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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4011_Библиотеки_им_академика_М_И_Перельмана
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250 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
mortality to be substantially reduced at 30 d among 6458 diabetic patients receiving active
therapy vs placebo (6.2% vs 4.6%; odds ratio, 0.74; 95% CI, 0.59–0.92; p = 0.007; Fig. 12).
Among the remaining patients (>23,000 without diabetes), no survival benefit was noted
with platelet GPIIb/IIIa inhibition versus placebo (3.0% for both groups; Fig. 13). The
largest and most systematic meta-analysis of these trials confirmed the finding of Roffi
et al. (43) among diabetic patients. Boersma and colleagues (42) also evaluated the 31,402
patients from the six GPIIb/IIIa ACS trials listed in Table 2. This meta-analysis showed
that 30-d mortality was 3.4% among the 18,297 patients receiving active therapy and 3.7%
among the 13,105 patients receiving placebo. The odds ratio (0.91; 95% CI, 0.81–1.03)
Fig. 11. Kaplan-Meier curves of mortality to 30 d from the PRISM trial. With a risk ratio of 0.62
favoring tirofiban, although wide confidence intervals, PRISM was the only study to show a sur-
vival benefit with GPIIb/IIIa therapy. (From ref. 20, with permission.)
Fig. 12. Odds ratio and 95% confidence intervals for 30-d mortality among diabetic patients in GPIIb/
IIIa ACS trials. Values <1.0 indicate a survival benefit from GPIIb/IIIa therapy. (From ref. 43, with
permission.)
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Chapter 10 / Unstable Angina Trials 251
again suggests a minor overall mortality benefit (p = 0.14) with GPIIb/IIIa therapy. In the
smaller meta-analysis by Kong et al. (41), the odds ratio for mortality at an early (48–96 h)
timepoint was found to be 0.71 (95% CI, 0.50–1.01), favoring GPIIb/IIIa therapy. The
odds ratio for mortality, shifting from 0.71 to 0.90 between two and 30 d in this meta-anal-
ysis, further strengthens the argument for considering one endpoint at a specific follow-up
interval when comparing multiple trials. For example, had the primary endpoint of GUSTO-
IV been at 7 d, abciximab would have been found to reduce the ischemic events by 10%,
as opposed to increasing them by nearly 14% at 30 d (Fig. 3). Since most ACS trials have
previously reported the treatment effect on death and nonfatal MI at 30 d as the primary
endpoint, this may be the most appropriate point of comparison.
30-Day Myocardial Infarction
Enzymatic (serologic) evidence of myocardial infarction is not uncommonly present
following percutaneous coronary intervention, especially among patients with an ACS.
This must be kept in mind when interpreting unstable angina trials among patients also
undergoing coronary interventions, since it can be unclear whether the increase in CK-MB
or troponin occurred as a result of the primary disease process, the coronary intervention,
or both. Among all patients randomized to GPIIb/IIIa therapy in the 5-P and GUSTO-IV
trials, 7.4% had a nonfatal MI compared with 8.1% of the placebo cohort (42).
30-Day Death or Myocardial Infarction
The composite rate of death or nonfatal MI among overall trial cohorts (i.e., treated
and placebo groups) may be an indicator of the illness severity of the patients enrolled,
the background medical treatment given, or the level of endpoint adjudication. The high-
est overall rate of 30-d death or MI was in PURSUIT (15.7%), and the lowest was in PRISM
(5.8%). Among all patients receiving GPIIb/IIIa therapy in the Boersma et al. meta-anal-
ysis (42), the 30-d death or MI composite was 10.8% compared with 11.8% for those
receiving placebo (p = 0.015; Fig. 14). The 30-d odds ratio was 0.91 (95% CI, 0.85–0.98),
or 10 fewer events per 1000 treated patients. Among the final or best GPIIb/IIIa treatment
groups (PURSUIT and PRISM-PLUS had a treatment arm discontinued), the greatest
Fig. 13. Odds ratio and 95% confidence intervals for 30-d mortality among nondiabetic patients in
GPIIb/IIIa ACS trials. Values <1.0 indicate a survival benefit from GPIIb/IIIa therapy. (From ref.
43, with permission.)
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252 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
relative reduction (27% fewer events) was seen in PRISM-PLUS among patients receiv-
ing 0.10 µg/kg/min of tirofiban combined with heparin, but confidence intervals around
this odds ratio are wide (OR = 0.70; 95% CI, 0.50–0.98), and the magnitude of risk reduc-
tion is not statistically different from that seen in other trials.
Considering multiple subgroups, Boersma and colleagues (42) showed that the benefit
of GPIIb/IIIa inhibitors in reducing death or MI at 30 d was consistent across many dem-
ographic and baseline characteristics (Fig. 15). Patients receiving the absolute greatest treat-
ment benefit were those with high-risk characteristics. An unexpected although statistically
significant interaction was seen according to gender: men received a marked benefit, and
women had a significantly worse outcome if receiving GPIIb/IIIa therapy. After stratifying
patients according to evidence of myonecrosis (troponin elevation), no evidence remained
for a gender effect in treatment response. The greatest relative risk reductions for 30-d
death or MI with GPIIb/IIIa treatment has been repeatedly seen among patients who were
troponin-positive on admission. For example, Newby and colleagues (44) prospectively
studied 1160 patients in PARAGON B. Using a blinded core laboratory, they measured
troponin levels before and during study treatment. Compared with placebo, lamifiban-treated
patients who were troponin-positive had a significant reduction in 30-d death or MI (19.0%
vs 11.0%). No treatment benefit was seen among troponin-negative patients (10.3% vs
9.6%, respectively). A similarly striking effect was seen with tirofiban in PRISM, as reported
by Heeschen et al. (45). Using CK-MB measurements in PURSUIT and troponin in GUSTO-
IV, neither study showed a particular benefit for patients with an MI at enrollment.
Bleeding Events
An important side effect of GPIIb/IIIa inhibitors is bleeding (Table 4), and hence an
overall estimate of bleeding parameters from the unstable angina trials is helpful. There
Fig. 14. Kaplan-Meier estimates of the cumulative occurrence of 30-d composite of death or myocar-
dial infarction in a pooled analysis of 31,402 patients. (From ref. 42, with permission.)
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Chapter 10 / Unstable Angina Trials 253
are two different bleeding classifications (i.e., the one developed by the TIMI study group
and the one developed by the GUSTO study group) and two different patient groups (those
undergoing vascular surgery, such as CABG, and those not undergoing surgery). Major
bleeding events by the TIMI criteria include a >5 g hemoglobin loss. This occurred in as
few as 0.4% of GPIIb/IIIa-treated patients in PRISM and as many as 10% of GPIIb/IIIa-
treated patients in PURSUIT when considering bleeding related to bypass surgery and
Fig. 15. Odds ratio and 95% confidence intervals for the occurrence of a 30-d composite of death
or myocardial infarction among subgroups from a meta-analysis of the six large-scale GPIIb/IIIa-ACS
trials. CABG, coronary artery bypass graft; SBP, systolic blood pressure; CK-MB, creative kinase
MB; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty. (From ref. 42,
with permission.)
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254 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
angioplasty. The highest bleeding among patients not undergoing CABG was understand-
ably among those receiving the highest doses of GPIIb/IIIa inhibitor, especially when com-
bined with heparin. Severe bleeding according to the GUSTO classification (bleeding that
is life-threatening, leading to hemodynamic compromise, or an intracranial hemorrhage)
occurred in ≤1% of most trials study groups and was highest in the 2.0 µg/kg/min cohort
of PURSUIT (1.5%). Pooling all large-scale GPIIb/IIIa-ACS trial data, major bleeding
increased from 1.4% with heparin and aspirin (control), to 2.4% when adding a GPIIb/IIIa
antagonist (42).
Blood product transfusion (usually RBC’s and classified as moderate bleeding) occurred
in 8.3% of patients randomized to GPIIb/IIIa therapy and 6.5% of those receiving placebo.
Most transfusions were related to surgery or angioplasty procedures. Thrombocytopenia
(platelet count ≤ 100,000/mm
3
) was infrequent, although it was more common with abcixi-
mab (Table 4). Major thrombocytopenia (platelet count ≤ 50,000/µL) was infrequent (≤1%)
in most study groups, as were platelet transfusions. Fortunately, intracranial hemorrhage
remains very rare with this class of drug, with no events occurring in many study groups.
The overall rate of intracranial hemorrhage was <0.1% for both the placebo and treatment
groups.
6-Month Death or Myocardial Infarction
Although information on events between 30-d and 6-mo follow-up are limited (i.e.,
there are no data on the number of patients who had revascularization procedures or were
maintained on β-blockers, angiotensin-converting enzyme inhibitors, or statins), most
trials collect a composite rate of death and nonfatal MI by survey. Quite encouragingly,
treatment benefit has been maintained at late follow-up. Even though there is an initial
decay in benefit (between the first week and first month of follow-up), the benefit at 30 d
is preserved at 6 mo. The relative reduction in death or MI present was 10% in the 30-d com-
posite in PURSUIT and 8% at 6 mo. Likewise, the tirofiban plus heparin arm of PRISM-
PLUS reported a 20% relative reduction in the composite at late follow-up (Fig. 7). Somewhat
surprisingly, the 9% composite reduction at 30-d follow-up in PARAGON for low-dose
lamifiban was improved to a 23% reduction in death or MI over control. These data collec-
tively suggest that although there is an initial decay of acute benefit, passivation probably
also occurs, which protects against intermediate-term events. The 6-mo odds ratio for death
or MI with GPIIb/IIIa treatment compared with placebo was 0.88 (95% CI, 0.79–0.97)
which translates into 16 fewer events per 1000 treated patients (−0.016; 95% CI, −0.027
to −0.004) (41).
CURRENT ISSUES
A number of important issues remain to be discussed and understood regarding the
5-P and GUSTO-IV Trials, and their application to contemporary medical practice. It is
unarguable that GPIIb/IIIa receptor blockage provides an improved outcome during per-
cutaneous coronary interventions. On the other hand, the small molecules that are highly
specific for the GPIIb/IIIa receptor, are distinct from the monoclonal antibody and have
differences among themselves. Questions therefore remain regarding the extent and tim-
ing of inhibition needed with these compounds, the importance of concomitant heparin,
the duration of receptor blockage required, and the importance of underlying renal func-
tion. Since the small-molecule GPIIb/IIIa receptor antagonists have an important plasma
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Chapter 10 / Unstable Angina Trials 255
phase (i.e., short half-life, need for continuous infusion, moderate dissociation constants),
they are quite sensitive to renal function and excretion. Finally, as many patients with ACS
undergo percutaneous revascularization, it is important to separate primary (medical)
treatment effects from those associated with percutaneous coronary intervention.
Primary Therapy vs PCI Effect
In the CAPTURE trial, abciximab was given the day prior to angioplasty among patients
with unstable angina. In this 24-h interim before PTCA, 2.1% of placebo patients had an
MI compared with 0.6% of the abciximab group (71% relative reduction). A larger
number of MI events occurred during and immediately after the procedure, and these were
reduced 58% by abciximab (Fig. 16). This early observation suggested that GPIIb/IIIa
inhibitors have both a primary and PTCA-related treatment effect. Therefore, in consid-
ering the results of PARAGON A and B, PURSUIT, PRISM, PRISM-PLUS, and GUSTO-
IV, one must also consider the primary and PTCA-related effects separately.
By protocol design, PARAGON A and GUSTO-IV did not allow PTCA during the first
48 h and 60 h, respectively, unless the patient had medically refractory angina. PRISM and
PRISM-PLUS discouraged procedures before 48 h, and the PURSUIT design allowed
usual clinical practice. Between 48 and 96 h, angiography and (if appropriate) angioplasty
were encouraged in the PRISM-PLUS protocol. With these protocol differences, the rate
of PTCA among the studies varied from 13 to 31% (Table 2). Because only 13 and 19%
of patients in PARAGON A and GUSTO-IV, respectively, underwent angioplasty, and
few of these patients were still receiving study drug, the strength of subgroup analyses
is limited. Meaningful information is available from the other trials.
In PURSUIT, 24% of patients underwent percutaneous coronary revascularization.
Roughly half of these patients (12.7% of total cohort) underwent intervention within 72 h
of randomization and were therefore still receiving study drug. Among these 1228 patients,
Fig. 16. Occurrence of preprocedural and periprocedural myocardial infarction in the CAPTURE study.
Abciximab provided both a primary (preprocedural) and angioplasty-related reduction in the inci-
dence of infarction. (From ref. 29, with permission.)
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256 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
609 were in the eptifibatide group, and the composite of death and MI at 30-d follow-up was
reduced by 30% compared with placebo (11.8% vs 16.8%, p = 0.013). As in the CAPTURE
trial, the rate of preprocedural MIs was reduced by GPIIb/IIIa treatment (1.7% vs 5.5%).
Considering then the remaining 8149 patients not undergoing early percutaneous revas-
cularization in PURSUIT, the 30-d composite was relatively reduced 7% with eptifibatide
(14.6% vs 15.7%, p = 0.185). Finally, patients who underwent late intervention (i.e., after
discontinuation of eptifibatide) had no reduction in 30-d adverse events.
Since angiography and revascularization were discouraged in the first 48 h of PRISM,
few of the 21% of the study cohort who had percutaneous revascularization were receiv-
ing study drug (Fig. 17). The 30-d composite of death and MI was reduced by 21% (7.2%
vs 9.1%, p = NS) among those receiving prior or ongoing tirofiban. On the other hand,
in those treated without percutaneous or surgical revascularization (i.e., medical manage-
ment only), the composite was reduced 42% by tirofiban (3.6% vs 6.2%, p < 0.05). Finally,
in PRISM-PLUS, in which percutaneous revascularization was encouraged during study
drug infusion, 31% of the patients had angioplasty, and tirofiban reduced the 30-d death
or MI composite by an impressive although nonsignificant 42% (5.9% vs 10.2%, p = NS)
(Fig. 18). Among the 719 patients treated medically in PRISM-PLUS, tirofiban reduced the
30-d composite by 23% (7.8% vs 10.1%, p = NS). Overall, these data include 2357 patients
undergoing PTCA, and prior or ongoing GPIIb/IIIa therapy reduced the 30-d composite
of death or nonfatal MI by 30% (9.3% vs 13.3%). A smaller benefit was seen among the
10,867 patients treated without revascularization, as GPIIb/IIIa therapy relatively reduced
the 30-d composite by 11% (12.1% vs 13.6%).
In the meta-analysis by Boersma and colleagues (42), the six GPIIb/IIIa-unstable angina
trials were analyzed for patients undergoing percutaneous coronary intervention within
5 d of enrollment versus those not undergoing percutaneous coronary intervention during
Fig. 17. Schematic of the study design timeline for the PRISM and PRISM-PLUS studies. In PRIS M,
percutaneous coronary revascularization (PTCA) was not recommended during the first 48 h, but was
allowed thereafter, although administration of study drug was completed. PRISM-PLUS also did not
recommend angiography in the first 48 h, although it was strongly recommended that angiography be
performed along with angioplasty if possible during study drug infusion. (Data from refs. 20 and 21.).
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Chapter 10 / Unstable Angina Trials 257
this time. This analysis, therefore, reflects patients receiving a GPIIb/IIIa inhibitor at the
time of percutaneous coronary intervention as well as those who had drug discontinued
in the days prior. Regardless, patients who were randomized to GPIIb/IIIa therapy had
a significantly lower likelihood of having an MI before revascularization. Of the 2421
patients undergoing percutaneous coronary intervention and receiving active therapy, 5.8%
had a preprocedural MI vs 8.0% among the 1957 who underwent percutaneous coronary
intervention and received placebo (odds ratio, 0.70; 95% CI, 0.55–0.89). These same
subgroups had rates of 30-d death or MI of 11.8 and 14.5%, respectively (odds ratio, 0.77;
95% CI, 0.64–0.92). Thus, considering a somewhat selected cohort (i.e., those needing
to undergo percutaneous coronary intervention during index hospitalization), there was
an approx 28% reduction in preprocedural MI. A similar relative reduction was seen in
30-d death or MI. In assessing patients not undergoing percutaneous coronary interven-
tion within 5 d, the meta-analysis included 15,876 patients receiving GPIIb/IIIa therapy
and 11,148 patients receiving placebo. The 30-d death or MI composite for these two sub-
groups was 10.7 and 11.4%, respectively (odds ratio, 0.95; 95% CI, 0.87–1.02). This
approx 6% relative risk reduction was not statistically significant.
The overall 9% relative reduction in death or MI at 30 d among these nearly 32,000
patients studied is similar to that reported for direct thrombin inhibitors or low-molecular-
weight heparins tested against unfractionated heparin in ACSs. Likewise, the nearly 30%
reduction seen in death or MI among those undergoing percutaneous revascularization
is similar to that reported from other (interventional) studies testing GPIIb/IIIa inhibitors.
Taken together, these observations confirm a primary treatment effect of GPIIb/IIIa on
the ruptured plaque of unstable angina and an amplified benefit during further plaque dis-
ruption (i.e., angioplasty).
Fig. 18. Kaplan-Meier curves showing the cumulative incidence of death or myocardial infarction
(MI) among patients randomly assigned to heparin or heparin plus tirofiban in PRISM-PLUS. The left
panel shows events during the initial 48 h of medical stabilization and prior to recommended angio-
graphy and intervention. The right panel shows the incidence of death or myocardial infarction from
the time of the procedure to 30 d. (From ref. 21, with permission.)
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258 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
“Toxic Doses” vs Dose-Dependent Responses
Since most GPIIb/IIIa inhibitors are fully platelet-specific, “toxicity” has been mani-
fest as excess bleeding. Fortunately, the overwhelming majority of bleeding is at the site
of vascular puncture. Less commonly, gastrointestinal and genitourinary bleeding occur.
On the other hand, the question has arisen of whether GPIIb/IIIa receptor antagonists can
otherwise become “toxic.” Several antithrombotics, such as heparin, hirudin, and fibrino-
lytics, have been associated with a narrow therapeutic window, and higher doses have been
associated with both heightened bleeding and mortality. Among some GPIIb/IIIa trials,
“high-dose” antagonism has been associated with an increase in bleeding and a neutral or
negative effect on ischemic outcome. In IMPACT-II (see Chapter 6), angioplasty patients
receiving the “higher dose” (0.75 µg/kg) eptifibatide infusion were found to have a simi-
lar or worse outcome compared with those receiving “lower dose” (0.5 µg/kg) eptifibatide
or placebo. However, subsequent to this trial’s completion, both eptifibatide doses were
found to inhibit platelet function only modestly. Thus, rather than a toxic effect, the lack of
demonstrated benefit from the higher dose regimen could be speculated to be from sam-
pling error or toxic, procoagulant, or counterbalancing effects that remain to be illuminated.
The high-dose GPIIb/IIIa treatment arms of PARAGON A and PRISM-PLUS should
have provided extensive platelet inhibition (>90% inhibition of ADP-induced aggrega-
tion). These also did not show benefit over low-dose treatment or placebo. Lamifiban at
5 µg/kg in the Canadian Lamifiban Study lowered 30-d death or nonfatal MI 70% com-
pared with placebo. In this dose-exploring study, only 41 patients received the 5-µg/kg
dose. In PARAGON, 769 patients received this dose, and the 30-d death or MI rate was 3%
higher than placebo. A similar seeming discrepancy between trials with high-dose antag-
onists is seen with 0.6 µg/kg/min of tirofiban in PRISM and PRISM-PLUS. In PRISM, this
high dose of antagonist without heparin reduced adverse events (death, MI, and refractory
ischemia) by 32% at 48 h and by 7% at 30 d. These findings were considered favorable.
On the other hand, this same dose of tirofiban in PRISM-PLUS was prematurely discon-
tinued because of an increase in mortality at 7 d compared with placebo (4.6% vs 1.1%,
respectively). At 30-d follow-up, the effect was statistically neutral (6.1% vs 4.0%, respec-
tively) for this cohort. Thus, the question remains: why did high-dose tirofiban and lami-
fiban perform worse than their respective moderate doses and no better than placebo? These
observations are in contrast to previous large studies of this class of antithrombotic therapy
and suggests an upper limit of benefit or potential toxicity. Theoretical explanations for
the apparent “toxicity” of high doses of tirofiban and lamifiban include intraplaque
hemorrhage, paradoxic platelet activation, an interplay between excessive bleeding and
clinical outcomes, or a question of chance.
The GUSTO-IV study importantly raised questions regarding toxicity of GPIIb/IIIa
inhibitors. Similar to the administration of long-term oral GPIIb/IIIa inhibitors (46), the
48-h administration of abciximab to medically treated patients with unstable angina led to
a slightly worse outcome than those receiving placebo (Fig. 3). Of the 2612 patients receiv-
ing abciximab bolus and 48-h infusion, 9.1% died or had MI by 30 d. This was in contrast
to the 8% rate among 2598 patients receiving placebo (odds ratio, 1.1; 95% CI, 0.94–
1.39). Even patients who were troponin-positive at study enrollment received no benefit
from the 48-h infusion of abciximab. Other than a reduction in mortality among diabetic
patients, no other subgroup benefited (Fig. 12). These findings were quite disappointing
and suggest again a partial agonist activity to these agents. Peter et al. (47) demonstrated
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Chapter 10 / Unstable Angina Trials 259
antagonist-induced activation of the GPIIb/IIIa receptor with abciximab and small mole-
cule agents. This occurs during trough periods or at low drug concentrations. Although
this mechanism probably had an important consequence with oral therapy since recurrent
trough levels occur between doses (48), a similar phenomenon may have occurred with
long-term abciximab administration. Steinhubl and colleagues (48) noted that a sizable
proportion of patients fell to a relatively low level of aggregation inhibition at ≥8 h of
abciximab infusion. These and other observations (49) suggest that there are counter-
balancing forces associated with GPIIb/IIIa receptor antagonism, especially with longer
term administration of these agents.
IIa/IIIa and Concomitant Heparin Thearpy
PARAGON was the only trial that factorially tested the benefit of antithrombin (hepa-
rin) therapy administered concomitantly with GPIIb/IIIa therapy. Overall, heparin pro-
vided no consistent benefit when combined with lamifiban. This may reflect the fact that
bleeding events were increased among those receiving heparin with high-dose lamifiban
but not with low-dose lamifiban. Likewise, at 30 d and 6 mo, the composite ischemic event
rate was numerically highest among those receiving heparin with high-dose lamifiban
and lowest for those receiving heparin with low-dose lamifiban. The group assigned to
high-dose lamifiban with heparin had no improved parameter and had the highest percen-
tage of patients discontinuing drug prematurely, usually because of bleeding or an ische-
mic event. In the 5-P trials, as well as in previous GPIIb/IIIa angioplasty studies, bleeding
and adverse events were linked to the combination of potent platelet inhibition and full-
dose heparin.
Although PARAGON A alone was not adequately powered to assess the extent of clini-
cal benefit provided by concomitant heparin, collectively assessing these data in combi-
nation with other observations is helpful. These include the following findings: (1) the
meta-analysis by Oler et al. (50); (2) the largest relative benefit in the ACS trials was with
moderate-dose tirofiban with heparin; (3) the intermediate-term benefit present in PRISM-
PLUS with heparin added to tirofiban was not seen in PRISM’s tirofiban without heparin
group; and (4) PARAGON’s low-dose lamifiban with heparin group had the best early,
intermediate, and long-term outcomes. These findings suggest that heparin adds a modest
benefit to antiplatelet therapy in ACS. Whether low-molecular-weight heparins added to
GPIIb/IIIa antagonists will provide a more favorable risk/benefit ratio than unfractionated
heparin, is the subject of ongoing clinical trials.
SUMMARY AND FUTURE DIRECTIONS
Despite contemporary medical therapies, patients presenting with unstable angina and
electrocardiographic evidence of ischemia or serologic evidence of myocardial necrosis
have a substantial 30-d rate of death or important nonfatal MI. Although antiplatelet agents
such as aspirin, ticlopidine, and clopidogrel have substantially improved this outcome
compared with placebo, intermediate and long-term follow-up shows that plaque passiva-
tion is not complete. The GPIIb/IIIa receptor antagonists are severalfold more potent
than previous antiplatelet therapies, and they have been shown to be markedly beneficial
in making the plaque disruption of percutaneous coronary revascularization quiescent.
The PARAGON A and B, PRISM, PRISM-PLUS, and PURSUIT trials have alone and col-
lectively demonstrated a reduction in ischemic events beyond that of aspirin and heparin
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