Rakesh K Sharma

Aspirin and clopidogrel hyporesponsiveness and nonresponsiveness in patients with coronary artery stenting.

Patients undergoing coronary artery stenting receive an antiplatelet regimen to reduce the risk of antithrombotic complications. Current guidelines recommend the use of acetyl salicylic acid (aspirin) and clopidogrel as evidenced by large clinical trials. There has been a concern about variable responses of patients to aspirin and clopidogrel which may predispose them to subacute stent thrombosis or late stent thrombosis. Up to 25% of patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) were found to have hyporesponsiveness or resistance to clopidogrel which may predispose them to recurrent events. Dual antiplatelet regimen is a standard therapy in these patients and there is always a concern about variable responses to aspirin and clopidogrel predisposing them to acute coronary syndrome (ACS). Prevalence of this hyporesponsiveness or resistance may be due to noncompliance, genetic mutations, co-morbid situations and concomitant use of other drugs. This issue is of considerable importance in the era of coronary drug eluting stents when a long-term dual antiplatelet regimen is needed. This paper is a review for clinicians taking care of such patients with hyporesponsiveness or nonresponsiveness to dual antiplatelet regimen.

Thinking beyond low-density lipoprotein cholesterol: strategies to further reduce cardiovascular risk

Several large statin trials and meta-analyses have demonstrated a reduction in low-density lipoprotein cholesterol (LDL-C) and cardiovascular morbidity and mortality. Some trials have also highlighted the significance of residual cardiovascular risk after treatment of LDL-C to target levels. This reflects the complex nature of residual cardiovascular risk. This residual risk is partially due to low HDL-C and high triglycerides (TG) despite achievement of LDL goals with statin therapy. The NCEP ATP III guidelines reported that low HDL-C is a significant and an independent risk factor for coronary heart disease (CHD) and is inversely related to CHD. Epidemiologic studies have also shown a similar inverse relationship of HDL-C with CHD. High-density lipoprotein cholesterol (HDL-C) may directly participate in the anti-atherogenic process by promoting efflux of cholesterol of the foam cells of atherogenic lesions. Many studies have demonstrated multiple anti-atherogenic actions of HDL-C and its role in promoting efflux of cholesterol from the foam cells. The residual risk by increased TG with or without low HDL-C can be assessed by calculating non–HDL-C and a reduction in TG results in decreased CHD.

Low high-density lipoprotein cholesterol: current status and future strategies for management

Atherosclerotic cardiovascular disease is the foremost cause of death and disability in the Western world, and it is rapidly becoming so in the developing nations. Even though the use of statin therapy aiming at the low-density lipoprotein cholesterol (LDL) has significantly reduced cardiovascular events and mortality, substantial residual cardiac events still occur in those being treated to the currently recommended targets. In fact, residual risk is also seen in those who are treated “aggressively” such as the “high risk” patients so defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III). Consequently, one must look for the predictors of risk beyond LDL reduction. High-density lipoprotein cholesterol (HDL) is the next frontier. The protectiveness of elevated HDL against atherosclerosis is well described in the literature. HDL subdues several atherogenic processes, such as oxidation, inflammation, cell proliferation and thrombosis. It also helps mobilize the excess LDL via reverse cholesterol transport. Low levels of HDL have been shown to be independent predictors of risk. Thus, therapies to raise the HDL hold promise for additional cardiac risk reduction. In this regard, several randomized trials have recently tested this hypothesis, especially in patients at high risk. In addition to the use of aggressive lifestyle modification, clinical outcomes have been measured following augmentation of HDL levels with various treatment modalities, including aggressive statin therapy, combination therapy with fibrates and niacin, and direct HDL-raising drug treatments. These data for low HDL as an independent risk factor and as the new treatment target are reviewed in this paper.

Cardiac risk stratification: Role of the coronary calcium score

Coronary artery calcium (CAC) is an integral part of atherosclerotic coronary heart disease (CHD). CHD is the leading cause of death in industrialized nations and there is a constant effort to develop preventative strategies. The emphasis is on risk stratification and primary risk prevention in asymptomatic patients to decrease cardiovascular mortality and morbidity. The Framingham Risk Score predicts CHD events only moderately well where family history is not included as a risk factor. There has been an exploration for new tests for better risk stratification and risk factor modification. While the Framingham Risk Score, European Systematic Coronary Risk Evaluation Project, and European Prospective Cardiovascular Munster study remain excellent tools for risk factor modification, the CAC score may have additional benefit in risk assessment. There have been several studies supporting the role of CAC score for prediction of myocardial infarction and cardiovascular mortality. It has been shown to have great scope in risk stratification of asymptomatic patients in the emergency room. Additionally, it may help in assessment of progression or regression of coronary artery disease. Furthermore, the CAC score may help differentiate ischemic from nonischemic cardiomyopathy.

Evolving role of platelet function testing in coronary artery interventions

The substantial reduction in ischemic events provided by the dual antiplatelet regimen with aspirin and clopidogrel is well documented in patients with acute coronary syndrome and patients undergoing percutaneous coronary intervention. Recently the variable response to the antiplatelet agents has received considerable attention after several “boxed warnings” on clopidogrel. This led to intense controversy on pharmacokinetic, pharmacodynamic, and pharmacogenomic issues of antiplatelet drugs, especially clopidogrel. Research use of platelet function testing has been successfully validated in identifying new antiplatelet drugs like prasugrel and ticagrelor. These platelet function assays are no longer regarded just as a laboratory phenomenon but rather as tools that have been shown to predict mortality in several clinical trials. It is believed that suboptimal response to an antiplatelet regimen (pharmacodynamic effect) may be associated with cardiovascular, cerebrovascular, and peripheral arterial events. There has been intense controversy about this variable response of antiplatelet drugs and the role of platelet function testing to guide antiplatelet therapy. While the importance of routine platelet function testing may be uncertain, it may be useful in high-risk patients such as those with diabetes mellitus, diffuse three vessels coronary artery disease, left main stenosis, diffuse atherosclerotic disease, and those with chronic renal failure undergoing percutaneous coronary intervention. It could also be useful in patients with suspected pharmacodynamic interaction with other drugs to assure the adequacy of platelet inhibition. While we wait for definitive trials, a predictive prognostic algorithm is necessary to individualize antiplatelet therapy with P2Y12 inhibitors based on platelet function assays and genetic testing.

Platelet function testing to predict hyporesponsiveness to clopidogrel in patients with chest pain seen in the emergency department

Background A dual antiplatelet regimen has been shown to reduce the risk of major adverse cardiovascular events after percutaneous coronary intervention. However, there is little information available on inhibition of platelet aggregation in patients with a prior coronary stent presenting with chest pain. This study evaluated the prevalence of hyporesponsiveness to clopidogrel and factors associated with this in patients presenting to our emergency department with chest pain who had previously undergone coronary stent placement and were prescribed dual antiplatelet therapy. Methods Responsiveness to clopidogrel was evaluated in a cohort of 533 consecutive stented patients presenting to the emergency department with chest pain. P2Y12 reaction units (PRU) and percent P2Y12 inhibition with clopidogrel were measured in all patients. Of 533 patients, 221 (41.6%) had PRU ≥ 230. A multivariate logistic regression model was used to determine the relationship between hyporesponsiveness to clopidogrel (defined as PRU ≥ 230) and several potential risk factors, ie, gender, age, race, type 1 or type 2 diabetes, hypertension, smoking, chronic renal failure, and obesity. Results There was a greater risk of hyporesponsiveness in African Americans than in non-African American patients (adjusted odds ratio [OR] = 2.165), in patients with type 2 diabetes than in those without (adjusted OR = 2.109), and in women than in men (adjusted OR = 1.813), as well as a greater risk of hyporesponsiveness with increasing age (adjusted OR = 1.167 per decade). Conclusion There was a high prevalence of hyporesponsiveness to clopidogrel in patients presenting with chest pain and a prior coronary stent. Non-insulin-dependent diabetes mellitus and African American race were the strongest predictors of hyporesponsiveness to clopidogrel, followed by gender and age.

Coronary computed tomographic angiography (CCTA) in community hospitals: "current and emerging role".

Coronary computed tomographic angiography (CCTA) is a rapidly evolving test for diagnosis of coronary artery disease. Although invasive coronary angiography is the gold standard for coronary artery disease (CAD), CCTA is an excellent noninvasive tool for evaluation of chest pain. There is ample evidence to support the cost-effective use of CCTA in the early triage process of patients presenting with chest pain in the emergency room. CCTA plays a critical role in the diagnosis of chest pain etiology as one of potentially fatal conditions, aortic dissection, pulmonary embolism, and myocardial infarction. This ‘triple rule out’ protocol is becoming an increasingly practicable and popular diagnostic tool in ERs across the country. In addition to a quick triage of chest pain patients, it may improve quality of care, decrease cost, and prevent medico-legal risk for missing potentially lethal conditions presenting as chest pain. CCTA is also helpful in the detection of subclinical and vulnerable coronary plaques. The major limitations for wide spread acceptance of this test include radiation exposure, motion artifacts, and its suboptimal imaging with increased body mass index.

The interaction between clopidogrel and proton pump inhibitors (PPI): is there any clinical relevance?

The potential interaction between clopidogrel and proton pump inhibitors (PPI) in patients with acute coronary syndrome (ACS) raises serious concerns for cardiologists. However, in patients on this combination of drugs, there is no conclusive evidence of an increase in adverse cardiovascular events. From pharmacologic and pharmacodynamic perspectives, there is a real interaction between clopidogrel and PPIs because of the competitive inhibition of CYP2C19 isoenzyme which is required for biotransformation of clopidogrel to its active metabolite. The consequent decrease in the availability of this active metabolite leads to attenuation of antiplatelet efficacy of clopidogrel. In several observational trials, it was shown that decreased antiplatelet effect of clopidogrel due to PPIs may translate into poor cardiovascular outcomes. However, an incomplete RCT (COGENT) and a post hoc analysis of two large trials (PRINCIPLE-TIMI 44 and TRITON-TIMI 38 trial) showed no significant adverse cardiovascular events with this combination. Caution is however needed in patients who are hypometabolizers of clopidogrel putting them at a higher risk of adverse coronary events. Since 3% of patients are likely to be hypometabolizers of clopidogrel, routine combination of clopidogrel and PPIs should be avoided. There is a heightened awareness of this interaction following multiple advisory warnings. At the same time, one should not withhold PPIs in patients who are at a high risk of developing gastrointestinal (GI) bleeding. In these patients, selected choices of PPI such as pantoprazole may be helpful and for low risk patients, serious consideration should be given to H2 receptor antagonists or antacids. Therefore, while not compromising the cardioprotective effect of antiplatelet agents, the gastroprotective benefit of PPI should be strongly considered in patients who need both. Health care providers should remain alert to more outcome data. Future researchers will need to demonstrate the safety of coadministration of PPIs and clopidogrel and trials should be powered to detect major adverse cardiovascular events and facilitate risk stratification based on genetic polymorphism.

Understanding the application of stem cell therapy in cardiovascular diseases

Throughout their lifetime, an individual may sustain many injuries and recover spontaneously over a period of time, without even realizing the injury in the first place. Wound healing occurs due to a proliferation of stem cells capable of restoring the injured tissue. The ability of adult stem cells to repair tissue is dependent upon the intrinsic ability of tissues to proliferate. The amazing capacity of embryonic stem cells to give rise to virtually any type of tissue has intensified the search for similar cell lineage in adults to treat various diseases including cardiovascular diseases. The ability to convert adult stem cells into pluripotent cells that resemble embryonic cells, and to transplant those in the desired organ for regenerative therapy is very attractive, and may offer the possibility of treating harmful disease-causing mutations. The race is on to find the best cells for treatment of cardiovascular disease. There is a need for the ideal stem cell, delivery strategies, myocardial retention, and time of administration in the ideal patient population. There are multiple modes of stem cell delivery to the heart with different cell retention rates that vary depending upon method and site of injection, such as intra coronary, intramyocardial or via coronary sinus. While there are crucial issues such as retention of stem cells, microvascular plugging, biodistribution, homing to myocardium, and various proapoptotic factors in the ischemic myocardium, the regenerative potential of stem cells offers an enormous impact on clinical applications in the management of cardiovascular diseases.

The Prevalence of Left Ventricular Hypertrophy and Altered Geometry in Patients with Right Ventricular Diastolic Dysfunction

Background: Left ventricular diastolic dysfunction (LVDD) associated with left ventricular hypertrophy (LVH) has been reported to play a major role in cardiovascular heart failure. Although, right ventricular diastolic dysfunction (RVDD) in patients with LVH was known to be clinically relevant, no systematic study had been performed regarding this relationship between left ventricular (LV) geometry associated with LVH and RVDD. The goal of this study was to evaluate an association between RVDD; LVDD, LVH and LV altered geometry for early diagnosis of heart failure. Methods and Results: Out of 426 patients, 396 patients (93%) were found to have both RVDD and LVDD. In this cohort, LV concentric geometry (LVCG) was identified in 138 patients (32.3%). RVDD and LVDD were diagnosed by measurement of E/A and tissue doppler imaging (E’/A’) for mitral and tricuspid valves. The mean value of mitral E/A in the LVCG group was lower than that of controls; 0.63±0.03 vs. 1.44±0.03, p<0.02. Mitral E’/A’ was also lower in LVCG than that of controls; 0.60±0.02 vs. 1.36±0.03, p<0.01. Similarly, E/A of Tricuspid valve in patients with LVCG was found to be lower than E/A of Tricuspid valve of controls; 0.52±0.07 vs. 0.69±0.02, p<0.001 and E’/A’ of tricuspid valve was lower than that of controls; 0.44±0.02 vs. 0.63±0.06, p<0.05. Conclusions: This study demonstrated that simple doppler trans-valvular inflow parameters and tissue doppler imaging may identify patients with biventricular diastolic dysfunction. This finding was more often observed in patients with LV concentric geometry, a pattern associated with an increased risk of cardiovascular events.