Cath Lab Drugs

Question 1

What conversion is required to turn Clopidogrel into its active metabolites?

Answer 1

Hepatic cytochrome P450-3A4. 85% of clopidogrel is hydrolyzed by human carboxyl esterase-1 into an inactive metabolite and the remaining 15% then undergoes a two step hepatic cytochrome P450 (CYP)-dependent oxidation process.

Question 2

The activation process of clopidogrel leads to a delay in peak anti platelet activity. How long is this delay?

Answer 2

6 to 9 hours, depending on the loading dose.

Question 3

The inhibition of platelet aggregation by clopidogrel is dependent on ______.

Answer 3

Concentration

Question 4

Following cessation of clopidogrel therapy, platelet function recovers in _____ days. Why?

Answer 4

5 to 7 days. Inhibition on platelet aggregation of clopidogrel is irreversible; platelet function recovers due to synthesis of new platelets.

Question 5

Polymorphisms in which enzymes create variability in the degree of platelet inhibition of clopidogrel?

Answer 5

Hepatic enzymes CYP2C192 and CYP2C193 (30-60% prevalence); ABCB1 (influences GI absorption)

Question 6

List the 3 classes of anti-platelet drugs for PCI (also give a drug example of each class)

Answer 6

1. COX inhibitor (aspirin)
2. Platelet P2Y12 ADP Receptor antagonists (clopidogrel, ticlopidine, prasugrel, ticagrelor)
3. GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban)

Question 7

Where is aspirin absorbed? How long to peak plasma levels? How long is COX inhibited?

Answer 7

Rapidly absorbed in UGI tract; <40 minutes; irreversibly inhibited for the life of the platelet (7-10 days)

Question 8

What is the optimal aspirin dose for PCI? What study investigated this as part of its 2x2 design?

Answer 8

No firmly established (75-325mg acceptable options). CURRENT/OASIS-7 compared 75-100mg vs 300-325mg with no significant difference in efficacy; trend toward increased GI bleed in higher dose group.

Question 9

Why isn’t ticlopidine used much anymore?

Answer 9

Safety concerns from high rates of neutropenia (1.3-2.1% that develops within first 3 months of therapy, as compared to 0.1% with clopidogrel), NVD (30-50%) and bone marrow aplasia/TTP is also reported with ticlopidine (lower rates with clopidogrel). Ticlopidine also has twice daily dosing.

Question 10

Prasugrel is a 3rd generation irreversible thienopyridine ADP receptor antagonist. What is the time to onset? What other benefits as compared to clopidogrel?

Answer 10

Rapid 1-2 hour onset (it is a pro-drug that is converted ia more efficient hepatic oxidation pathways, resulting in peak platelet inhibition 30-60 min after loading dose). Fewer drug interactions and less inter-individual response variability.

Question 11

Ticagrelor is a 3rd generation non-thienopyridine ADP receptor antagonist that reversibly binds; direct non-competitive agent. What is the time of onset? How long after use does platelet function normalize?

Answer 11

Ticagrelor is NOT a pro-drug; does not require metabolic conversion time. Time of onset

Question 12

What is the loading and daily dose for PCI of the following drugs:
Clopidogrel?
Prasugrel?
Ticagrelor (what is the ASA dose with this)?

Answer 12

Clopidogrel: 600mg asap before PCI; 75mg daily
Prasugrel: 60mg (preloading not routinely done prior to diagnostic angiography due to rapid onset); 10mg daily
Ticagrelor: 180mg; 90mg twice daily (ASA dose should be low 81-100mg due to reduced efficacy when co-administered)

Question 13

ASA combined with thienopyridine at PCI has demonstrated a 5-fold reduction in acute and subacute stent thrombosis when compared to ______.

Answer 13

ASA alone, warfarin, heparin or long-term LMWH

Question 14

What study randomized 12,562 patients who presented within 24 hours of symptoms to receive clopidogrel 300mg load, followed by 75mg daily and ASA vs ASA and placebo? Results showed a significant reduction (9.3% v 11.4%, RRR 20%) in primary endpoint of ______. Benefit was noted within 24 hours, sustained at 1 year and was observed in all ACSs regardless of risk.

Answer 14

CURE study. Primary endpoint was death from CV cause, nonfatal MI or stroke. Study showed a 31% RRR in death and MI in clopidogrel patients compared to placebo-treated PCI patients. Long-term (9-12 month) compared to short-term (4 week) clopidogrel therapy post PCI was associated with a 31% lower rate of CV death, MI or revascularization (P=0.03).

Question 15

What study demonstrated the benefit of clopidogrel pre-treatment and long-term therapy in a relatively stable CAD population undergoing PCI?

Answer 15

CREDO study. Demonstrated a 27% (P=0.02) reduction in death, MI or stroke in patients receiving clopidogrel; suggesting clopidogrel in addition to ASA should be continued for a minimum of 9 months post-PCI.

Question 16

What studies suggest that CABG be delayed for 5 days after stopping clopidogrel and (possibly) avoiding preloading of clopidogrel in unstable angina/NSTEMI patients until after the coronary anatomy is identified and the need for CABG excluded?

Answer 16

CURE demonstrated a significant increase in major bleeding (3.7% v 2.7%, P=0.001) in patients receiving clopidogrel compared to placebo (most notable in patients requiring CABG). CREDO showed a trend toward more TIMI major bleeding with clopidogrel compared to placebo (8.8% v 6.7% P=0.07).

Question 17

What study compared clopidogrel head to head with prasugrel? Randomized 13,608 patient with mod-high risk ACS (10,074 with UA or NSTEMI and 3,534 with STEMI) undergoing PCI to prasugrel (60/10mg) or clopidogrel (300/75mg) for a duration of 6-15 months (median 14 mo).

Answer 17

TRITON-TIMI 38 trial

Question 18

What was the primary efficacy and primary safety endpoints for TRITON-TIMI 38? This study led to FDA approval for prasugrel use in ACS patients undergoing PCI in 2009.

Answer 18

1. Death from CV causes, nonfatal MI, or nonfatal stroke and 2. primary safety endpoint was non-CABG TIMI major bleeding. 1. Occurred in 9.9% of patients receiving prasugrel and 12.1% receiving clopidogrel (P<0.001).

Question 19

What study in 2011 led to FDA approval of ticagrelor (180/90mg bid) for ACS patients by comparing it head to head with clopidogrel (300-600/75mg)?

Answer 19

PLATO trial randomized 18,624 patients and examined the rate of adverse CV events for up to 12 months. Primary endpoint (a composite of death from vascular causes, MI or stroke) occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of patient receiving clopidogrel (P<0.001). Secondary endpoints also reduced.

Question 20

Increased risk of bleeding in what subgroups lead to an FDA Black Box warning for prasugrel?

Answer 20

Avoid prasugrel in patients with any history of stroke or TIA or to patients with severe liver dysfunction. Prasugrel is not recommended for elderly patients (>75 years) as this group had increased risk of fatal and intracranial bleeding. Use with caution in patients with low body weight (<60 kg).

Question 21

What are the two most common non-hemorrhagic side effects seen with ticagrelor?

Answer 21

Dyspnea (ticagrelor 13.8% vs clopidogrel 7.8%) and bradycardia/ventricular pauses (t 6% v c 3.5%)