Variability in Responsiveness to Oral Antiplatelet Therapy

doi:10.1016/j.amjcard.2008.11.020

The American Journal of Cardiology

Volume 103, Issue 3, Supplement, 2 February 2009, Pages 27A-34A

https://doi.org/10.1016/j.amjcard.2008.11.020 Get rights and content

Patients who have acute coronary syndromes or are undergoing percutaneous coronary intervention receive antiplatelet therapy to reduce the risk of atherothrombotic complications. Current guidelines favor the use of aspirin in combination with clopidogrel based on the results of a number of large-scale clinical trials. Aspirin alone is a relatively weak antiplatelet agent because it inhibits only one of many paths to platelet activation. By blockade of an adjunctive signaling pathway, the addition of clopidogrel to aspirin leads to synergistic platelet inhibitory effects. Dual antiplatelet therapy reduces the number of patients who experience adverse cardiovascular outcomes by 20% over aspirin alone. Nevertheless, approximately 10% of patients experience further atherothrombotic events, even while receiving dual antiplatelet therapy. Variability in individual responsiveness, including “resistance,” has been attributed to the occurrence of these events. This article discusses variability in individual responses to oral antiplatelet therapy and its implications for clinical outcomes.

Section snippets

Definitions

Despite the use of what is generally regarded as optimal antiplatelet therapy, major adverse cardiac events occur in some patients because of what is commonly termed resistance. More strictly, resistance is a laboratory finding that consists of failure of an antiplatelet agent to block its specific target. For aspirin, resistance involves inadequate inhibition or lack of inhibition of the cyclooxygenase-1 (COX-1)–mediated thromboxane A₂ pathway, and for clopidogrel, resistance involves P2Y₁₂

Aspirin

Recent observations have demonstrated that the primary cause of aspirin resistance is poor compliance to medication.15, 16 Therefore, it is imperative when performing a platelet function test assessing for aspirin responsiveness that the patient is compliant with treatment. The second most important factor in the management of aspirin-resistant patients is whether the patients are receiving treatment with substances, such as ibuprofen, which interfere with COX-1 acetylation. Some investigators

Conclusion

Variable response to oral antiplatelet therapy is a well-established phenomenon. However, a distinction must be made between resistance (the failure to inhibit platelet reactivity in vitro) and treatment failure (the recurrence of ischemic events in patients despite antiplatelet therapy). The prevalence of resistance is a function of the methodology used to measure platelet reactivity. It also depends on the cutoff values used to define response. Accumulating evidence has shown that patients

Author Disclosures

The author who contributed to this article has disclosed the following industry relationships.

Dominick J. Angiolillo, MD, PhD, has served on the Advisory Board of Accumetrics, Arena Pharmaceuticals, Bristol-Myers Squibb Company/sanofi-aventis, Eli Lilly and Company/Daiichi Sankyo, Inc, Medicure, The Medicines Company, Novartis, and Portola Pharmaceuticals, Inc; has been an investigator for Accumetrics, AstraZeneca, Eisai, Eli Lilly and Company/Daiichi Sankyo, Inc, GlaxoSmithKline, The Medicines

References (65)

L.C. Wallentin
Aspirin (75 mg/day) after an episode of unstable coronary artery disease: long-term effects on the risk for myocardial infarction, occurrence of severe angina and the need for revascularization
J Am Coll Cardiol
(1991)
K.H. Grotemeyer et al.
Two-year follow-up of aspirin responder and aspirin non responder: a pilot-study including 189 post-stroke patients
Thromb Res
(1993)
P.A. Gum et al.
A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease
J Am Coll Cardiol
(2003)
U.S. Tantry et al.
Overestimation of platelet aspirin resistance: detection by thromboelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation
J Am Coll Cardiol
(2005)
A.D. Michelson et al.
Aspirin resistance: position paper of the Working Group on Aspirin Resistance
J Thromb Haemost
(2005)
K. Andersen et al.
Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease
Thromb Res
(2002)
G. Cotter et al.
Lack of aspirin effect: aspirin resistance or resistance to taking aspirin?
Am Heart J
(2004)
D. Stejskal et al.
Aspirin resistance measured by cationic propyl gallate platelet aggregometry and recurrent cardiovascular events during 4 years of follow-up
Eur J Intern Med
(2006)
R.S. Poston et al.
Endothelial injury and acquired aspirin resistance as promoters of regional thrombin formation and early vein graft failure after coronary artery bypass grafting
J Thorac Cardiovasc Surg
(2006)
W.H. Chen et al.
Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment
J Am Coll Cardiol
(2004)

E.I. Lev et al.

Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance

J Am Coll Cardiol

(2006)

W.M. Samara et al.

The difference between clopidogrel responsiveness and posttreatment platelet reactivity

Thromb Res

(2005)

P.A. Gurbel et al.

Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE Post-Stenting study

J Am Coll Cardiol

(2005)

T. Cuisset et al.

High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome

J Thromb Haemost

(2006)

T. Cuisset et al.

Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting

J Am Coll Cardiol

(2006)

W. Hochholzer et al.

Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective stent placement

J Am Coll Cardiol

(2006)

K.P. Bliden et al.

Increased risk in patients with thigh platelet aggregation on chronic clopidogrel therapy undergoing PCI: is the current antiplatelet therapy adequate?

J Am Coll Cardiol

(2007)

L. Bonello et al.

Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events

J Thromb Haemost

(2007)

D.J. Angiolillo et al.

Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease

J Am Coll Cardiol

(2007)

N. Ajzenberg et al.

Enhanced shear-induced platelet aggregation in patients who experience subacute stent thrombosis: a case-control study

J Am Coll Cardiol

(2005)

P. Buonamici et al.

Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis

J Am Coll Cardiol

(2007)

D.J. Angiolillo et al.

Clopidogrel-statin interaction: myth or reality?

J Am Coll Cardiol

(2007)

C. Patrono et al.

Platelet-active drugs: the relationships among dose, effectiveness, and side effects

Chest

(2001)

J. Hirsh et al.

Aspirin and other platelet-active drugs: the relationship between dose, effectiveness, and side effects

Chest

(1992)

G. Montalescot et al.

A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial

J Am Coll Cardiol

(2006)

P. Fontana et al.

Biological effect of increased maintenance dose of clopidogrel in cardiovascular outpatients and influence of the cytochrome P450 2C19*2 allele on clopidogrel responsiveness

Thromb Res

(2008)

D.J. Angiolillo et al.

Functional effects of high clopidogrel maintenance dosing in patients with inadequate platelet inhibition on standard dose treatment

Am J Cardiol

(2008)

S.W. Lee et al.

Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis

J Am Coll Cardiol

(2005)

S.W. Lee et al.

Comparison of triple versus dual antiplatelet therapy after drug-eluting stent implantation (from the DECLARE-Long trial)

Am J Cardiol

(2007)

J.C. Smith et al.

ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention)

J Am Coll Cardiol

(2006)

J.L. Anderson et al.

ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: executive summary

Circulation

(2007)

A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE)

Lancet

(1996)

Cited by (143)

Moving from dual antiplatelet therapy to monotherapy based on P2Y<inf>12</inf> receptor blockade-why it could be a novel paradigm?
2021, Dual Antiplatelet Therapy for Coronary and Peripheral Arterial Disease
Pivotal clinical trials conducted in the bare metal stent and first-generation drug-eluting stent (DES) eras established the superiority of dual antiplatelet therapy (DAPT) over aspirin monotherapy in preventing ischemic events. Nonetheless, recent advances in stent technology improved the safety profile of these devices, lowered the risk of stent thrombosis, and reduced the need for prolonged DAPT. Furthermore, several studies have shown that the bleeding associated with prolonged DAPT confers an increase in mortality following percutaneous coronary intervention (PCI). Hence, DAPT strategies that minimize the bleeding risk and conserve the ischemic protection became an utmost need. While several studies have shown that short DAPT durations followed by aspirin monotherapy may be safe and feasible in relatively low-risk patients, extrapolation to higher risk patients remains uncertain. Even though aspirin has been the most widely used antiplatelet drug for many decades, recent evidence suggests potential benefits with the use of P2Y₁₂ inhibitor monotherapy after a shortened DAPT duration in patients undergoing percutaneous coronary intervention with current-generation DESs. This concept is even being taken one step further as P2Y₁₂ inhibitor monotherapy after PCI is currently being investigated in selected patients.
Anti-aggregant effect of butanolic extract of Rubia tinctorum L on platelets in vitro and ex vivo
2019, Journal of Ethnopharmacology
Assessment of Platelet REACtivity After Transcatheter Aortic Valve Replacement: The REAC-TAVI Trial
2019, JACC: Cardiovascular Interventions
The REAC-TAVI (Assessment of platelet REACtivity after Transcatheter Aortic Valve Implantation) trial enrolled patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) pre-treated with aspirin + clopidogrel, aimed to compare the efficacy of clopidogrel and ticagrelor in suppressing high platelet reactivity (HPR) after TAVI.
Current recommendations support short-term use of aspirin + clopidogrel for patients with severe AS undergoing TAVR despite the lack of compelling evidence.
This was a prospective, randomized, multicenter investigation. Platelet reactivity was measured at 6 different time points with the VerifyNow assay (Accriva Diagnostics, San Diego, California). HPR was defined as (P2Y₁₂ reaction units (PRU) ≥208. Patients with HPR before TAVR were randomized to either aspirin + ticagrelor or aspirin + clopidogrel for 3 months. Patients without HPR continued with aspirin + clopidogrel (registry cohort). The primary endpoint was non-HPR status (PRU <208) in ≥70% of patients treated with ticagrelor at 90 days post-TAVR.
A total of 68 patients were included. Of these, 48 (71%) had HPR (PRU 273 ± 09) and were randomized to aspirin + ticagrelor (n = 24, PRU 277 ± 08) or continued with aspirin + clopidogrel (n = 24, PRU 269 ± 49). The remaining 20 patients (29%) without HPR (PRU 133 ± 12) were included in the registry. Overall, platelet reactivity across all the study time points after TAVR was lower in patients randomized to ticagrelor compared with those treated with clopidogrel, including those enrolled in the registry (p < 0.001). The primary endpoint was achieved in 100% of patients with ticagrelor compared with 21% with clopidogrel (p < 0.001). Interestingly, 33% of clopidogrel responder patients at baseline developed HPR status during the first month after TAVR.
HPR to clopidogrel is present in a considerable number of patients with AS undergoing TAVR. Ticagrelor achieves a better and faster effect, providing sustained suppression of HPR to these patients. (Platelet Reactivity After TAVI: A Multicenter Pilot Study [REAC-TAVI]; NCT02224066)
Low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes: Benefit or risk?
2018, Diabetes and Metabolism
Primary prevention aims to avert the onset of cardiovascular disease (CVD) by targeting its natural causes and risk factors; secondary prevention includes strategies and therapies that address preclinical or clinical evidence of CVD progression. The value of aspirin for primary CVD prevention is controversial because of increased bleeding, which may offset the overall modest benefits in patients with no overt CVD. In contrast, the benefits of aspirin for secondary prevention have been repeatedly and convincingly demonstrated to outweigh the risk of bleeding. Diabetes mellitus is a strong risk factor for cardiovascular events, and has been associated with an increased risk of both first and recurrent atherothrombotic events. Therefore, prevention of CVD, the major cause of mortality in patients with diabetes, is one of the most important therapeutic goals. Although the benefit of low-dose aspirin for secondary prevention of CVD is well established, its role for primary prevention remains inconclusive and controversial in diabetes patients. The benefit of aspirin for patients with CVD clearly exceeds the risk of bleeding, and even though a modest benefit has also been demonstrated in primary prevention, the trade-off for aspirin initiation against the increased risk of intracranial and gastrointestinal bleeding is more uncertain. Thus, aspirin for primary CVD prevention should be highly individualized, based on a benefit–risk ratio assessment for the given patient. In conclusion, the mere presence of diabetes is apparently not enough for aspirin to confer a benefit that clearly outweighs the risk of bleeding, and further evidence to the contrary is now needed.
The Role of Cilostazol, a Phosphodiesterase-3 Inhibitor, in the Development of Atherosclerosis and Vascular Biology: A Review with Meta-Analysis
2024, International Journal of Molecular Sciences
Using the PEAR1 Polymorphisms Rs12041331 and Rs2768759 as Potential Predictive Markers of 90-Day Bleeding Events in the Context of Minor Strokes and Transient Ischemic Attack
2023, Brain Sciences

View all citing articles on Scopus

: Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

View full text

Variability in Responsiveness to Oral Antiplatelet Therapy

Section snippets

Definitions

Aspirin

Conclusion

Author Disclosures

J Am Coll Cardiol

Thromb Res

J Am Coll Cardiol

J Am Coll Cardiol

J Thromb Haemost

Thromb Res

Am Heart J

Eur J Intern Med

J Thorac Cardiovasc Surg

J Am Coll Cardiol

J Am Coll Cardiol

Thromb Res

J Am Coll Cardiol

J Thromb Haemost

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Thromb Haemost

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Chest

Chest

J Am Coll Cardiol

Thromb Res

Am J Cardiol

J Am Coll Cardiol

Am J Cardiol

ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention)

J Am Coll Cardiol

ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: executive summary

Circulation

A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE)

Lancet