Pharmacotherapy in the cardiac catheterization laboratory: evolution and recent developments

Figures & data

Table 1 FDA-approved antiplatelet and anticoagulant drugs listed in order of their year of approval

Number	Drug name	Class	Route	Year approved	Notes
1	Heparin	Anticoagulant	IV	1939	Oldest drug in class.
2	Warfarin	Anticoagulant	Oral	1954	First oral anticoagulant, no role in ACS.
3	Aspirin	Antiplatelet	Oral	Late 1980s	Approved as analgesic in 1965.
4	Ticlopidine	Antiplatelet	Oral	1991	Rarely used now because of side effects.
5	Enoxaparin	Anticoagulant	SC/IV	1993	First LMWH.
6	Dalteparin	Anticoagulant	SC/IV	1994	Only approved for UA/NSTEMI.
7	Clopidogrel	Antiplatelet	Oral	1997	Most-popular second antiplatelet.
8	Abciximab	Antiplatelet	IV	1997	First glycoprotein IIb/IIIa inhibitor.
9	Eptifibatide	Antiplatelet	IV	1998	Second glycoprotein IIb/IIIa inhibitor.
10	Tirofiban	Antiplatelet	IV	1999	Third glycoprotein IIb/IIIa inhibitor.
11	Tinzaparin	Anticoagulant	SC/IV	2000	No role in ACS.
12	Bivalirudin	Anticoagulant	IV	2000	Approved for use before PCI.
13	Argatroban	Anticoagulant	IV	2000	Only approved for patients with HIT.
14	Fondaparinux	Anticoagulant	SC	2001	First and only synthetic pentasaccharide.
15	Prasugrel	Antiplatelet	Oral	2009	First alternative to clopidogrel.
16	Dabigatran	Anticoagulant	Oral	2010	No role in ACS.
17	Ticagrelor	Antiplatelet	Oral	2011	Second alternative to clopidogrel.
18	Rivaroxaban	Anticoagulant	Oral	2011	No role in ACS.
19	Apixaban	Anticoagulant	Oral	2012	No role in ACS.
20	Vorapaxar	Antiplatelet	Oral	2014	Introduced triple antiplatelet therapy.

Abbreviations: ACS, acute coronary syndrome; FDA, Food and Drug Administration; HIT, heparin induced thrombocytopenia; IV, intravenous; LMWH, low-molecular-weight heparin; PCI, percutaneous coronary intervention; SC, subcutaneous; UA/NSTEMI, unstable angina/non-stent thrombosis segment elevation myocardial infarction.

Figure 1 An overview of the mechanism of action of antiplatelet drugs, showing their effects on various steps of platelet activation and aggregation.

Abbreviations: AA, arachidonic acid; ADP, adenosine diphosphate; COX, cyclooxygenase; gpIb, glycoprotein Ib; gpIIb–IIIa, glycoprotein IIb/IIIa; PAR-1, platelet-activated receptor 1; PGG₂, prostaglandin G2; PGH₂, prostaglandin H2; TXA₂, thromboxane A2.

Figure 2 An overview of mechanism of action of the anticoagulant drugs, showing their effects on various steps in the normal coagulation cascade.

Abbreviations: ATIII, antithrombin III; DTI, direct thrombin inhibitor; LMWH, low-molecular-weight heparin.

Table 2 Summary of the findings from some of the salient trials on bivalirudin

Sr no	Trial	Comparison	Gp IIb/IIIa therapy	Efficacy endpoint	Safety endpoint	Stent thrombosis
1a	ACUITY trial^Citation53	Bivalirudin versus UFH/enoxaparin plus Gp IIb/IIIa inhibitor	Differential: bailout (∼7%) versus routine (100%)	9% versus 8%; P=0.45	4% versus 7%; RR=0.52; 95% CI: 0.40–0.66; P<0.0001	1.5% versus 1.1%; P=0.37
1b	ACUITY trial^Citation53	Bivalirudin plus Gp IIb/IIIa inhibitor versus UFH/enoxaparin plus Gp IIb/IIIa inhibitor	Nondifferential: routine (100%) versus routine (100%)	9% versus 8%; P=0.16	8% versus 7%; P=0.32	1.6% versus 1.1%; P=0.26
2	HORIZONS-AMI trial^Citation54	Bivalirudin versus heparin plus Gp IIb/IIIa inhibitor	Differential: bailout (7.2%) versus routine (100%)	5.4% versus 5.5%; P=0.95	4.9% versus 8.3%; RR=0.60; 95% CI: 0.46–0.77; P<0.001	1.3% versus 0.3%, P<0.001a
3	EUROMAX trial^Citation55	Bivalirudin versus UFH/enoxaparin plus optional Gp IIb/IIIa inhibitorb	Differential: bailout (11.5%) versus optional (69.1%)	65% versus 61%; RR=1.09; 95% CI: 0.77–1.52; P=0.64	2.6% versus 6.0%; RR=0.43; 95% CI: 0.28–0.66; P<0.001	1.1% versus 0.2%; RR=6.11; 95% CI: 1.37–27.24; P=0.007
4	BRAVE-4 trial^Citation56	Prasugrel plus bivalirudin versus clopidogrel plus heparin	Similar: bailout (3.0%) versus bailout (6.1%)	4.8% versus 5.5%; RR=0.89; 95% CI: 0.40–1.96; P=0.894	14.1% versus 12%; RR=1.18; 95% CI: 0.74–1.88; P=0.543	1.1% versus 1.5%; RR=0.77; 95% CI: 0.11, 4.49; P=0.976
5	HEAT-PPCI trial^Citation57	Bivalirudin versus heparin	Nondifferential: bailout (13%) versus bailout (15%)	8.7% versus 5.7%; RR=1.52; 95% CI: 1.09–2.13; P=0.01	3.5% versus 3.1%; RR=1.15; 95% CI: 0.70–1.89; P=0.59	3.4% versus 0.9%; RR=3.91; 95% CI: 1.6–9.5; P=0.001

Notes:

a This increase in stent thrombosis was within the first 24 hours post-PCI.

b Optional Gp IIb/IIIa therapy was left to physician’s discretion.

Abbreviations: CI, confidence interval; Gp, glycoprotein; PCI, percutaneous coronary intervention; RR, relative risk; UFH, unfractionated heparin.

Figure 3 A decision tree depicting the various therapeutic options available for the management of ACS, and highlighting their unique characteristics based on the current evidence.

Notes: ^aA strategy for the timing of introducing the second antiplatelet drug (a newer P2Y₁₂ inhibitor – prasugrel or ticagrelor): modified from the algorithm proposed by Marchini et al.³³
Abbreviations: ACS, acute coronary syndrome; Addl, additional; CABG, coronary artery bypass grafting; GPI, glycoprotein IIb/IIIa inhibitor; NTG, nitroglycerine; O₂, oxygen; PCI, percutaneous coronary intervention; ST, stent thrombosis.

Table 3 List of clinical trials in order of their mention in the review

1 CURRENT/OASIS7 trial^Citation7	16 BRAVE-4 trial^Citation56
2 ALBION trial^Citation12	17 HEAT-PPCI trial^Citation57
3 TRITON-TIMI 38 trial^Citation16	18 OASIS 6 trial^Citation58
4 PLATO trial^Citation19	19 ATLAS ACS 2-TIMI 51 trial^Citation60
5 ISAR REACT 5 trial^Citation23	20 APPRAISE-2 trial^Citation62
6 CIPAMI trial^Citation30	21 RE-DEEM trial^Citation63
7 FINESSE trial^Citation36	22 WOEST trial^Citation65
8 ISAR-REACT 2 trial^Citation39	23 CHAMPION PLATFORM trial^Citation69
9 TRA 2°P-TIMI 50 trial^Citation45	24 CHAMPION PCI trial^Citation70
10 SYNERGY trial^Citation47	25 CHAMPION PHOENIX trial^Citation71
11 ATOLL trial^Citation49	26 INNOVATE-PCI trial^Citation74
12 STEEPLE trial^Citation50	27 BRIDGE trial^Citation75
13 ACUITY trial^Citation53	28 EMINENCE trial^Citation76
14 HORIZONS-AMI trial^Citation54	29 REVERSAL-PCI trial^Citation77
15 EUROMAX trial^Citation55

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