Background— There is an ongoing debate as to whether the gastrointestinal safety of COX-2 inhibition compared with nonsteroidal antiinflammatory drugs (NSAIDs) may come at the cost of increased cardiovascular events. In view of the large number of patients at cardiovascular risk requiring chronic analgesic therapy with COX-2 inhibitors for arthritic and other inflammatory conditions, the effects of selective COX-2 inhibition on clinically useful surrogates for cardiovascular disease, particularly endothelial function, need to be determined. Methods and Results— Fourteen male patients (mean age, 66±3 years) with severe coronary artery disease (average of 2.6 vessels with stenosis >75%) undergoing stable background therapy with aspirin and statins were included. The patients received celecoxib (200 mg BID) or placebo for a duration of 2 weeks in a double-blind, placebo-controlled, crossover fashion. After each treatment period, flow-mediated dilation of the brachial artery, high-sensitivity C-reactive protein, oxidized LDL, and prostaglandins were measured. Celecoxib significantly improved endothelium-dependent vasodilation compared with placebo (3.3±0.4% versus 2.0±0.5%, P =0.026), whereas endothelium-independent vasodilation, as assessed by nitroglycerin, remained unchanged (9.0±1.6% versus 9.5±1.3%, P =0.75). High-sensitivity C-reactive protein was significantly lower after celecoxib (1.3±0.4 mg/L) than after placebo (1.8±0.5 mg/L, P =0.019), as was oxidized LDL (43.6±2.4 versus 47.6±2.6 U/L, P =0.028), whereas prostaglandins did not change. Conclusions— This is the first study to demonstrate that selective COX-2 inhibition improves endothelium-dependent vasodilation and reduces low-grade chronic inflammation and oxidative stress in coronary artery disease. Thus, selective COX-2 inhibition holds the potential to beneficially impact outcome in patients with cardiovascular disease.

There are several guidelines addressing the issues around the use of NSAIDs. However, none has specifically addressed the upper versus lower gastrointestinal (GI) risk of COX-2 selective and non-selective compounds nor the interaction at both the GI and cardiovascular (CV) level of either class of drugs with low-dose aspirin. This Consensus paper aims to develop statements and guidance devoted to these specific issues through a review of current evidence by a multidisciplinary group of experts. A modified Delphi consensus process was adopted to determine the level of agreement with each statement and to determine the level of agreement with the strength of evidence to be assigned to the statement. For patients with both low GI and CV risks, any non-selective NSAID (ns-NSAID) alone may be acceptable. For those with low GI and high CV risk, naproxen may be preferred because of its potential lower CV risk compared with other ns-NSAIDs or COX-2 selective inhibitors, but celecoxib at the lowest approved dose (200 mg once daily) may be acceptable. In patients with high GI risk, if CV risk is low, a COX-2 selective inhibitor alone or ns-NSAID with a proton pump inhibitor appears to offer similar protection from upper GI events. However, only celecoxib will reduce mucosal harm throughout the entire GI tract. When both GI and CV risks are high, the optimal strategy is to avoid NSAID therapy, if at all possible. Time is now ripe for offering patients with osteoarthritis the safest and most cost-effective therapeutic option, thus preventing serious adverse events which could have important quality of life and resource use implications. Please see related article: http://dx.doi.org/ 10.1186/s12916-015-0291-x .

Background— Dark chocolate has potent antioxidant properties. Coronary atherosclerosis is promoted by impaired endothelial function and increased platelet activation. Traditional risk factors, high oxidative stress, and reduced antioxidant defenses play a crucial role in the pathogenesis of atherosclerosis, particularly in transplanted hearts. Thus, flavonoid-rich dark chocolate holds the potential to have a beneficial impact on graft atherosclerosis. Methods and Results— We assessed the effect of flavonoid-rich dark chocolate compared with cocoa-free control chocolate on coronary vascular and platelet function in 22 heart transplant recipients in a double-blind, randomized study. Coronary vasomotion was assessed with quantitative coronary angiography and cold pressor testing before and 2 hours after ingestion of 40 g of dark (70% cocoa) chocolate or control chocolate, respectively. Two hours after ingestion of flavonoid-rich dark chocolate, coronary artery diameter was increased significantly (from 2.36±0.51 to 2.51±0.59 mm, P <0.01), whereas it remained unchanged after control chocolate. Endothelium-dependent coronary vasomotion improved significantly after dark chocolate (4.5±11.4% versus −4.3±11.7% in the placebo group, P =0.01). Platelet adhesion decreased from 4.9±1.1% to 3.8±0.8% ( P =0.04) in the dark chocolate group but remained unchanged in the control group. Conclusions— Dark chocolate induces coronary vasodilation, improves coronary vascular function, and decreases platelet adhesion 2 hours after consumption. These immediate beneficial effects were paralleled by a significant reduction of serum oxidative stress and were positively correlated with changes in serum epicatechin concentration.

Background—: Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease.Methods and Results—: The 33 patients with coronary artery disease included in this randomized, double-blind, placebo-controlled, crossover study received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4±11.9 to 125.3±12.0 mm HgP=0.02 versus placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mm HgP=0.02 versus placebo) ambulatory blood pressures. On the other hand, heart rate, endothelial function, early endothelial progenitor cells, and platelet function did not change.Conclusions—: This study demonstrates for the first time that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease. Thus, the use of acetaminophen should be evaluated as rigorously as traditional nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors, particularly in patients at increased cardiovascular risk.Clinical Trial Registration—: URL:http://www.clinicaltrials.gov. Unique identifier: NCT00534651.

Endothelial dysfunction and platelet activation are cornerstones in the pathogenesis of atherothrombosis, leading to vasoconstriction, thrombus formation, and inflammation. Smoking is a major cardiovascular risk factor. The mechanisms promoting atherothrombosis in smokers primarily include increased oxidative stress that enhances proatherogenic processes such as low density lipoprotein oxidation and inactivation of endothelium derived nitric oxide. Platelets contribute both to acute coronary syndromes and to the progression of atherothrombosis. Both active and passive cigarette smoking has consistently been shown to induce endothelial dysfunction. Therefore, smokers serve as an ideal model to study the beneficial vascular effects of antioxidant strategies such as dark chocolate.¹