Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives.

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes and/or undergoing percutaneous coronary interventions. Clopidogrel, in combination with aspirin, is currently the antiplatelet treatment of choice for prevention of stent thrombosis, and clinical trials have shown that, in high-risk patients, prolonged dual antiplatelet treatment is more effective than aspirin alone in preventing major cardiovascular events. However, despite the use of clopidogrel, a considerable number of patients continue to have cardiovascular events. Numerous in vitro studies have shown that individual responsiveness to clopidogrel is not uniform in all patients and is subject to inter- and intraindividual variability. Notably, there is a growing degree of evidence that recurrence of ischemic complications may be attributed to poor response to clopidogrel. The mechanisms leading to poor clopidogrel effects are not fully elucidated and are likely multifactorial. Although the gold standard definition to assess antiplatelet drug response has not been fully established, there is sufficient evidence to support that persistence of enhanced platelet reactivity despite the use of clopidogrel is a clinically relevant entity. This paper reviews the impact of individual response variability to clopidogrel on clinical outcomes and current and future directions for its management.     

Residual platelet reactivity after aspirin and clopidogrel treatment predicts 2-year major cardiovascular events in patients undergoing percutaneous coronary intervention

Background

Studies on the prognostic significance of residual platelet reactivity despite the use of dual anti-platelet agents are limited and seldom extend beyond 1 year.

Methods

This study enrolled 144 patients treated with standard-dose aspirin and clopidogrel and undergoing percutaneous coronary intervention (PCI). Platelet reactivity was measured by the Platelet Function Analyzer-100 (PFA-100) just before PCI and presented as collagen/epinephrine closure time (CEPI-CT) and collagen/adenosine diphosphate closure time (CADP-CT). Primary endpoint included cardiovascular death, myocardial infarction, and stroke. Secondary endpoint was the primary endpoint plus hospitalization due to unstable angina or urgent target vessel revascularization.

Results

During the 24-month follow-up, 14 patients (9.7%) developed the primary endpoint events and 33 had the secondary endpoints. After controlling possible confounding factors, both CEPI-CT < 193 s and CADP-CT < 95 s were independently predictive of the primary endpoint (hazard ratio = 3.5; 95% confidence interval: 1.04–11.7; p = 0.044 and 5.3; 1.4–20.1; p = 0.015, respectively). Only CADP-CT < 95 s remained significantly predictive of secondary endpoints in the follow-up periods of 0–9 and 9–24 months, during which clopidogrel was mostly discontinued.

Conclusion

This study demonstrates that increased residual platelet reactivity measured by PFA-100 CADP-CT consistently predicts the occurrence of cardiovascular events following PCI throughout the 24-month follow-up period, irrespective of the changes in anti-platelet use.     

Polymorphisms of MDR1, CYP2C19 and P2Y12 genes in Indian population: Effects on clopidogrel response

Aims/objectiveInfluence of genetic variations on the response of clopidogrel, an antiplatelet drug is implicated. In the present study, the prevalence of single nucleotide polymorphisms of MDR1 (C3435T), CYP2C19 [CYP2C19*2 CYP2C19*3, CYP2C19*17] and P2Y₁₂ (i-T744C) in Indian population and their effects on clopidogrel response was analyzed.Methods and resultsTo analyze the prevalence of polymorphisms, 102 healthy individuals were recruited. Clopidogrel response was assessed by ADP induced platelet aggregation in clopidogrel naïve acute myocardial infarction (AMI) patients (n = 26) screened from 100 AMI cases, before loading dose of 300 mg, at 24 h before next dose and 6 days after on 75 mg per day and platelet aggregation inhibition (PAI) was calculated between these time intervals. Genotyping was carried out by PCR-based restriction enzyme digestion method for C3435T of MDR1 and i-T744C of P2Y₁₂, by multiplex PCR for CYP2C19*2 (G681A) and CYP2C19*3 (G636A) and by nested PCR for CYP2C19*17 (C806T). The effect of the above mentioned genetic variations on PAI was analyzed. Variant allele of CYP2C19*3 was not observed while the prevalence of 3435T of MDR1 (0.524), CYP2C19*2 (681A, 0.352); i-744C of P2Y₁₂ (0.088), as well as wild type allele CYP2C19*17 (C806, 0.897) associated with decrease clopidogrel response were observed. Trend toward poor response to clopidogrel was observed at 24 h with the variant genotypes of CYP2C19*2 and i-T744C of P2Y₁₂ as compared to wild type.ConclusionThe present study did show a trend toward impaired response of clopidogrel to inhibit platelet aggregation with variant genotypes of CYP2C19*2 and iT744C of P2Y₁₂ compared to respective wild type genotype at 24 h.     

Study on the predictive ability of emergency CHADS2 score and CHA2DS2-VASc score for coronary artery disease and prognosis in patients with acute ST-segment elevation myocardial infarction

BackgroundAcute ST-segment elevation myocardial infarction (STEMI) has a high morbidity and mortality rate. The congestive heart failure, hypertension, age, diabetes, previous stroke/transient ischemic attack (2 points) (CHADS₂) and CHADS₂ score with 2 points assigned for age >75 years-vascular disease (CHA₂DS₂-VASc) scores are widely used for risk stratification management of non-valvular atrial fibrillation stroke and have high prognostic value in cardiovascular disease. This study aims to investigate the predictive value of the emergency CHADS₂ and CHA₂DS₂-VASc score on coronary artery lesions and prognosis in patients with acute STEMI.MethodsA total of 524 patients with STEMI from May 2018 to October 2021 were selected for emergency CHADS₂ and CHA₂DS₂-VASc. Clinical data and laboratory indicators were collected. Patients were evaluated for coronary artery disease (CAD) and prognosis. Logistic regression and the receiver operating characteristic (ROC) curve were used to analyze the data.ResultsIn severe group, CysC levels, CHADS₂, CHA₂DS₂-VASc score and the proportion of diabetes, stroke or transient ischemic attack (TIA), congestive heart failure, smoking history, Killip class ≥2 was higher than that in mild and moderate group. In poor prognosis group, levels of serum creatinine (Crea), CysC, hemoglobin (Hb), CHADS₂, CHA₂DS₂-VASc score and the proportion of hypertension, diabetes, stroke or TIA, congestive heart failure, smoking history, and Killip class ≥2 was higher than that in good prognosis group. Diabetes (OR, 3.678; 95% CI: 2.876–5.872, 0.008), CHADS₂ (OR, 3.829; 95% CI: 2.310–5.832, 0.003) and CHA₂DS₂-VASc score (OR, 4.671; 95% CI: 3.125–6.187, 0.000) were independent risk factors for the severity of CAD (P<0.05). Diabetes (OR, 3.287; 95% CI: 2.231–5.123, 0.012), Killip class ≥2 (OR, 2.212; 95% CI: 1.023–2.987, 0.045), LVEF (OR, 3.110; 95% CI: 2.124–5.031, 0.023), CHADS₂ (OR, 3.228; 95% CI: 2.133–5.886, 0.005) and CHA₂DS₂-VASc score (OR, 3.988; 95% CI: 2.987–5.873, 0.001) were independent risk factors for prognosis of acute STEMI patients. Area under curve (AUC) value of CHA₂DS₂-VASc score in evaluating CAD and prognosis was 0.947, 0.931, higher than that of the CHADS₂ score (0.836, 0.812) (P<0.05).ConclusionsMultiple factors jointly affect the severity and prognosis of CAD in patients with acute STEMI. The CHA₂DS₂-VASc score is better than the CHADS₂ score in predicting the severity of coronary artery lesions and prognosis of patients, providing theoretical support for clinical practice.     

A new risk score predicting 1- and 5-year mortality following acute myocardial infarction Soroka Acute Myocardial Infarction (SAMI) Project

Background

Risk stratification of patients following acute myocardial infarction (AMI), in order to identify patients whose clinical outcomes can be improved through specific medical interventions, is needed.

Objectives

Development and validation of a prognostic tool comprising a variety of non-cardiovascular co-morbidities, to predict mortality of hospital survivors after AMI.

Methods

The study cohort included 2773 consecutive patients with AMI who were discharged live from the Soroka University Medical Center between 2002 and 2004. Two-thirds were used obtain the model (training set) and one-third to validate it (validation set). Data were collected from the hospital's routine computerized information systems. The primary outcome was post-discharge 1-year all-cause mortality. The weight of each variable in the final score was computed based on the odds ratio values of the multivariate model. Additionally, the ability of the index to predict 5-year mortality was assessed.

Results

These are comprised of the following parameters: 4 points — age > 75 years, abnormal echocardiography findings; 3 points — at least one of following: gastro-intestinal hemorrhage, COPD, malignancy, alcohol or drug addiction, neurological disorders, psychiatric disorders; 2 points — no echocardiography results, renal diseases, anemia, hyponatremia; −3 points for PCI or thrombolytic therapy; −6 points — CABG; −2 points — obesity. The c-statistics for 1-year all-cause mortality were 0.86 and 0.83 in the training and validation sets, respectively. The c-statistics for 5-year mortality was 0.858 for both sets combined.

Conclusions

The new score is a simple robust tool for predicting mortality in patients discharged alive following AMI.     

Thermogenic adipocytes: From cells to physiology and medicine

The identification of active brown fat in humans has evoked widespread interest in the biology of non-shivering thermogenesis among basic and clinical researchers. As a consequence we have experienced a plethora of contributions related to cellular and molecular processes in thermogenic adipocytes as well as their function in the organismal context and their relevance to human physiology. In this review we focus on the cellular basis of non-shivering thermogenesis, particularly in relation to human health and metabolic disease.     

Clinically evident polyvascular disease and regression of coronary atherosclerosis after intensive statin therapy in patients with acute coronary syndrome: serial intravascular ultrasound from the Japanese assessment of pitavastatin and atorvastatin in acute coronary syndrome (JAPAN-ACS) trial

Aim

To clarify whether the effects of statin treatment on plaque regression vary according to the presence or absence of polyvascular disease (PVD) in patients with acute coronary syndrome (ACS).

Methods

307 patients with ACS who underwent percutaneous coronary intervention for the culprit lesion at 33 centers were treated with atorvastatin or pitavastatin. Noncoronary atherosclerosis was defined as coexistent, clinically recognized arterial disease other than coronary artery disease (CAD) (cerebral, aortic, or lower extremity). Intravascular ultrasound (IVUS) was performed to assess non-culprit coronary atherosclerosis at baseline and at 8–12 months follow-up. Serial IVUS examinations were obtained in 252 patients. Atheroma volume and percent change in atheroma volume of the target plaque was assessed.

Results

Patients of the CAD + PVD (n = 19) were older (68 vs. 62 years, p = 0.02), had lower low-density lipoprotein cholesterol (LDL-C) levels at baseline (116 vs. 134 mg/dL, p = 0.03) than those of the CAD-only group (n = 233), whereas LDL-C levels at follow-up were similar (81 vs. 83 mg/dL). Although the baseline plaque volume was similar in the two groups (59 vs. 57 mm³), patients of the CAD + PVD group showed milder regression of atherosclerosis than those of the CAD-only group (−8.9% vs. −18.2%, p = 0.005). This difference remained significant even after adjustment for coronary risk factors including age and serum LDL-C (p = 0.047).

Conclusions

Statin treatment results in milder regression of coronary atherosclerosis in CAD patients with polyvascular disease compared to those with CAD only.