Clopidogrel resistance

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Editors-in-Chief: C. Michael Gibson, M.S., M.D. [1]; Dominick Angiolillo, M.D. [2]; Gabriel Steg, M.D.[3], Tabassome Simon, M.D. [4] and Paul Gurbel, M.D. [5]

Associate Editors-in-Chief: Davide Capodanno, M.D. [6]

Assistant Editor-in-Chief: Leah Biller


Synonyms and related keywords: Clopidogrel non-responders, clopidogrel hyporesponders, clopidogrel non-responsiveness, clopidogrel hyporesponsiveness, clopidogrel failure

Overview

Administration of the same dose of a drug to all patients has the advantages of simplicity and ease of use. However, data regarding the variability in platelet inhibition across patients highlights the potential importance of tailoring the antiplatelet or dose of an antiplatelet to the pharmacodynamic response of the patient. Patients who do not achieve adequate inhibition in response to a dose of clopidogrel are variably termed “Clopidogrel non-responders” or “Clopidogrel hyporesponders”. A recent European Society of Cardiology working group has suggested the term "elevated platelet reactivity despite treatment".[1]

This chapter reviews the underlying etiology and clinical relevance of clopidogrel non-responsiveness.

Definitions of Clopidogrel Non Responsiveness

There are multiple definitions of clopidogrel non-responsiveness [2]

  1. Gurbel et al: Change in inhibition of platelet aggregation (IPA) of < 10% using light transmittance aggregometry (LTA)[3]
  2. Angiolillo et al: IPA < 40% by LTA [4]
  3. Lau et al: Platelet aggregation >= to 70% by LTA [5]

It should also be noted that the degree of non-responsiveness will also vary depending upon the timing following clopidogrel administration that responsiveness is tested. For instance, Gurbel et al have shown that using the same assay and the same definition, at 2 hours following clopidogrel administration, the rate of non-responsiveness was 60%; by one day the number was 33%, and by one month the number was 15%. Thus, non-responsiveness may vary depending upon the degree of activation of the platelets themselves. As the platelets become less activated following an acute coronary syndrome episode, the rate of non-responsiveness may be lower. This variability in platelet activation and variability in non-responsiveness raises important questions regarding the potential differences in the optimal acute dose and the optimal chronic dose of clopidogrel and other thienopyridines.

Incidence of Clopidogrel Resistance

The incidence of clopidogrel resistance varies significantly from 5% to 44%. The incidence varies depending upon

  1. The definition of clopidogrel resistance
  2. The timing of assessing clopidogrel resistance in relation to an acute coronary syndrome episode
  3. There may be circadian rhythm to platelet aggregation



Clopidogrel Resistance: World Experience
(Courtesy of Paul Gurbel MD)
Investigators n Patients Clopidogrel Dose (mg Load) Resistance
Jaremo et al. [6] 18 PCI 300 28%
Gurbel et al.[3] 92 PCI 300 31%
Muller et al. [7] 105 PCI 600 5-11%
Mobley et al.[8] 50 PCI 300 30%
Lepantalo et al.[9] 50 PCI 300 40%
Angiolillo et al.[4] 48 PCI 300 44%
Matetzky et al.[10] 60 PCI 300 25%
Dziewierz et al.[11] 31 Stable angina 300 23%
Gurbel et al.[12] 190 PCI 300/600 8-32%
Lev et al.[13] 150 PCI 300 24%
Total 794 5-44%



Association of Clopidogrel Non-Responsiveness with Adverse Clinical Outcomes

There are a large number of studies associating clopidogrel non-responsiveness with adverse outcomes:

Studies Linking Ex-Vivo Platelet Function to Clinical Events
(Courtesy of Paul Gurbel MD)
Study Results Clinical Relevance
Barragan et al. [14] ↑ P2Y12 reactivity ratio (VASP-P levels) Stent Thrombosis
Ajzenberg et al.[15] ↑ Shear- Induced platelet aggregation Stent Thrombosis
Gurbel et al.

(CREST study)[16]

↑ADP- induced aggregation

↑Stimulated GPIIb/IIIa expression

Stent Thrombosis
Matetzky et al.[10] ↑ ­ ADP-Induced platelet aggregation Recurrent Cardiac Events (4th quartile)
Gurbel et al.

(CLEAR PLATELETS[17] and CLEAR PLATELETS Ib[18])

↑ Periprocedural platelet aggregation Myonecrosis and Inflammation Marker Release
Bliden et al.[19] ↑ Platelet aggregation (pre-PCI) on chronic clopidogrel 1 yr Post-PCI Events
Cuisset et al.[20] ↑ Platelet aggregation 30-day Post-PCI events
Lev et al.[13] Clopidogrel/Aspirin resistant patients Post-PCI Myonecrosis
Cuisset et al.[21] ↑ Platelet aggregation 30-day Post-PCI events, 600mg - less events
Hochholzer et al.[22] ↑ Platelet aggregation (Upper quartile) 30 day MACE

Despite these associations of clopidogrel hyporesponsiveness with adverse outcomes, there is no large scale data suggesting that acting upon test results and modifying therapy based upon test results is associated with improved outcomes. It is important to ascertain if the patient has been compliant with the medication before declaring that the patient is a clopidogrel non-responder.

Is there a Threshold Effect to Efficacy or are Clinical Outcomes Improved with Higher and Higher Doses (a Continuous Relationship to Clinical Outcomes)

One unresolved question is whether there is a “threshold effect” whereby clinical outcomes are not further improved above a certain level of platelet inhibition, or alternatively whether clinical outcomes are further improved with higher and higher doses in which case there is a “continuous variable” relationship between platelet inhibition and clinical outcomes. Data supporting a potential threshold effect comes from Gurbel et al. [23] [24]When data regarding the relationship between stent thrombosis and clinical outcomes was plotted as a cumulative distribution function rather than a bell curve, it was noted that stent thrombosis was infrequent above 40-50% inhibition.

Mechanisms Underlying Clopidogrel Resistance

There are multpiple mechanisms underlying clopidogrel resistance: [25]

Clinical Factors

  • Poor patient compliance
  • Under-dosing: Some patients may alter the dosing to take the drug every other day
  • Poor absorption
  • The presence of an acute coronary syndrome and increased platelet activation
  • Co-morbidities such as diabetes mellitus that is known to be assoicated with heightened platelet activation [26]
  • Elevated body mass index
  • Elevated platelet count

Cellular Factors

  • Accelerated platelet turnover
  • Reduced CYP3A metabolic activity
  • Increased ADP exposure
  • Up-regulation of the P2Y12 pathway
  • Up-regulation of the P2Y1 pathway
  • Up-regulation of the P2Y–independent pathways (collagen, epinephrine, thomboxane A2, thrombin)

Genetic Basis

Clopidogrel is a pro-drug. When it appears in the bloodstream following absorption, it is not in the active form. This inactive metabolite or pro-drug must circulate to the liver to be metabolized and converted to the active metabolite (there appear to be 4 active isomers). Genetic polymorphisms that have been related to variability in clopidogrel metabolism include:

  • Polymorphisms of CYP
  • Polymorphisms of GPIa
  • Polymorphisms of P2Y12
  • Polymorphisms of GPIIIa

Variability in the function of the CYP 2C19 allele has been postulated to be related to the ability to metabolize clopidogrel. [27]

The three individual alleles and their relative ability to metabolize clopidogrel are as follows:

  • *17 hypermetabolizer allele
  • *1 normal metabolizer allele
  • *2 poor metabolizer allele, genetic functional variant 681 G>A

Based upon the combinations (pairs) of these three alleles, four types of metabolizers have been identified based upon the ability of the patients to generate active metabolite and pharmacodynamics:

  • Ultra-metabolizers (UM): (30% of patients)
*1 / *17 allele
*17 / *17 allele
  • Extensive metabolizers (EM): (36% of patients)
*1 / *1 allele
  • Intermediate metabolizers (IM): (29% of patients)
*1 / *2 allele
  • Poor metabolizers (PM): (5% of patients)
*2 / *2 allele

It should be noted that the active metabolites of clopidogrel and prasugrel are equally potent, [28] and that differences in pharmacodynamic and clinical outcomes are due to differences in the generation of active metabolite rather than potency of the active metabolite. Carriers of the allele (those patients with a least one copy of the *2 allele) had a higher 450 day event rate (12.1%) versus those patients with no copies of the allele (an 8.0% event rate, HR 1.53, p=0.014).

[29]

In a similar but slightly different finding, Simon et al have demonstrated that it was only those patients who carried two copies of the *2 allele (*2 / *2) and not just one copy (*1 / *2) who had a higher risk of adverse events (death, MI, stroke).[30]

In a third study, Collet et al demonstrated that among 259 young survivors of a first myocardial infarction who were treated with chronic clopidogrel, death, MI, and urgent revascularization occurred more often in carriers (*2 / *2 or *1 / *2) than in non-carriers (*1 / *1)(HR = 3.69 [95% CI 1.69-8.05], p=0.0005), as did stent thrombosis (HR = 6.02 [1.81-20.04], p=0.0009). [29] These findings were true in a multivariate model of potential confounders.

Although both prasugrel and clopidogrel require cytochrome P450 (CYP) enzymes for activation, a substudy of 1,466 patients enrolled in the TRITON-TIMI 38 study found that CYP variations did not affect:

  • Levels of prasugrel's active metabolite
  • Prasugrel's inhibition of platelet aggregation, or
  • Clinical cardiovascular event rates in persons treated with prasugrel [31]

Inhibition of Metabolism by Co-Ingestion of Other Drugs

Statins

Statins have been found to interfere with the generation of clopidogrel’s active metabolite. [5] [32] [33] One statin that does not interfere with clopidogrel metabolism is pravastatin. Non-randomized data from clinical trials have not confirmed a higher risk of adverse outcomes among patients co-ingesting statins in addition to clopidogrel versus those treated with clopidogrel alone. It is possible that the higher loading dose of 600 mg used in current clinical pracitce overcomes this interference.

Omeprazole and Proton Pump Inhibitors

Omeprazole induces a conformational change in the CYP enzyme system and may alter the metabolism of clopidogrel. In a double-blind placebo-controlled trial, stented patients treated with clopidogrel were randomized to treatment with either omeprazole (20 mg/day) or placebo. Following 7 days of treatment, the residual platelet aggregation was significantly hgiher in the omeprazole group (p < 0.0001). [34] The clinical impact of this finding and whether this inhibition can be overcome with a higher dose of clopidogrel is not clear.

There have been non-randomized retrospective analyses of the clinical outcomes among patients treated with omeprazole vs no omeprazole. [35] [36] [37] However, these non-randomized analyses are very confounded by the fact that patients treated with omeprazole are more often diabetics, had undergone CABG, had a history of cerebrovascular disease and peripheral arterial disease, had previously been on clopidogrel, and more often had renal disease. [36] Indeed, it is notable that among patients not treated with clopidogrel, treatment with a proton pump inhibitor (PPI) was associated with a 1.6 fold higher event rate in CREDO despite multivariate adjustment for confounders [38] This points to the potential role of unidentified confounders in the association of PPIs with clinical outcomes.

Pantoprazole and esomeprazole are not associated with a phramcodynamic or clinical effect in non-randomized analyses [39]

Gold Standard Tests of Clopidogrel Responsiveness

Light transmittance aggregometry (LTA): This is a laboratory based study that evaluates the aggregation or clumping of platelets in response to aggregating stimuli. For historical reasons, it is broadly accepted as the gold standard in-vitro test of platelet function. The most immediate information for basic diagnostic considerations is obtained by using agents such as adenosine diphosphate (ADP), epinephrine and collagen. Both ADP and epinephrine are contained in storages organelles within the platelets and are released during formation of the primary hemostatic plug thus enhancing further platelet aggregation. Conversely, collagen is found in the supporting connective tissue of the vessels and is considered to be the first proagulant factor that the platelet encounters following vessel’s injury. Other reagents such as arachidonic acid, ristocetin, serotonin, calcium and Factor VIII are also used to study platelet response for more specific purposes. Different aggregating agents stimulate alternative pathways of activation in the platelets and different concentrations of the same agonist are often used to elicit dose-dependent response.

Aside from the detection and diagnosis of acquired or congenital qualitative platelet defects, LTA has an important role to reveal patterns of GPIIb/IIIa-dependent platelet-to-platelet aggregation in response to specific agonists (e.g. arachidonic acid to assess aspirin response; ADP to test thienopyridines response). The chambers of a typical aggregometer are designed so that a beam of infrared light shines through two cuvettes. One of these contains the sample, namely a suspension of platelet rich plasma (PRP) obtained by a relatively low centrifugal force centrifugation. The other cuvette contains a reference sample of platelet poor plasma (PPP) obtained by centrifuging the blood sample at a relatively high force. Silicon photodiodes detect the light able to pass through the samples, with PRP arbitrarily considered to be 0% light transmission (or 0% aggregation) and PPP considered to be 100% light transmission (or 100% aggregation). The optical aggregation output is proportional to the continuously measured difference in light transmission between the PRP and PPP samples. Following the addition of a stimulus to the cuvette containing PRP, changes in light transmission occur as a consequence of platelet response and are recorded over time. In fact, the larger size of activated platelet allows less light to pass through the PRP: this is recorded as less light transmission relative to the PPP. Conversely, when platelets form aggregates, more light is able to pass through the test sample. Aggregation recordings are curves characterized by several features:

  1. Shape changes;
  2. A first wave of aggregation that may reverse (primary aggregation);
  3. A second wave of aggregation that occurs when the granule contents become the stimulus and lead to further aggregation;
  4. Maximum amount of change in light transmission caused by the stimulus (percent aggregation);
  5. Late amount of aggregation recorded after a certain timeframe;
  6. Slope of the aggregation, or percentage of aggregation per minute.

Designed as a measure of defective platelet function, the main disadvantage of LTA is that the test is time-consuming, expensive, weakly standardized and need to be performed in specialized lab by specialized personnel. Additionally, several procedural variables may account for poor reproducibility.


Vasodilator-Stimulated Phosphoprotein (VASP) The phosphorylation (P) of vasodilator-stimulated phosphoprotein (VASP) is a test based on flow cytometry which is very specific to the P2Y12 signaling pathway. It is commercially available as a kit marketed as PLT VASP/P2Y12 (BioCytex, Marseilles, France). VASP is an intracellular platelet protein that is not phosphorilated at baseline. VASP-P is mediated by the cAMP cascade, which is enhanced by prostaglandin E1 (PGE1) and inhibited by the link between ADP and P2Y12 receptors. Therefore, VASP-P is a marker of P2Y12 receptor inhibition, whereas its non-phosphorylated counterpart correlates with the non-inhibited form of the P2Y12 receptor. By using the PLT VASP/P2Y12 kit, the effect of clopidogrel can be demonstrated by the persistence of VASP in its phosphorylated state (VASP-P) induced by PGE1 despite the simultaneous addition of ADP. More in detail, the blood sample is first incubated with PGE1 alone or PGE1 + ADP. Subsequently, after a cellular permeabilization, VASP-P is labeled by indirect no wash immunofluorescence using a specific monoclonal antibody. The two tested conditions are then evaluated by means of dual color flow cytometry analysis. Final results are usually expressed in terms of platelet reactivity index (PRI), which is calculated using corrected mean fluorescence intensities (MFIc) in the presence of PGE1 alone or PGE1 and ADP simultaneously, according to the following formula:

PRI = [(MFIcPGE1 - MFIc PGE1+ADP)/ MFIcPGE1]x100

Assessment of VASP-P requires a low sample volume and is performed on whole blood. Another advantage is the opportunity to ship blood samples at room temperature to a central core laboratory. Ultimately, it correlates well with light transmittance aggregometry and VerifyNow technologies. However, sample preparation is time consuming and the reliability of the results is highly dependent from the presence of a skilled technician. Also, a flow cytometer is required.

Point of Care Devices

VerifyNow

The VerifyNow system (Accumetrics, San Diego, Ca, USA; [7]) is a bedside test that allows for monitoring of the efficacy of thienopyridines, aspirin, and glycoprotein IIbIIIa inhibitors. Formerly known as the Ultegra rapid platelet function analyzer, the VerifyNow system is a turbidimetric based optical detection system which measures platelet induced aggregation as an increase in light transmittance. This system is a point-of-care and consists of an instrument, a disposable assay device and controls. The assay device contains a lyophilized preparation of human fibrinogen-coated beads, platelet agonist, preservative and buffer. Three assays are currently available, which differ according to the platelet agonist contained in the mixing chamber:

Assay device Platelet agonist Drug(s) of interest
VerifyNow GP IIb/IIIa Thombin receptor-activating peptide (TRAP) [iso-TRAP] Abciximab, eptifibatide, tirofiban
VerifyNow Aspirin Arachidonic acid Aspirin
VerifyNow P2Y12 Adenosine diphosphate Clopidogrel, prasugrel

After activation, the GP IIb/IIIa receptors on platelets will bind to the fibrinogen-coated microbeads and cross link to other microbeads resulting in a clearing of the beads and platelets within the detection well. The instrument uses light transmittance to measure the rate at which this clearing occurs. The main advantage of this test is that the patient sample is a low sample volume of 3.2% citrated whole blood, which is automatically dispensed from the blood collection tube into the assay device by the instrument, with no blood handling required by the user. Another advantage is that the instrument provides the results in minutes.

Platelet Function Analyzer (PFA-100)

The Platelet Function Analyzer-100(PFA-100, Siemens Healthcare Diagnostics, Inc., Deerfield, IL) is a test based on the principle of shear-induced aggregation. Although it is not a COX-1specific assay, it allows monitoring of aspirin effects by providing a quantitative measure of platelet-related hemostasis in anticoagulated whole blood.

The system comprises a microprocessor-controlled tool and a disposable test cartridge containing a biologically active nitrocellulose membrane. To perform the test, 0.8 ml of citrated whole blood is transferred into the reservoir of the cartridge within 4 h of blood sampling. After warming the anticoagulated blood to 37 °C, the instrument aspirates a blood sample under vacuum from the reservoir through a 200 μm diameter stainless steel capillary and a 150 μm aperture cut into the membrane, which is coated with collagen and epinephrine (CEPI) or collagen and ADP (CADP).

The presence of these biochemical stimuli, and the high shear rates of 5000–6000 s−1 generated under the standardized flow conditions, result in platelet aggregate forms that block the aperture of the membrane. The time required to obtain full occlusion of the aperture is reported as the closure time (CT).

Prolonged CT with only the CEPI cartridge is observed with mild inherited platelet function disorders and with aspirin ingestion, while prolonged CTs with both CEPI and CADP cartridges are associated with more severe inherited platelet dysfunctions. An advantage of the PFA-100 application as a platelet function assay is that it is a rapid, accurate, simple, and reproducible test that requires only a small volume of blood. It cannot be considered as a point of care as minimal pipetting is required to use this test. One of its major disadvantages is that it is poorly sensitive in detecting effects of thienopyridines and therefore should not be used for this purpose. Newer generation assays are currently under development to assess thienopyridine effects.

Clinical Utility of Point of Care Testing Versus Genetic Testing

In so far as point of care testing results are more readily available, these may be a more suitable choice for use in clinical practice as compared to genetic testing. Furthermore, there may be mechanisms other than variability in metabolism that account for differences in response to clopidogrel which are assessed by point of care tests and not by genetic testing.

Strategies to Overcome Clopidogrel Non-Responsiveness

Due to the severity of its consequences, how to manage suboptimal clopidogrel response is a major clinical problem. The most important aspect is to guarantee patient compliance. The second aspect to evaluate is any potential drug-drug interactions. Studies are currently ongoing with the goal to better elucidate the interaction between clopidogrel and PPIs. The following strategies can be proposed to overcome inadequate clopidogrel responsiveness:

  1. increase clopidogrel dosing
  2. triple antiplatelet therapy
  3. using a different P2Y12 antiplatelet agent.

Increase clopidogrel dosing

Several studies have shown that a high clopidogrel loading dose regimen (≥ 600 mg) achieves more potent platelet inhibition when compared to a standard 300 mg loading dose[40][41][42][43]. This has also been associated with better clinical outcomes in patients undergoing PCI [44][45][21]. ]. A high maintenance dose (150 mg/day) dose regimen of clopidogrel has found to be associated with enhanced platelet inhibition compared to the currently recommended 75 mg/day [46][47][48], in particular in patients with high posttreatment platelet reactivity while on 75mg [46]. The OPTIMUS (Optimizing antiPlatelet Therapy In diabetes MellitUS) study selectively evaluated type 2 diabetes mellitus patients with high platelet reactivity while on 75mg clopidogrel and showed that 150 mg clopidogrel maintenance dose induced greater platelet inhibition compared with 75 mg dosing [47]. In a recently published observational study[49], Lemesle et al. showed better clinical outcomes in PCI patients treated with 600-mg loading dose followed by a high maintenance dose (150 mg/day) without a significant increase in bleeding events. The CURRENT OASIS 7 TRIAL (Clopidogrel optimal loading dose Usage to Reduce recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS; NCT00335452) showed that doubling the loading and maintenance dose of clopidogrel is associated with improved outcomes in cardiovascular mortality, MI and stroke at 30 days in patients undergoing PCI[50]. This trial enrolled 25087 patients which were then divided into PCI and no PCI cohots. Patients were then also randomized in 2X2 factorial distribution to double dose clopidogrel and standard dose clopidogrel, as well as low dose aspirin(75=100mg) and high dose aspirin(300-325mg). Patients were followed at day 30 for primary end points which were cardiovascular death, MI and stroke and safety outcome which was major bleeding at day 30. Results of this study showed that among the PCI patients, the risk of stent thrombosis was reduced by 30% and the risk of MI was reduced by 22% in the group that received the high dose Clopidogrel compared to the group that received the standard dose. Thsi was statistically significant. The high dose group had more major bleeding, but there was no increase in intracerebral or fatal bleeds. No benefit of the higher dose was found in the group of patients who did not have PCI. Several currently ongoing clinical trials are evaluating safety and/or efficacy of a tailored treatment with high clopidogrel maintenance dose in patients with inadequate response to clopidogrel. These include GRAVITAS (Gauging Responsiveness with a VerifyNow Assay: Impact on Thrombosis And Safety; NCT00645918), ARCTIC (Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and Interruption Versus Continuation of Double Antiplatelet Therapy; NCT00827411), and DANTE (Dual Antiplatelet Therapy Tailored on the Extent of Platelet Inhibition, NCT00774475).

Triple Antiplatelet Therapy

In the acute phase of therapy, adding a glycoprotein IIb/IIIa inhibitor may be considered as this leads to more potent platelet inhibition. Recently, Cuisset et al. showed that the rate of cardiovascular events at 1 month was significantly lower when abciximab was added compared to conventional dual antiplatelet therapy in clopidogrel nonresponders (n=149) referred for elective PCI [51]. The 3T/2R trial showed that better clinical outcomes in aspirin or clopidogrel non responders undergoing elective PCI treated with tirofiban[52]. In the maintenance phase of therapy, triple antiplatelet therapy achieved with the adjunctive use of cilostazol, a phosphodiesterase III inhibitor, is another option. The OPTIMUS-2 study showed that in a diabetic population cilostazol markedly enhances P2Y12 inhibition[53]This may explain the reduced stent thrombosis rates observed with this triple antiplatelet treatment regimen compared to standard dual antiplatelet therapy and reduced target lesion revascularization rates in patients treated with both bare-metal and drug-eluting stents with greater effects among diabetics[54][55][56][57][58]. All the above strategies have not been associated with increased bleeding.

Using a different P2Y12 receptor antagonists

Although clopidogrel has largely replace ticlopidine due to its better safety profile, it has been shown that ticlopidine may improve platelet inhibition among suboptimal responders[59]. However, the future likely resides with the use of newer agents. New [[P2Y12 receptor antagonist]]s are currently under different phases of clinical development (e.g. prasugrel, cangrelor, ticagrelor, elinogrel)[60][61][62]. These agents have more potent and less variable inhibitory effects than clopidogrel. Prasugrel, a third generation thienopyridine, has already completed its phase III investigation and received approval for clinical use in Europe [63]. If prasugrel yields better clinical outcomes without increasing bleeding hazards in clopidogrel non-responders is under investigation.

References

  1. ↑ Kuliczkowski W, Witkowski A, Polonski L; et al. (2009). "Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology". Eur. Heart J. 30 (4): 426–35. doi:10.1093/eurheartj/ehn562. PMID 19174428. Unknown parameter |month= ignored (help)
  2. ↑ Barsky AA, Arora RR (2006). "Clopidogrel resistance: myth or reality?". J. Cardiovasc. Pharmacol. Ther. 11 (1): 47–53. PMID 16703219. Unknown parameter |month= ignored (help)
  3. ↑ 3.0 3.1 Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM (2003). "Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity". Circulation. 107 (23): 2908–13. doi:10.1161/01.CIR.0000072771.11429.83. PMID 12796140. Unknown parameter |month= ignored (help)
  4. ↑ 4.0 4.1 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E; et al. (2005). "Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting". Thromb. Res. 115 (1–2): 101–8. doi:10.1016/j.thromres.2004.07.007. PMID 15567460.
  5. ↑ 5.0 5.1 Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER (2003). "Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction". Circulation. 107 (1): 32–7. PMID 12515739. Retrieved 2009-04-28. Unknown parameter |month= ignored (help)
  6. ↑ Järemo P, Lindahl TL, Fransson SG, Richter A (2002). "Individual variations of platelet inhibition after loading doses of clopidogrel". J. Intern. Med. 252 (3): 233–8. PMID 12270003. Unknown parameter |month= ignored (help)
  7. ↑ Müller I, Besta F, Schulz C, Massberg S, Schönig A, Gawaz M (2003). "Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement". Thromb. Haemost. 89 (5): 783–7. doi:10.1267/THRO03050783. PMID 12719773. Unknown parameter |month= ignored (help)
  8. ↑ Mobley JE, Bresee SJ, Wortham DC, Craft RM, Snider CC, Carroll RC (2004). "Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization". Am. J. Cardiol. 93 (4): 456–8. doi:10.1016/j.amjcard.2003.10.042. PMID 14969622. Unknown parameter |month= ignored (help)
  9. ↑ Lepäntalo A, Virtanen KS, Heikkilä J, Wartiovaara U, Lassila R (2004). "Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions". Eur. Heart J. 25 (6): 476–83. doi:10.1016/j.ehj.2003.12.016. PMID 15039127. Unknown parameter |month= ignored (help)
  10. ↑ 10.0 10.1 Matetzky S, Shenkman B, Guetta V; et al. (2004). "Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction". Circulation. 109 (25): 3171–5. doi:10.1161/01.CIR.0000130846.46168.03. PMID 15184279. Unknown parameter |month= ignored (help)
  11. ↑ Dziewierz A, Dudek D, Heba G, Rakowski T, Mielecki W, Dubiel JS (2005). "Inter-individual variability in response to clopidogrel in patients with coronary artery disease". Kardiol Pol. 62 (2): 108–17, discussion 118. PMID 15815794. Unknown parameter |month= ignored (help)
  12. ↑ Gurbel PA, Bliden KP, Hayes KM, Yoho JA, Herzog WR, Tantry US (2005). "The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting". J. Am. Coll. Cardiol. 45 (9): 1392–6. doi:10.1016/j.jacc.2005.01.030. PMID 15862408. Unknown parameter |month= ignored (help)
  13. ↑ 13.0 13.1 Lev EI, Patel RT, Maresh KJ; et al. (2006). "Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance". J. Am. Coll. Cardiol. 47 (1): 27–33. doi:10.1016/j.jacc.2005.08.058. PMID 16386660. Unknown parameter |month= ignored (help)
  14. ↑ Barragan P, Bouvier JL, Roquebert PO; et al. (2003). "Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation". Catheter Cardiovasc Interv. 59 (3): 295–302. doi:10.1002/ccd.10497. PMID 12822144. Unknown parameter |month= ignored (help)
  15. ↑ Ajzenberg N, Aubry P, Huisse MG; et al. (2005). "Enhanced shear-induced platelet aggregation in patients who experience subacute stent thrombosis: a case-control study". J. Am. Coll. Cardiol. 45 (11): 1753–6. doi:10.1016/j.jacc.2004.10.079. PMID 15936600. Unknown parameter |month= ignored (help)
  16. ↑ Gurbel PA, Bliden KP, Samara W; et al. (2005). "Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study". J. Am. Coll. Cardiol. 46 (10): 1827–32. doi:10.1016/j.jacc.2005.07.056. PMID 16286166. Unknown parameter |month= ignored (help)
  17. ↑ Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US (2005). "Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study". Circulation. 111 (9): 1153–9. doi:10.1161/01.CIR.0000157138.02645.11. PMID 15738352. Unknown parameter |month= ignored (help)
  18. ↑ Gurbel PA, Bliden KP, Tantry US (2006). "Effect of clopidogrel with and without eptifibatide on tumor necrosis factor-alpha and C-reactive protein release after elective stenting: results from the CLEAR PLATELETS 1b study". J. Am. Coll. Cardiol. 48 (11): 2186–91. doi:10.1016/j.jacc.2005.12.084. PMID 17161243. Unknown parameter |month= ignored (help)
  19. ↑ Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA (2007). "Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?". J. Am. Coll. Cardiol. 49 (6): 657–66. doi:10.1016/j.jacc.2006.10.050. PMID 17291930. Unknown parameter |month= ignored (help)
  20. ↑ Cuisset T, Frere C, Quilici J; et al. (2006). "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. 4 (3): 542–9. doi:10.1111/j.1538-7836.2005.01751.x. PMID 16371119. Unknown parameter |month= ignored (help)
  21. ↑ 21.0 21.1 Cuisset T, Frere C, Quilici J; et al. (2006). "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. 48 (7): 1339–45. doi:10.1016/j.jacc.2006.06.049. PMID 17010792. Unknown parameter |month= ignored (help)
  22. ↑ Hochholzer W, Trenk D, Bestehorn HP; et al. (2006). "Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement". J. Am. Coll. Cardiol. 48 (9): 1742–50. doi:10.1016/j.jacc.2006.06.065. PMID 17084243. Unknown parameter |month= ignored (help)
  23. ↑ Gurbel P, et al. J Am Coll Cardiol. 2005;46(10):1827-1832
  24. ↑ Gurbel P, et al. J Am Coll Cardiol. 2005;46(10):1820-1826
  25. ↑ Angiolillio DJ et al. J Am Coll Cardiol. 2007;49:1505-1516
  26. ↑ Angiolillo DJ et al. Diabetes. 2005;54:2430-2435.
  27. ↑ Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS (2009). "Cytochrome p-450 polymorphisms and response to clopidogrel". The New England Journal of Medicine. 360 (4): 354–62. doi:10.1056/NEJMoa0809171. PMID 19106084. Retrieved 2009-04-28. Unknown parameter |month= ignored (help)
  28. ↑ Sugidachi A et al. J Thromb Haemos. 2007;5:1545-1551
  29. ↑ 29.0 29.1 Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G (2009). "Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study". Lancet. 373 (9660): 309–17. doi:10.1016/S0140-6736(08)61845-0. PMID 19108880. Retrieved 2009-04-28. Unknown parameter |month= ignored (help)
  30. ↑ Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L (2009). "Genetic determinants of response to clopidogrel and cardiovascular events". The New England Journal of Medicine. 360 (4): 363–75. doi:10.1056/NEJMoa0808227. PMID 19106083. Retrieved 2009-04-28. Unknown parameter |month= ignored (help)
  31. ↑ "Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel. Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes -- Mega et al., 10.1161/CIRCULATIONAHA.109.851949 -- Circulation".
  32. ↑ Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DG, Guyer KE, Tait AR, Bates ER (2004). "Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance". Circulation. 109 (2): 166–71. doi:10.1161/01.CIR.0000112378.09325.F9. PMID 14707025. Retrieved 2009-04-28. Unknown parameter |month= ignored (help)
  33. ↑ Lau WC, Carville DG, Bates ER (2004). "Clinical significance of the atorvastatin-clopidogrel drug-drug interaction". Circulation. 110 (6): e66–7, author reply e66–7. doi:10.1161/01.CIR.0000137956.92971.4A. PMID 15302813. Retrieved 2009-04-28. Unknown parameter |month= ignored (help)
  34. ↑ Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J (2008). "Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study". Journal of the American College of Cardiology. 51 (3): 256–60. doi:10.1016/j.jacc.2007.06.064. PMID 18206732. Retrieved 2009-04-28. Unknown parameter |month= ignored (help)
  35. ↑ Aubert RE et al. Circulation. 2008;118:S_815.
  36. ↑ 36.0 36.1 Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS (2009). "Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome". JAMA : the Journal of the American Medical Association. 301 (9): 937–44. doi:10.1001/jama.2009.261. PMID 19258584. Retrieved 2009-04-28. Unknown parameter |month= ignored (help)
  37. ↑ Dunn SP et al. Circulation. 2008;118:S_815
  38. ↑ Dunn SP et al. Circulation. 2008;118:S_815
  39. ↑ Sibbing D et al. Thromb Haemost. 2009;101:714-719
  40. ↑ von Beckerath N, Taubert D, Pogatsa-Murray G, Schömig E, Kastrati A, Schömig A (2005). "Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial". Circulation. 112 (19): 2946–50. doi:10.1161/CIRCULATIONAHA.105.559088. PMID 16260639. Unknown parameter |month= ignored (help)
  41. ↑ Angiolillo DJ, Fernández-Ortiz A, Bernardo E; et al. (2004). "High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability". Eur. Heart J. 25 (21): 1903–10. doi:10.1016/j.ehj.2004.07.036. PMID 15522469. Unknown parameter |month= ignored (help)
  42. ↑ Montalescot G, Sideris G, Meuleman C; et al. (2006). "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. 48 (5): 931–8. doi:10.1016/j.jacc.2006.04.090. PMID 16949482. Unknown parameter |month= ignored (help)
  43. ↑ Gurbel PA, Bliden KP, Hayes KM, Yoho JA, Herzog WR, Tantry US (2005). "The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting". J. Am. Coll. Cardiol. 45 (9): 1392–6. doi:10.1016/j.jacc.2005.01.030. PMID 15862408. Unknown parameter |month= ignored (help)
  44. ↑ Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G (2005). "Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study". Circulation. 111 (16): 2099–106. doi:10.1161/01.CIR.0000161383.06692.D4. PMID 15750189. Unknown parameter |month= ignored (help)
  45. ↑ Bonello L, Lemesle G, De Labriolle A; et al. (2008). "Impact of a 600-mg loading dose of clopidogrel on 30-day outcome in unselected patients undergoing percutaneous coronary intervention". Am. J. Cardiol. 102 (10): 1318–22. doi:10.1016/j.amjcard.2008.07.007. PMID 18993148. Unknown parameter |month= ignored (help)
  46. ↑ 46.0 46.1 Angiolillo DJ, Bernardo E, Palazuelos J; et al. (2008). "Functional impact of high clopidogrel maintenance dosing in patients undergoing elective percutaneous coronary interventions. Results of a randomized study". Thromb. Haemost. 99 (1): 161–8. doi:10.1160/TH07-09-0562. PMID 18217149. Unknown parameter |month= ignored (help)
  47. ↑ 47.0 47.1 Angiolillo DJ, Shoemaker SB, Desai B; et al. (2007). "Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study". Circulation. 115 (6): 708–16. doi:10.1161/CIRCULATIONAHA.106.667741. PMID 17261652. Unknown parameter |month= ignored (help)
  48. ↑ von Beckerath N, Kastrati A, Wieczorek A; et al. (2007). "A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days". Eur. Heart J. 28 (15): 1814–9. doi:10.1093/eurheartj/ehl489. PMID 17272357. Unknown parameter |month= ignored (help)
  49. ↑ Lemesle G, Delhaye C, Sudre A; et al. (2009). "Impact of high loading and maintenance dose of clopidogrel within the first 15 days after percutaneous coronary intervention on patient outcome". Am. Heart J. 157 (2): 375–82. doi:10.1016/j.ahj.2008.09.013. PMID 19185648. Unknown parameter |month= ignored (help)
  50. ↑ Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Fox KA, Granger CB, Jolly S, Rupprecht HJ, Widimsky P, Yusuf S; CURRENT-OASIS 7 Steering Committee. Am Heart J. 2008 Dec;156(6):1080-1088.e1. Epub 2008 Nov 1. PMID: 19033002
  51. ↑ Cuisset T, Frere C, Quilici J, et al. Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders. J Am Coll Cardiol Interv 2008;1:649-53.
  52. ↑ Valgimigli M, Campo G, de Cesare N, et al. Intensifying Platelet Inhibition With Tirofiban in Poor Responders to Aspirin and/orClopidogrel Undergoing Elective Coronary Intervention. Results from the double-blind, prospective, randomized 3T/2R study. Circulation 2009 (in press)
  53. ↑ Angiolillo DJ, Capranzano P, Goto S; et al. (2008). "A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study". Eur. Heart J. 29 (18): 2202–11. doi:10.1093/eurheartj/ehn287. PMID 18567918. Unknown parameter |month= ignored (help)
  54. ↑ Lee SW, Park SW, Hong MK; et al. (2005). "Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis". J. Am. Coll. Cardiol. 46 (10): 1833–7. doi:10.1016/j.jacc.2005.07.048. PMID 16286167. Unknown parameter |month= ignored (help)
  55. ↑ Lee SW, Park SW, Kim YH; et al. (2007). "Comparison of triple versus dual antiplatelet therapy after drug-eluting stent implantation (from the DECLARE-Long trial)". Am. J. Cardiol. 100 (7): 1103–8. doi:10.1016/j.amjcard.2007.05.032. PMID 17884371. Unknown parameter |month= ignored (help)
  56. ↑ Douglas JS, Holmes DR, Kereiakes DJ; et al. (2005). "Coronary stent restenosis in patients treated with cilostazol". Circulation. 112 (18): 2826–32. doi:10.1161/CIRCULATIONAHA.104.530097. PMID 16246948. Unknown parameter |month= ignored (help)
  57. ↑ Biondi-Zoccai GG, Lotrionte M, Anselmino M; et al. (2008). "Systematic review and meta-analysis of randomized clinical trials appraising the impact of cilostazol after percutaneous coronary intervention". Am. Heart J. 155 (6): 1081–9. doi:10.1016/j.ahj.2007.12.024. PMID 18513523. Unknown parameter |month= ignored (help)
  58. ↑ Lee SW, Park SW, Kim YH; et al. (2008). "Drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabetes mellitus the DECLARE-DIABETES Trial (A Randomized Comparison of Triple Antiplatelet Therapy with Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation in Diabetic Patients)". J. Am. Coll. Cardiol. 51 (12): 1181–7. doi:10.1016/j.jacc.2007.11.049. PMID 18355656. Unknown parameter |month= ignored (help)
  59. ↑ Campo G, Valgimigli M, Gemmati D; et al. (2007). "Poor responsiveness to clopidogrel: drug-specific or class-effect mechanism? Evidence from a clopidogrel-to-ticlopidine crossover study". J. Am. Coll. Cardiol. 50 (12): 1132–7. doi:10.1016/j.jacc.2007.04.092. PMID 17868803. Unknown parameter |month= ignored (help)
  60. ↑ Angiolillo DJ, Guzman LA (2008). "Clinical overview of promising nonthienopyridine antiplatelet agents". Am. Heart J. 156 (2 Suppl): S23–8. doi:10.1016/j.ahj.2008.06.006. PMID 18657683. Unknown parameter |month= ignored (help)
  61. ↑ Angiolillo DJ, Bhatt DL, Gurbel PA, Jennings LK (2009). "Advances in antiplatelet therapy: agents in clinical development". Am. J. Cardiol. 103 (3 Suppl): 40A–51A. doi:10.1016/j.amjcard.2008.11.023. PMID 19166712. Unknown parameter |month= ignored (help)
  62. ↑ Angiolillo DJ, Suryadevara S, Capranzano P, Bass TA (2008). "Prasugrel: a novel platelet ADP P2Y12 receptor antagonist. A review on its mechanism of action and clinical development". Expert Opin Pharmacother. 9 (16): 2893–900. doi:10.1517/14656566.9.16.2893. PMID 18937620. Unknown parameter |month= ignored (help)
  63. ↑ Wiviott SD, Braunwald E, McCabe CH; et al. (2007). "Prasugrel versus clopidogrel in patients with acute coronary syndromes". N. Engl. J. Med. 357 (20): 2001–15. doi:10.1056/NEJMoa0706482. PMID 17982182. Unknown parameter |month= ignored (help)


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