) with a common therapy (eg, UFH) in different trials does not allow a conclusion to be made about the relative effectiveness of the different LMWHs because of the variability in both control group and experi- mental group event rates due to protocol differences, differ- ences in concomitant therapies due to geographic and time variability, and the play of chance. Similar considerations apply to comparisons among platelet GP IIb/IIIa inhibitors.
In the Enoxaparin Versus Tinzaparin (EVET) trial, 2 LMWHs, enoxaparin and tinzaparin, administered for 7 d, were compared in 436 patients with UA/NSTEMI. Enoxaparin was associated with a lower rate of death/MI/recurrent angina at 7 and 30 d compared with tinzaparin.562,563 Bleeding rates
were similar with the 2 LMWHs.
The advantages of LMWH preparations are the ease of subcutaneous administration and the absence of a need for monitoring. Furthermore, the LMWHs stimulate platelets less than UFH564 and are less frequently associated with
heparin-induced thrombocytopenia.556 In the ESSENCE trial,
minor bleeding occurred in 11.9% of enoxaparin patients and 7.2% of UFH patients (P<0.001), and major bleeding occurred in 6.5% and 7.0%, respectively.175 In TIMI 11B,
the rates of minor bleeding in hospital were 9.1% and 2.5%, respectively (P<0.001), and the rates of major bleeding were 1.5% and 1.0% (P=0.14).186 In the FRISC study, major bleed-
ing occurred in 0.8% of patients given dalteparin and in 0.5% of patients given placebo, and minor bleeding occurred
Table 17. Trials of LMWH Versus UFH in UA/NSTEMI Trial
(Reference) LMWH/Dose UFH End Point/Drug Effect Analysis 95% CI P Major Bleeding (P) FRISC (371) 1506 (a) 6 d*: dalteparin
120 IU per kg† SC twice daily (maximum 10,000 IU) (b) During first 40 d:
dalteparin 7500 IU SC once per day
(a) 6 d: placebo (b) During first 40 d: placebo
(a) Death or new MI (6 d): LMWH 1.8%, Placebo 4.8% (b) Death or new MI (during first 40 d‡): LMWH 8%, placebo 10.7% (a) RR 0.37 ARR 3% (b) RR 0.75 ARR 2.7% (a) 0.20 to 0.68 (b) 0.54 to 1.03 (a) 0.001 (b) 0.07 (a) LMWH 0.8%, placebo 0.5%; ARR –0.3% (P=NR) (b) During first 40 d: LMWH 0.3%, placebo 0.3%; ARR 0% (P=NR) ESSENCE (169) 3171 Enoxaparin 1 mg per kg SC twice daily (minimum 48 h, maximum 8 d)
UFH IV bolus (usually 5000 units) and continued IV infusion
(a) Death, MI, or recurrent angina at 14 d: LMWH 16.6% UFH 19.8% (b) Death, MI, or recurrent angina at 30 d: LMWH 19.8%, UFH 23.3% (a) OR at 14 d = 0.80 ARR 3.2% (b) OR at 30 d = 0.81 ARR 3.5% (a) 0.67 to 0.96 (b) 0.68 to 0.96 (a) 0.019 (b) 0.016 At 30 d: LMWH 6.5%, UFH 7%; ARR 0.5% (P = 0.57)
FRIC (462) 1482 (a) Days 1 to 6: dalteparin 120 IU per kg SC twice daily (b) Days 6 to 45§:
dalteparin 7500 IU SC once per day
(a) Days 1 to 6: UFH 5000 units IV bolus and IV infusion of 1000 units per h for 48 h (b) Days 6 to 45: