Vibhuti Singh

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.

Atherogenic dyslipidemia and diabetes mellitus: what's new in the management arena?

When compared with the general population, the diabetic population is at higher risk of cardiovascular disease (CVD), as predicted by the Framingham Risk Score calculations (10-year risk 20%). For this reason diabetes is considered a “coronary disease equivalent” condition, as classified by the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III. Furthermore, patients with diabetes who experience a myocardial infarction have a poorer prognosis than nondiabetic patients, which contributes to their overall higher mortality. Dyslipidemia is a major underlying risk factor contributing to the excess CVD risk, and is usually more atherogenic in the presence of diabetes. It is uniquely manifested by raised levels of triglycerides, low levels of high-density lipoprotein cholesterol, and smaller, denser, and more atherogenic low-density lipoprotein particles. Recent trials have suggested the need for more aggressive treatment of dyslipidemia in this subpopulation than the current recommendations by the NCEP-ATP III. This review addresses the newer developments in the diabetes arena in terms of our current understanding of atherogenic dyslipidemia in diabetes and data from the latest randomized trials addressing its management.

Low High-Density Lipoprotein Cholesterol and Increased Cardiovascular Disease Risk: An Analysis of Statin Clinical Trials

It is well established that low high-density lipoprotein (HDL) cholesterol is a risk factor for coronary artery disease (CAD). Growing evidence from epidemiologic as well as intervention studies have identified that a low level of HDL cholesterol contributes to cardiovascular disease risk. In addition, a number of clinical trials have substantiated that an inverse association between HDL cholesterol concentrations and cardiovascular risk exists. Decreasing low-density lipoprotein cholesterol levels with statins has a major impact on cardiovascular risk reduction, and statin therapy plays a significant role in the management of CAD. However, low levels of HDL cholesterol remain as a cardiovascular risk factor despite statin therapy. This article presents an overview of statin clinical trials and discusses implications for the clinical management of patients with low HDL cholesterol levels and increased cardiovascular risk.

Reducing morbidity and mortality in high risk patients with statins

Residual coronary heart disease remains a significant problem even after adequate statin therapy for cardiovascular risk reduction as currently recommended by the Adult Treatment Panel III (ATP-III) of the National Cholesterol Education Program (NCEP). This is particularly true for the high risk patients as defined by ATP-III that includes those patients who have a greater than 20% 10-year risk of adverse cardiac events. For such patients the current goal of a low-density lipoprotein cholesterol (LDL-cholesterol) maintenance level of ≤100 mg/dL plasma appears to be suboptimal. Accumulating data from several recent randomized studies of more aggressive LDL-cholesterol reduction to levels below 70 mg/dL in the high risk patients favor acceptance of such a new lower target for LDL-cholesterol using more intensive statin therapy which would affect the treatment strategy for patients with coronary heart disease pre-percutaneous intervention, metabolic syndrome, diabetes mellitus, congestive heart failure, cerebrovascular disease and chronic kidney disease.

The role of gas analysis with exercise testing

Evaluation of exercise performance is an integral component of every medical history. Currently, it is accomplished by means of subjective history taking. Routine exercise testing adds very little information; however, the addition of gas analysis (or cardio pulmonary exercise [CPX] testing) provides the crucial objective assessment by analyzing breath-by-breath oxygen uptake, carbon dioxide production, and anaerobic threshold (AT). Cardiac and pulmonary causes can be reliably differentiated, e.g., cardiac patients cross AT and attain VO2max, use less than 50% of maximal voluntary ventilation (MVV) at peak exercise, and do not develop desaturation. Pulmonary patients, on the contrary, fail to cross AT or achieve VO2max, utilize more than 70% of MVV at peak exercise, and develop arterial desaturation. In the current cost-conscious health care system, CPX proves to be a better cost-effective test because it is objective and more directly targeted to the issues than the conventional exercise test. CPX provides an important link between the disease process and its effect on exercise performance, which is crucial to a comprehensive clinical evaluation, diagnosis, prognosis, exercise prescription, and follow-up after medical or surgical intervention in patients with various diseases causing cardiopulmonary dysfunction.

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.