Michael E. Farkouh

Diagnosis and Treatment of Chronic Arterial Insufficiency of the Lower Extremities: A Critical Review

Atherosclerosis is the most common cause of chronic arterial occlusive disease of the lower extremities. The arterial narrowing or obstruction that occurs as a result of the atherosclerotic process reduces blood flow to the lower limb during exercise or at rest. A spectrum of symptoms results, the severity of which depends on the extent of the involvement and the available collateral circulation. Thus, symptoms may range from intermittent claudication to pain at rest. Intermittent claudication denotes pain that develops in the affected limb with exercise and is relieved with rest. This pain usually occurs distal to the arterial narrowing or obstruction. Since the superficial femoral and popliteal arteries are the vessels most commonly affected by the atherosclerotic process, the pain of intermittent claudication is most often localized to the calf. The distal aorta and its bifurcation into the two iliac arteries are the next most frequent sites of involvement. Narrowing of these arteries may produce pain in the buttocks or the thighs as well as the legs. Epidemiological studies indicate that up to 5% of men and 2.5% of women 60 years of age or older have symptoms of intermittent claudication.1 2 The prevalence is at least threefold higher when sensitive noninvasive tests are used to make the diagnosis of arterial insufficiency in asymptomatic and symptomatic individuals.3 The symptoms of chronic arterial insufficiency of the lower extremities progress rather slowly over time. Thus, after 5 to 10 years, more than 70% of patients report either no change or improvement in their symptoms, while 20% to 30% have progressive symptoms and require intervention, and less than 10% need amputation.4 5 Despite the relatively benign prognosis for the affected limb, however, symptoms of intermittent claudication should be viewed as a sign of systemic atherosclerosis. This explains why, compared with …

Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials.

IMPORTANCE Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents. OBJECTIVE To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions. DATA SOURCES Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles. STUDY SELECTION Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression. DATA EXTRACTION AND SYNTHESIS Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated. MAIN OUTCOMES AND MEASURES Depression scores after treatment and adverse effects. RESULTS Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n=4,258) and 4 investigated cytokine inhibitors (n=2,004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, -0.34; 95% CI, -0.57 to -0.11; I2=90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, -0.54; 95% CI, -1.08 to -0.01; I2=68%) and depressive symptoms (SMD, -0.27; 95% CI, -0.53 to -0.01; I2=68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, -0.29; 95% CI, -0.49 to -0.08; I2=73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2=0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2=0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity. CONCLUSIONS AND RELEVANCE Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted.

Association of Myocardial Enzyme Elevation and Survival Following Coronary Artery Bypass Graft Surgery

CONTEXT Several small studies have suggested that cardiac enzyme elevation in the 24 hours following coronary artery bypass graft (CABG) surgery is associated with worse prognosis, but a definitive study is not available. Also, the long-term prognostic impact of small increases of perioperative enzyme has not been reported. OBJECTIVE To quantify the relationship between peak post-CABG elevation of biomarkers of myocardial damage and early, intermediate-, and long-term mortality, including determining whether there is a threshold below which elevations lack prognostic significance. DATA SOURCES Studies (randomized clinical trials or registries) of patients undergoing CABG surgery in which postprocedural biomarker and mortality data were collected and included. A search of the PubMed database was performed in July 2008 using the search terms coronary artery bypass, troponin, CK-MB, and mortality. STUDY SELECTION Studies evaluating mortality and creatine kinase (CK-MB), troponin, or both were included. One study investigator declined to participate and 3 had insufficient data. DATA EXTRACTION Two independent reviewers determined study eligibility. The principal investigator from each eligible study was contacted to request his/her participation. Once institutional review board approval for the use of these data for this purpose was obtained, we requested patient-level data from each source. Data were examined to ensure that cardiac markers had been measured within 24 hours after CABG surgery, key baseline covariates, and mortality were available. RESULTS A total of 18,908 patients from 7 studies were included. Follow-up varied from 3 months to 5 years. Mortality was found to be a monotonically increasing function of the CK-MB ratio. The 30-day mortality rates by categories of CK-MB ratio were 0.63% (95% confidence interval [CI], 0.36%-1.02%) for 0 to <1, 0.86% (95% CI, 0.49%-1.40%) for 1 to <2, 0.95% (95% CI, 0.72%-1.22%) for 2 to <5, 2.09% (95% CI, 1.69%-2.57%) for 5 to <10, 2.78% (95% CI, 2.12%-3.58%) for 10 to <20, and 7.06% (95% CI, 5.46%-8.96%) for 20 to ≥40. Of the variables considered, the CK-MB ratio was the strongest independent predictor of death to 30 days and remained significant even after adjusting for a wide range of baseline risk factors (χ(2) = 143, P < .001; hazard ratio [HR] for each 5 point-increment above the upper limits of normal [ULN] = 1.12; 95% CI, 1.10-1.14). This result was strongest at 30 days, but the adjusted association persisted from 30 days to 1 year (χ(2) = 24; P < .001; HR for each 5-point increment above ULN = 1.17; 95% CI, 1.10-1.24) and a trend was present from 1 year to 5 years (χ(2) = 2.8; P = .10; HR for each 5-point increment above ULN = 1.05; 95% CI, 0.99-1.11). Similar analyses using troponin as the marker of necrosis led to the same conclusions (χ(2) = 142 for 0-30 days and χ(2) = 40 for 30 days to 6 months, both P < .001; HR for each 50 points above the ULN = 1.28; 95% CI, 1.23-1.33 and 1.15; 95% CI, 1.10-1.21, respectively). CONCLUSIONS Among patients who had undergone CABG surgery, elevation of CK-MB or troponin levels within the first 24 hours was independently associated with increased intermediate- and long-term risk of mortality.

Comparison of coronary artery bypass surgery and percutaneous coronary intervention in patients with diabetes: a meta-analysis of randomised controlled trials

BACKGROUND The choice between coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI) for revascularisation in patients with diabetes and multivessel coronary artery disease, who account for 25% of revascularisation procedures, is much debated. We aimed to assess whether all-cause mortality differed between patients with diabetes who had CABG or PCI by doing a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing CABG with PCI in the modern stent era. METHODS We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from Jan 1, 1980, to March 12, 2013, for studies reported in English. Eligible studies were those in which investigators enrolled adult patients with diabetes and multivessel coronary artery disease, randomised them to CABG (with arterial conduits in at least 80% of participants) or PCI (with stents in at least 80% of participants), and reported outcomes separately in patients with diabetes, with a minimum of 12 months of follow-up. We used random-effects models to calculate risk ratios (RR) and 95% CIs for pooled data. We assessed heterogeneity using I(2). The primary outcome was all-cause mortality in patients with diabetes who had CABG compared with those who had PCI at 5-year (or longest) follow-up. FINDINGS The initial search strategy identified 3414 citations, of which eight trials were eligible. These eight trials included 7468 participants, of whom 3612 had diabetes. Four of the RCTs used bare metal stents (BMS; ERACI II, ARTS, SoS, MASS II) and four used drug-eluting stents (DES; FREEDOM, SYNTAX, VA CARDS, CARDia). At mean or median 5-year (or longest) follow-up, individuals with diabetes allocated to CABG had lower all-cause mortality than did those allocated to PCI (RR 0.67, 95% CI 0.52-0.86; p=0.002; I(2)=25%; 3131 patients, eight trials). Treatment effects in individuals without diabetes showed no mortality benefit (1.03, 0.77-1.37; p=0.78; I(2)=46%; 3790 patients, five trials; p interaction=0.03). We identified no differences in outcome whether PCI was done with BMS or DES. When present, we identified no clear causes of heterogeneity. INTERPRETATION In the modern era of stenting and optimum medical therapy, revascularisation of patients with diabetes and multivessel disease by CABG decreases long-term mortality by about a third compared with PCI using either BMS or DES. CABG should be strongly considered for these patients.

Quality of Life After PCI vs CABG Among Patients With Diabetes and Multivessel Coronary Artery Disease: A Randomized Clinical Trial

IMPORTANCE The FREEDOM trial demonstrated that among patients with diabetes mellitus and multivessel coronary artery disease, coronary artery bypass graft (CABG) surgery resulted in lower rates of death and myocardial infarction but a higher risk of stroke when compared with percutaneous coronary intervention (PCI) using drug-eluting stents. Whether there are treatment differences in health status, as assessed from the patients perspective, is unknown. OBJECTIVES To compare the relative effects of CABG vs PCI using drug-eluting stents on health status among patients with diabetes mellitus and multivessel coronary artery disease. DESIGN, SETTING, AND PARTICIPANTS Between 2005 and 2010, 1900 patients from 18 countries with diabetes mellitus and multivessel coronary artery disease were randomized to undergo either CABG surgery (n = 947) or PCI (n = 953) as an initial treatment strategy. Of these, a total of 1880 patients had baseline health status assessed (935 CABG, 945 PCI) and comprised the primary analytic sample. INTERVENTIONS Initial revascularization with CABG surgery or PCI. MAIN OUTCOMES AND MEASURES Health status was assessed using the angina frequency, physical limitations, and quality-of-life domains of the Seattle Angina Questionnaire at baseline, at 1, 6, and 12 months, and annually thereafter. For each scale, scores range from 0 to 100 with higher scores representing better health. The effect of CABG surgery vs PCI was evaluated using longitudinal mixed-effect models. RESULTS At baseline, mean (SD) scores for the angina frequency, physical limitations, and quality-of-life subscales of the Seattle Angina Questionnaire were 70.9 (25.1), 67.3 (24.4), and 47.8 (25.0) for the CABG group and 71.4 (24.7), 69.9 (23.2), and 49.2 (25.7) for the PCI group, respectively. At 2-year follow-up, mean (SD) scores were 96.0 (11.9), 87.8 (18.7), and 82.2 (18.9) after CABG and 94.7 (14.3), 86.0 (19.3), and 80.4 (19.6) after PCI, with significantly greater benefit of CABG on each domain (mean treatment benefit, 1.3 [95% CI, 0.3-2.2], 4.4 [95% CI, 2.7-6.1], and 2.2 [95% CI, 0.7-3.8] points, respectively; P < .01 for each comparison). Beyond 2 years, the 2 revascularization strategies provided generally similar patient-reported outcomes. CONCLUSIONS AND RELEVANCE For patients with diabetes and multivessel CAD, CABG surgery provided slightly better intermediate-term health status and quality of life than PCI using drug-eluting stents. The magnitude of benefit was small, without consistent differences beyond 2 years, in part due to the higher rate of repeat revascularization with PCI. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00086450.

Trends in the prevalence, awareness, treatment and control of high low density lipoprotein-cholesterol among United States adults from 1999-2000 through 2009-2010.

Marked increases in the awareness, treatment, and control of high low-density lipoprotein (LDL) cholesterol occurred among United States (US) adults from 1988-1994 to 1999-2004. An update to the Third Adult Treatment Panel guidelines was published in 2004, and it is unknown if these improvements have continued since the publication of these revised treatment recommendations. The aim of this study was to determine trends in the awareness, treatment, and control of high LDL cholesterol among US adults from 1999-2000 to 2009-2010 using nationally representative samples of US adults aged ≥20 years from 6 consecutive National Health and Nutrition Examination Surveys (NHANES) in 1999-2000 (n = 1,659), 2001-2002 (n = 1,897), 2003-2004 (n = 1,698), 2005-2006 (n = 1,692), 2007-2008 (n = 2,044), and 2009-2010 (n = 2,318). LDL cholesterol was measured after an overnight fast, and high LDL cholesterol and controlled LDL cholesterol were defined using the 2004 updated Third Adult Treatment Panel guidelines. Awareness and treatment of high cholesterol were defined using self-report. Among US adults, the prevalence of high LDL cholesterol did not change from 1999-2000 (37.2%) to 2009-2010 (37.8%). Awareness of high LDL cholesterol increased from 48.9% in 1999-2000 to 62.8% in 2003-2004 but did not increase further through 2009-2010 (61.5%). Among those aware of having high LDL cholesterol, treatment increased from 41.3% in 1999-2000 to 72.6% in 2007-2008 and was 70.0% in 2009-2010. Among US adults receiving treatment for high LDL cholesterol, the percentage with controlled LDL cholesterol increased from 45.0% in 1999-2000 to 65.3% in 2005-2006 and had decreased slightly by 2009-2010 (63.6%). In conclusion, high LDL cholesterol remains common among US adults. Additional efforts are needed to prevent high LDL cholesterol and increase the awareness, treatment, and control of high LDL cholesterol among US adults.

Modulating peroxisome proliferator-activated receptors for therapeutic benefit? Biology, clinical experience, and future prospects

Clinical trials of cardiovascular disease (CVD) prevention in patients with type 2 diabetes mellitus primarily have been directed at the modification of a single major risk factor; however, in trials that enroll patients with and without diabetes, the absolute risk in CVD events remains higher in patients with diabetes. Efforts to reduce the macrovascular and microvascular residual risk have been directed toward a multifactorial CVD risk-factor modification; nonetheless, long-term complications remain high. Dual-peroxisome proliferator-activated receptor (PPAR) α/γ agonists may offer opportunities to lower macrovascular and microvascular complications of type 2 diabetes mellitus beyond the reductions achieved with conventional risk-factor modification. The information presented elucidates the differentiation of compound-specific vs class-effect properties of PPARs as the basis for future development of a new candidate molecule. Prior experience with thiazolidinediones, an approved class of PPARγ agonists, and glitazars, investigational class of dual-PPARα/γ agonists, also provides important lessons about the risks and benefits of targeting a nuclear receptor while revealing some of the future challenges for regulatory approval.

Are patients with inflammatory bowel disease at increased risk of coronary artery disease

The inflammatory state of atherosclerosis has been established as those with chronic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus, who are at increased risk of coronary artery disease. A systematic search was conducted to retrieve high-quality, peer-reviewed studies of inflammatory bowel disease and coronary artery disease. Recent literature supports an association between inflammatory bowel disease and coronary artery disease. While hypertension increases the risk of coronary artery disease in inflammatory bowel disease patients, other typical risk factors have not been confirmed, and markers of inflammation may predict coronary artery disease risk in this population. Common cardiovascular drugs such as statins and angiotensin-converting enzyme inhibitors may have dual potential for controlling inflammatory bowel disease and preventing or treating coronary artery disease. Large, prospective, longitudinal studies can help to determine the true prevalence of coronary artery disease in this population and confirm risk factors. In the absence of such evidence, physicians should be cognizant of increased coronary artery disease risk in inflammatory bowel disease patients without traditional risk factors and consider primary preventive strategies.

AKI and Long-Term Risk for Cardiovascular Events and Mortality

AKI associates with increased long-term risk of mortality, but the prognostic significance of AKI in terms of long-term cardiovascular disease remains unconfirmed. We conducted a systematic review and meta-analysis to assess whether AKI associates with long-term cardiovascular disease. We included cohort studies that examined adults with and without AKI and reported a multivariable-adjusted relative risk (RR) for the association between AKI and cardiovascular mortality, major cardiovascular events, and disease-specific events: congestive heart failure, acute myocardial infarction, and stroke. Twenty-five studies involving 254,408 adults (55,150 with AKI) were included. AKI associated with an 86% and a 38% increased risk of cardiovascular mortality and major cardiovascular events, respectively ([RR 1.86; 95% confidence interval (95% CI), 1.72 to 2.01] and [RR 1.38; 95% CI, 1.23 to 1.55], respectively). For disease-specific events, AKI associated with a 58% increased risk of heart failure (RR 1.58; 95% CI, 1.46 to 1.72) and a 40% increased risk of acute myocardial infarction (RR 1.40; 95% CI, 1.23 to 1.59). The elevated risk of heart failure and acute myocardial infarction persisted in subgroup analyses on the basis of AKI severity and the proportion of adults with baseline ischemic heart disease. Finally, AKI was associated with a 15% increased risk of stroke (RR 1.15; 95% CI, 1.03 to 1.28). In conclusion, AKI associates with an elevated risk of cardiovascular mortality and major cardiovascular events, particularly heart failure and acute myocardial infarction.

Transcatheter aortic valve implantation in patients with bicuspid aortic valve: A patient level multi-center analysis

OBJECTIVE We sought to evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) in patients with bicuspid aortic valve (BiAV). BACKGROUND BiAV remains a relative contraindication to TAVI resulting in exclusion from TAVI trials and thus limiting data on the clinical performance of transcatheter valves in these patients. METHODOLOGY We conducted an international patient level multicenter analysis on outcomes in patients with BiAV undergoing TAVI. The primary outcome of the study was the combined early safety endpoint--a composite of 30 day mortality, stroke, life-threatening bleeding, acute kidney injury, coronary artery obstruction, major vascular complication and valve related dysfunction. Secondary endpoints included the individual components of the primary endpoint as well as post-TAVI paravalvular leak (PVL), rehospitalization, new pacemaker insertion and device success rates at 30 days and 1 year. RESULTS A total of 108 patients with BiAV were identified in 21 centers in Canada, Spain, Italy, Poland and Singapore who underwent TAVI between January 2005 and March 2014. The composite primary outcome occurred in one quarter of patients (26.9%)--mainly driven by re-intervention for valve malposition (9.3%). The 30-day and 1 year mortality rates were 8.3% and 16.9% respectively with AR ≥ 3+ occurring in 9.6% of patients. Device success was achieved in 85.2% of cases with pacemaker insertion in 19.4%. While PVL was not associated with an increased risk of 30 day or 1 year mortality--Type I BiAV anatomy with left and right cusp fusion had significantly better outcomes than other valve variants. CONCLUSION In selected patients with BiAV and severe aortic stenosis, TAVI appears both safe and feasible with acceptable clinical outcomes. Clinical studies of TAVI in this patient population are warranted.