Vice Chairman, Department of Internal Medicine

Texas Tech University Health Sciences Center

Professor of Medicine and the Michael and

Clinical Pharmacy Specialist—Cardiology

Residency Program Director—PGY2 Cardiology

San Mateo Multispecialty Physicians Group

Director of Cardiac Intermediate Care Unit

Philip J. and Harriet L. Goodhart Professor of

Director of Cardiovascular Imaging Program

Zena and Michael A. Wiener Cardiovascular

Associate Professor of Medicine (Cardiology)

Articles

Editorial Advisory Board

 Cardiology Review Editorial Advisory Board

Tonelli M, Muntner P, Lloyd A, et al. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort. Lancet.

The US National Cholesterol Education Program Adult Treatment Panel III recommends reduction of low-density lipoprotein cholesterol (LDL) levels to <100 mg/dL in people with known coronary heart disease (CHD) or those with a disorder designated as a CHD equivalent. 1 Diabetes is considered a CHD equivalent as it carries a risk of a major coronary event equal to that for people with a prior myocardial infarction (MI) or a 10-year risk of MI or coronary death >20%.2 While chronic kidney disease (CKD) has been strongly associated with the development of cardiovascular events and mortality, it has not yet been established as a CHD equivalent.3-5 Recently  Marcello Tonelli, MD, and colleagues assessed whether CKD is a CHD equivalent using a populationbased cohort in Alberta, Canada.6

The authors evaluated the risk of first hospitalization for MI and all-cause mortality in people with a prior MI, diabetes, or non—dialysis-dependent CKD (estimated glomerular filtration rate [eGFR] between 15 mL/min/1.73 m2 and 60 mL/min/1.73 m2—stage 3 or 4 kidney disease). Using the Alberta Kidney Disease Network database, adult outpatients without end-stage kidney disease and whose serum creatinine had been measured between 2002 and 2009 were identified for inclusion in the population-based cohort study. Subjects were classified as having CKD if the eGFR by the Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) equation was between 15 mL/min/1.73 m2 and 59 mL/min/1.73 m2. Five risk groups were used for the analysis:

• all subjects with a prior MI (regardless of presence or absence of CKD or diabetes)

• 4 groups of subjects without a prior MI, which included:

• patients with CKD but without diabetes,

• patients with diabetes but without CKD,

• patients with no CKD and no diabetes.

The primary study outcome was first hospitalization for MI; the secondary outcomes were all-cause mortality for all subjects and all-cause mortality following a new MI. Outcomes were determined until the study’s end date of March 31, 2009.

A total of 1,268,029 participants met the inclusion criteria. At study entry, only 12,960 participants had a prior MI, 15,368 had diabetes and CKD, 59,117 had CKD without diabetes, and 1,104,713 had no diabetes or CKD. After a median follow-up period of 48 months, the unadjusted rate of MI was highest among people with a prior MI (18.5 per 1000 person- years; 95% confidence interval [CI], 17.4-19.8). The rates for MI in both groups with no prior MI (one of which had CKD and no diabetes, and the other with diabetes but no CKD) were lower compared with the group with a prior MI.

When comparing the rate of MI between groups without a previous MI, the unadjusted rate of incident MI was higher for the group with CKD but no diabetes compared with the group with diabetes but no CKD (6.9 vs 5.4 per 1000 person-years; P <.0001). However, after multivariable adjustment (for age, sex, socioeconomic status, and comorbid conditions), the relative rate of MI was lower for people with CKD but no diabetes than for people with diabetes but no CKD: 1.4 (95% CI, 1.3-1.5) versus 2.0 (95% CI, 1.9-2.1), using as the reference group the patients with no prior MI, no diabetes, and no CKD.

When restricting the analyses of the CKD group to include an eGFR between 15 mL/min/1.73 m2 and 59 mL/ min/1.73 m2 and severe proteinuria, the adjusted rate of MI was similar to the diabetes group. Furthermore, when a more severe CKD definition was used (an eGFR between 15 mL/ min/1.73 m2 and 44 mL/min/1.73 m2 and severe proteinuria), the rate of MI was higher for the CKD group (12.4 per 1000 person-years; 95% CI, 9.7-15.9) compared with the diabetes group (6.6 per 1000 person-years; 95% CI, 6.4-6.9).

e adjusted all-cause mortality relative rate was fairly similar among people with a prior MI (1.4, 95% CI 1.4-1.5), CKD (1.3, 95% CI 1.3- 1.3), and diabetes (1.4, 95% CI 1.3- 1.4). However, the unadjusted 30-day mortality following an MI was higher for the CKD group (14%) compared with the diabetes with no CKD group (8%; P <.0001) and when compared with the previous MI group (10%; P = .0053). Furthermore, the unadjusted long-term, all-cause mortality relative rate was higher for the CKD group (3.6; 95% CI, 3.3-4.1) compared with the diabetes group (1.9; 95% CI, 1.7- 2.1) and compared with the prior MI group (2.7; 95% CI, 2.3-3.1) (Figure).

When considering the group without previous MI but with diabetes and CKD, both the rates of MI and all-cause mortality were similar to or exceeded the rates in the prior MI group. Additionally, following an admission for an MI, the all-cause longterm relative rate of mortality was highest for the diabetes with CKD group (5.0; 95% CI, 4.4-5.7).

1. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on  Detection, Evaluation, and Treatment of High

Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486- 2497.

2. Grundy SM. Diabetes and coronary risk equivalency: what does it mean? Diabetes Care. 2006;29:457-460.

3. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med.

4. Hernandez G, Sippel M, Mukherjee D. Interrelationship between chronic kidney disease and risk of cardiovascular diseases. Cardiovasc Hematol Agents Med Chem.

[published online ahead of print June 20, 2012] http://www.ncbi.nlm.nih.gov/pubmed/22721441. Accessed September 30, 2012.

5. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension.

6. Tonelli M, Muntner P, Lloyd A, et al. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort

7. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study

of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377:2181-2192.

This study by Tonelli et al aimed to assess whether CKD constitutes a CHD risk equivalent. The study has many strengths, including a large sample size, the use of a

methodologically rigorous population-based registry, and the inclusion of a significant proportion of participants with more severe CKD (eGFR between 15 mL/min/1.73 m2 and 44 mL/min/1.73 m2). The study has few limitations, the most notable of which is the reliance on a relatively short-term follow-up period of 4 years to establish a 10-year risk of MI.

In terms of the primary analyses, the study results do not strictly support the designation of CKD (defined as an eGFR between 15 mL/min/1.73 m2 and 59 mL/min/1.73 m2) as a CHD risk equivalent. The rate of first MI in the CKD-only group was lower than 20 per 1000 person-years and was significantly lower than the rate for the group with a previous MI. However, the study results do show that when a more severe definition of CKD is used (eGFR, 15 mL/ min/1.73 m2 to 44 mL/min/1.73 m2 with concomitant severe proteinuria), the rate of first MI in people with CKD exceeds that in people with diabetes, a condition already established as a CHD equivalent.

Furthermore, the study also shows that following hospitalization for an MI, the highest relative rate of all-cause unadjusted mortality is among the diabetes and CKD group, followed by the CKD-only group, and both rates exceed the rate for the previous MI group.

The Study of Heart and Renal Protection (SHARP) trial used low-dose lipid-lowering therapy versus placebo in 9270 patients with moderate to severe CKD (25% had severe proteinuria and 28% had an eGFR of 15 mL/min/1.73 m2 to 29 mL/min/1.73 m2) and without a prior MI. The use of lipid-lowering therapy did not significantly reduce the incidence of MI or CHD death, but it did decrease the incidence of major atherosclerotic events, non-hemorrhagic strokes, and arterial revascularization

While Tonelli’s study does not support the use of CKD as a CHD risk equivalent based solely on defining CKD as an eGFR between 15 mL/min/1.73 m2 and 59 mL/min/1.73 m2, it seems a reasonable approach to consider lipid-lowering therapy in patients with more severe CKD (eGFR 15 mL/min/1.73 m2 to 44 mL/

German T. Hernandez, MD , FASN, FACP, is an Associate Professor of Medicine in the Division of Nephrology & Hypertension and Biostatistics & Epidemiology at the Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center in El Paso. He is the El Paso site principal investigator for many multicenter clinical trials. Dr. Hernandez received his medical degree at Harvard Medical School. He completed his postgraduate studies in internal medicine and nephrology as well as advanced

training in clinical research at the University of California, San Francisco.

CME Reviews

Is CKD a Coronary Heart Disease Risk Equivalent?

Blumenthal JA, Babyak MA, O’Connor C, et al. Effects of exercise training on depressive symptoms in patients with chronic heart failure. The HF-ACTION randomized trial. JAMA. 2012;308:465-474.

Depression is a common comorbidity experienced by many patients with cardiovascular disease. It has been documented that depression affects as many as 40% of patients with heart failure (HF) specifically, and a few studies have determined that there is an association between increased depressive symptoms and increased morbidity and mortality, as well as decreased quality of life.1 Multiple rationales have been proposed to explain this association, including the potential for depressive symptoms to decrease compliance with evidence-based  pharmacologic therapy known to improve these outcomes. Despite this established association, few studies have been able to demonstrate that improvement in depression (with either pharmacologic or nonpharmacologic treatment) results in improved clinical outcomes.

The Sertraline Against Depression and Heart Disease-Heart Failure (SADHART-CHF) trial and Enhancing Recovery in Coronary Heart Disease (ENRICHD—CHF) trial were 2 of the first randomized controlled trials to look at depressive symptoms in patients with coronary disease, and then more specifically, HF.2,3 Both trials aimed to correlate the treatment of depression with clinical outcomes, using a selective serotonin reuptake inhibitor or cognitive behavior therapy, respectively. In both these trials, depressive symptoms improved; however, there was no correlation with improved clinical outcomes. Similarly, the Efficacy and Safety of Exercise Training in Patients with Chronic Heart Failure (HF-ACTION) trial, designed to test the effect of exercise in HF patients, showed nonsignificant reductions in terms of all-cause mortality

and hospitalizations.4,5 After adjustment for highly prognostic predictors of the primary end point, there was a modest significant reduction in all-cause mortality, all-cause hospitalization, and cardiovascular outcomes. These results imply that there may be some benefit of exercise training on clinical outcomes in HF patients.

The present HF-ACTION ancillary study was a predetermined subgroup analysis designed to assess the effects of exercise on depressive symptoms and to

determine whether reduced depressive symptoms were associated with improved patient outcomes.6

The HF-ACTION trial was a randomized, controlled trial that enrolled patients ≥18 years of age with symptomatic HF (LVEF ≤35% and NYHA Class II-IV). Patients were excluded if they had a disease, condition, or any other limitation that could interfere with exercise training, any recent or planned major cardiovascular event or procedure, HF secondary to congenital heart disease, performance of exercise training at regular intervals (more than once per week) in the previous 6 weeks, a fixedrate pacemaker or implantable cardioverter defibrillator with heart rate (HR) limits set lower than the target HR, or any exercise testing that would preclude safe exercise training. The  primary medical end point was all-cause mortality, hospitalization, or both; the primary psychological end point was depressive symptoms after 3 months of supervised exercise. Secondary outcomes included both medical and psychological end points. Assessment of depression was based on the Beck Depression Inventory II (BDI-II). BDI-II scores of ≥14 are considered to reflect clinically significant depressive symptoms.

A total of 2331 HF patients were enrolled in this study from April 2003 to February 2007. The structured exercise program focused on increasing workout intensity and duration over a period of at least 12 months. Patients received a total of 36 supervised 30-minute training sessions 3 times per week. Once patients achieved 18 supervised train-ing sessions, a treadmill or stationary bicycle was to be used at home and patients were advised to work out for 40 minutes, 5 times per week. Adherence was defined as 90 min/wk or more of supervised exercise training up until 3 months, followed by at least 120 min/ wk of home-based exercise for months

4 to 12. Follow-up was recorded at 3-month intervals for the first year. Patients in the usual care group received information regarding exercise, medications, fluid management, symptom control, and a recommendation of 30 minutes of moderate-intensity training most days of the week. (This recommendation comes from the American College of Cardiology/American Heart Association guidelines; in the study, however, exercise was simply encouraged but without specific recommendations on how to implement.)

The 2322 patients who completed the BDI-II self-assessment at baseline were included as a part of this subgroup analysis. Baseline demographics were similar between the 2 groups, including median BDI-II scores of 8 in both groups. The median follow-up was 30 months, during which primary medical outcome was reached in 68% of the usual care group versus 66% in the aerobic exercise group (95% CI, 0.81-0.99; P = .03). BDI-II scores at 3 months were also significantly lower in the aerobic

exercise subjects (8.95) compared with the usual care group (9.70) (difference, -0.76; P = .002) and 8.86 and 9.54 (difference, -0.68; P = .01) at 12 months. Similar reductions were seen in patients who had significant depression at baseline (BDI-II score of ≥14), 16.66 for patients in the exercise group versus 17.98 for usual care (difference, -1.31; P = .04). This difference was even more profound at 12 months (exercise versus usual care, 15.85 vs 17.34; P = .02). Patients in the aerobic exercise group exercised for a median of 76 min/wk during the first 3 months, increasing to a median of 95 min/wk during months 4 to 6 and then decreasing to 74 min/wk at

months 10 to 12. During the supervised months, 41% of the sample achieved full adherence; during the home-based  phase, 42% of the sample achieved full adherence for months 4 to 6, 41% for months 7 to 9, and 38% for months 10 to 12. In terms of subsequent clinical secondary end points, aerobic exercise was also associated with a lower risk of HF hospitalizations and death (25.7% vs 28.6%; P = .03) and a statistically nonsignificant lower risk of CV hospitalization and death (54.7% vs 57.7%;

1. Jiang W, Alexander J, Christopher E, et al. Relationship of depression to increased risk of mortality and rehospitalization in patients with congestive heart failure. Arch Intern Med. 2001;161:1849-1856.

2. O’Connor CM, Jiang W, Kuchibhatla M, et al. Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial. J Am Coll Cardiol. 2012;56:692-699.

3. Joynt KE, O’Connor CM. Lessons from SADHART, ENRICHD, and other trials. Psychosom Med. 2005;67(suppl 1):S63-S66.

4. O’Connor CM, Whellan DJ, Lee KL, et al. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA.

5. Whellan DJ, O’Connor CM, Lee KL, et al. Heart failure and a controlled trial investigating outcomes of exercise training (HFACTION): design and rationale. Am Heart J. 2007;153:201-211.

6. Blumenthal JA, Babyak MA, O’Connor C, et al. Effects of exercise training on depressive symptoms in patients with chronic heart failure: the HF-ACTION randomized trial. JAMA. 2012;308:465-474.

7. Uretsky BF, Thygesen K, Armstrong PW, et al. Acute coronary findings at autopsy in heart failure patients with sudden death: results from the assessment of treatment with lisinopril and survival (ATLAS) trial. Circulation. 2000;102:611-616.

Improving Clinical Outcome, Especially for the Most Severely Depressed

The HF-ACTION trial and ancillary evaluation provide us with evidence to support structured and supervised exercise as a treatment for depression and as a means of improving clinical outcomes in HF patients. In order to understand the impact of these findings, it is important to understand both the strengths and limitations of the study.

The patient population that was included in this trial is a typical systolic HF population, illustrating the study’s well-thought-out inclusion and exclusion criteria. Baseline demographics of this HF population are similar to previous HF studies in which almost 30% of patients were HF Class III-IV. One piece of demographic data that was not

noted in this patient population was the pharmacologic therapies patients were receiving. The median ß-blocker dose and median dose of loop diuretics were noted and compared; however, other drugs such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists, and hydralazine and nitrates— which have a proven morbidity and mortality benefit in the HF population&mdash;should ideally be noted and compared in any HF study.7 Even though this information was not directly stated, the authors note that patients were medically managed by guideline-based therapy.

The study also did a good job of capturing all the potential confounders in their primary outcome of all-cause mortality and all-cause hospitalizations. HF patients have multiple comorbidities in which exercise may potentially be harmful. Including outcome data that involve not solely cardiovascular outcomes helps practitioners

understand the full implications of exercise and whether this is something that can be introduced to these patients.

Although the results seem promising, there are a few potential limitations to implementation of exercise training in this patient population. Patients who were randomized to exercise had to be willing and able, which may mean these selected patients are motivated and healthier than the typical HF patient. Second, in a study involving a treatment arm that includes follow-up visits, the amount and type of attention given to both arms of the trial must be compared because increased patient interaction with clinicians and physicians may pose a potential bias to the treatment arm. Structured physical exercise includes follow-up visits with physicians and clinicians, posing the potential bias that patients are also encouraged to adhere to lifestyle management and medication compliance; it may also serve as a type of cognitive therapy. The study did address this potential bias, trying to reduce it by calling all patients every 2 weeks for the first 9 months, monthly until 24 months, and quarterly thereafter to provide an equal amount of contact time between study arms. The authors state that through biweekly phone calls to the usual care group, patients were asked if they were engaging in some sort of exercise, and an average of 40% to 50% stated that they were, causing a potential crossover that may decrease the impact of the results.

In terms of clinical implications of the trial, the statistically significant results of decreased BDI-II scores may not correlate well with clinical significance. Some reports have suggested that a 50% reduction in depressive symptoms is clinically meaningful in trials of patients with major depression, but this has never been correlated

between BDI-II scores. At study entry, the mean BDI-II score for these patients was 8, which may represent a less depressed population; other studies involving depressive symptoms have included patients with BDI-II scores of greater than 10. Further, in patients with BDI-II scores >14 at baseline, although they were decreased more significantly in the exercise group, the median still remained above 14 in both groups. Additionally, and possibly complicating evaluation of this end point, at baseline about 20% of patients were already taking an antidepressant medication. Antidepressant medication use was recorded at baseline and 12 months; however, this was not controlled. Participants with more severe depressive symptoms at baseline were more likely to be taking an antidepressant medication and also were more likely to have more severe HF. Despite this difference in results, the clinical significance of this was not determined.

Adherence to a treatment group, or exercise protocol in this case, is often a potential limitation to the outcomes of a study. Although the results do not show that adherence affected significance, adherence could have decreased the potential to find an even greater difference between groups. Although adherence was low, a promising result is that adherence seemed consistent for those patients who continued to adhere to the exercise program for the entire 12 months, possibly showing that this may be used as a specific therapy for certain patients who are willing to try an exercise program. This type of structured program comes with significant cost, which may not be available to all communities and patients. This may prevent practitioners from using this type of program for all patients, especially with there being the greatest benefit in patients with greater depressive symptoms. This could imply that only patients with severe clinical depression should receive this type of structured therapy. Another significant point that should be noted is that future studies that assess exercise therapy must be directed on how to increase adherence, reduce cost, and encourage patients to continue exercise management; this may mean assessing other types of exercise methods different from walking and cycling.

These limitations must be considered when assessing the results and considering initiation of similar exercise programs for HF patients. The results of the present study do seem promising, and can help justify increased counseling and, potentially, administration of structured exercise programs for patients suffering from symptomatic HF. Given the more drastic improvement in outcomes and depressive symptoms for exercise in the clinically severely depressed subset, this might represent a good initial target population for clinicians.

Carolyn Hempel, PharmD, is a PGY-2 Cardiology Pharmacy Specialty Resident and is Chief Pharmacy Resident at University of Kentucky HealthCare, Lexington, KY. Her residency research project at the University of Kentucky Chandler Medical Center is on evaluating a pharmacist’s impact on 30-day readmission rates in heart failure patients through implementation of a medication reconciliation process. Dr Hempel was assisted in the writing of this article by Tracy E. Macaulay, PharmD, BCPS-AQ Cardiology, Clinical Pharmacy Specialist-Cardiology, PGY2 Residency Program Director-Pharmacology, and Adjunct Assistant Professor at University of Kentucky Health- Care, Department of Pharmacy Services and Division of Cardiovascular Medicine, Lexington, KY.

Is Exercise the Missing Link in Treating Depression in Heart Failure?

Weight loss is crucial for all patients with metabolic syndrome, whether they have impaired fasting glucose or glucose intolerance or have been diagnosed with type 2 diabetes. As discussed in the previous edition of this column [“The Skinny on Weight Loss,” by Peter H. Jones, MD, FACP, FNLA, June 2012 Cardiology Review], weight

loss with diet control is key for this group of patients. In addition to weight loss, another important goal has been to maintain blood glucose levels for the diabetic population.

Does strict control of plasma glucose prevent cardiovascular disease? The answer is unknown as of yet. Going back to the United Kingdom Prospective Diabetes Study (UKPDS),1 it has been noted that adequate plasma glucose control reduces the incidence of microvascular, but not macrovascular, complications. Cardiovascular disease, which is the major macrovascular complication, starts prior to the development of a clinical diagnosis of type 2 diabetes. Studies are always ongoing to assess the relationship of cardiovascular disease and intensive glucose control. The recent ORIGIN trial2 aimed to evaluate whether stricter glucose control with long-acting insulin showed any positive or negative effect on the risk of cardiovascular disease. Similarly, the ACCORD trial3 sought to evaluate whether intensive glucose control reduced cardiovascular mortality and morbidity. However, the ACCORD study, as well as the recent ORIGIN trial, failed to show any positive outcomes of stricter glucose control with long-acting insulin. In fact, the ACCORD study had to be terminated early because intensive therapy targeting normal glycated hemoglobin levels caused increased mortality without any benefit of reducing cardiovascular events.

Hence, if adequate glucose control does not affect cardiovascular outcomes, then what are the factors that affect them? Several studies have linked insulin sensitivity and fasting insulin levels to cardiovascular disease.4,5

Insulin resistance and hyperinsulinemia are concerns in patients with metabolic syndrome, diabetes mellitus, and impaired fasting glucose or glucose intolerance. The Insulin Resistance Atherosclerosis Study4 showed an inverse relationship between insulin sensitivity and cardiovascular risks. Several studies have also assessed the relationship of fasting plasma insulin levels and cardiovascular disease.5-7 Measuring insulin sensitivity is more technically cumbersome than measuring fasting plasma insulin levels. However, insulin sensitivity is a better marker than fasting plasma insulin levels. Fasting plasma insulin levels are influenced by the action of the pancreas, levels of glucose, and with renal and hepatic clearance. Insulin sensitivity, on the other hand, is reduced with obesity and reduced physical activity, which are hallmarks of type 2 diabetes. 8 Reduced insulin sensitivity corresponds to increasing insulin resistance. Hyperinsulinemia develops due to insulin resistance in individuals with metabolic syndrome. Insulin is an atherogenic and growth-promoting hormone. It stimulates insulin-like growth factor 1, which in turn causes proliferation of smooth muscles and increases low-density lipoprotein (LDL) cholesterol receptor activity, thus contributing to atherosclerotic plaque formation and therefore coronary artery disease.8 Hyperinsulinemia, a common feature noted among patients with impaired fasting glucose and glucose intolerance, thus initiates the atherosclerotic process prior to their presenting with overt diabetes.8

Patients with diabetes mellitus have a 2 to 4 times increased incidence of coronary artery disease compared with the general population.9 According to the results of the recent ORIGIN trial,2 strict control of blood sugar levels has not improved cardiovascular outcomes. This trial aimed to evaluate the effect of maintaining normal plasma glucose on the development of cardiovascular disease. The ORIGIN trial studied 12,537 people with a mean age of 63 years with cardiovascular risk factors and impaired fasting glucose or with impaired glucose tolerance or type 2 diabetes mellitus. They were assigned to receive either insulin glargine or standard care for diabetes, which included metformin and n-3 fatty acids or placebo. The target fasting plasma glucose achieved was 95 mg/dL for the insulin glargine group and 123 mg/dL for standard care patients. At the end of the study at 6.2 years, it was noted that although fasting plasma glucose levels and A1C levels were lower in the group taking insulin glargine, there was no significant difference in mortality, microvascular events, or results of any interventions in both groups. Hypoglycemia was, however, noted more frequently in the group receiving insulin glargine. Median weight gain of 1.6 kg was noted in the insulin glargine group compared with the median weight loss of 0.5 kg in the standard care group. The study basically showed no significant benefits or harm with respect to cardiovascular effects with long-acting insulin or standard care. Whether using metformin had any cardioprotective benefits could not be clearly defined in this trial. Although we do not know whether strict glucose control is beneficial as far as cardiovascular outcomes are concerned in preventing coronary artery disease, there is enough evidence to prove that it decreases microvascular complications. The ultimate goal should be to target those patients with impaired fasting glucose and glucose intolerance and encourage them to lose weight and thus disrupt the cascade of insulin resistance and hyperinsulinemia leading to cardiovascular disease. Maintaining a normal blood glucose level in type 2 diabetics by use of either oral medications or insulin will only fulfill the guideline requirements and not achieve any long-term benefits. It will not decrease insulin resistance or hyperinsulinemia that is present in these patients.

Hence, the main aim should be to reduce insulin resistance by recommending weight loss and increased physical activity, and this should be stressed to patients in cardiology, primary care, and endocrinology clinics. A significant proportion of time should be spent on educating patients to eat right and exercise rather than only increasing their oral medications or insulin for achieving a better A1C. Unfortunately, simply increasing medications is an easy fix for most busy practices. More time and money should be invested in better programs to encourage lifestyle modifications. Whether this is done with the help of a nutritionist or diabetes specialist nurse practitioners should depend on each clinic.

1. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood glucose control with sulphonylureas or insulin compared to with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) [published correction appears in Lancet. 1999:354-602]. Lancet. 1998:352:837-853.

2. The ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319-328.

3. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.

4. Rewers M, Zaccaro D, D’Agostin R, et al. Insulin sensitivity, insulinemia, and coronary artery disease: the Insulin Resistance Atherosclerosis Study. Diabetes Care. 2004;27:781-787.

5. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14:173-194.

6. Young MH, Jeng CY, Sheu WH, et al. Insulin resistance, glucose intolerance, hyperinsulinemia and dyslipidemia in patients with angiographically demonstrated coronary artery disease. Am J Cardio. 1993;72:458-460.

7. Shinozaki K, Suzuki M, Ikebuchi M, Hara Y, Harano Y. Demonstration of insulin resistance in coronary artery disease documented with angiography. Diabetes Care. 1996;19:1-7.

8. DeFronzo RA. Insulin resistance, hyperinsulinemia, and coronary artery disease: a complex metabolic web. J Cardiovasc Pharmacol. 1992;20(suppl 11):S1-S16.

9. Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors and 12 year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993:1997; S425-S433.

Diabetes

Diabetes and Health: Going the Distance

Lagiou P, Sandin S, Lof M, Trichopolous D, Adami H-O, Weiderpass E. Low carbohydratehigh

protein diet and incidence of cardiovascular diseases in Swedish women: prospective

cohort study. BMJ. 2012;344:e4026. doi:10.1136/bmj.e4026.

With the growing national and worldwide obesity epidemic, numerous diet plans have been proposed to combat this serious health problem. The most popular diets have promoted low-carbohydrate and high-protein intake  (low-carb/high-protein). The short-term effect of such diets appears to be quick weight loss; however,

their long-term effects have raised concerns, particularly with respect to cardiovascular outcomes. In the past several years, there have been some confusing data regarding low-carb/high-protein diets in the medical literature. In the Nurses’ Health Study, the long-term effect of such a diet was not associated with an increased incidence of ischemic heart disease.1 However, 3 smaller studies—mainly in the European population&mdash;have shown that such a diet significantly increased cardiovascular mortality.2-4

A new study by Lagiou et al has entered into the controversy.5 This large, prospective study is the second from the same investigators to look at the effect of a low-carb/high-protein diet in a cohort of Swedish women. In their previous study, published in 2007, the authors looked at low-carb/high-protein diets in a young (30-49 years old) cohort of women and followed them for 12 years. The present study followed the same cohort of Swedish women, again using an extensive dietary questionnaire.

Data were gathered from 43,396 Swedish women aged 30 to 49 years at baseline, who were followed up for an average of 15.7 years. Using the Swedish

nationwide database, the authors looked not only at mortality, but were also able to assess incident cardiovascular disease, ischemic heart disease, ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, and peripheral arterial disease. They estimated the intake of protein and carbohydrate for each participant using the validated residual method, which allows evaluation of the “effect” of an energy-generating nutrient, controlling for the energy generated by this nutrient, by using a simple regression of that nutrient on energy intake to calculate the residual.

The study found that women who had a diet low in carbohydrates and high in protein significantly increased their risk of cardiovascular disease, ischemic heart disease, and ischemic stroke in a dose-dependent manner. The low-carb/high-protein diet had no effect on hemorrhagic stroke, subarachnoid stroke, or peripheral arterial disease. The authors state that an increase of 5 g of protein and a decrease of 20 g of carbohydrate daily is associated with a statistically significant 5% increase in the overall risk of cardiovascular disease.5

1. Halton, TL, Willett WC, Liu S, et al. Lowcarbohydrate- diet score and the risk of coronary heart disease in women. N Engl J Med. 2006;355:1991-2002.

2. Lagiou P, Sandin S, Weiderpass E, et al. Low carbohydrate-high protein diet and mortality in a cohort of Swedish women. J Intern Med. 2007;261:366-374.

3. Sjogren P, Becker W, Warensjo E, et al. Mediterranean and carbohydrate-restricted diets and mortality among elderly men: a cohort study in Sweden. Am J Clin Nutr.

4. Trichopoulous A, Psaltopoulou T, Orlanos P, Hsieh CC, Trichopoulous D. Low-carbohydrate- high-protein diet and long-term survival in a general population cohort. Eur

5. Lagiou P, Sandin S, Lof M, Trichopolous D, Adami H-O, Weiderpass E. Low carbohydrate-high protein diet and incidence of cardiovascular diseases in Swedish women: prospective cohort study. BMJ. 2012;344:e4026.

6. Willett WC. Low-carbohydrate diets: a place in health promotion? J Intern Med.2007;261:363-365.

7. Fung TT, van Dam RM, Harkinson SE, Stampfer MJ, Manson JE, Willett WC. Lowcarbohydrate diets and all-cause and causespecific mortality: two cohort studies. Ann

8. Preis SR, Stampfer MJ, Spiegelman D, Willett WC, Rimm EB. Dietary protein and risk of ischemic heart disease in middleaged men. Am J Clin Nutr. 2010;92:1265-

9. Preis SR, Stampfer MJ, Spiegelman D, Willett WC, Rimm EB. Lack of association between dietary protein intake and risk of stroke among middle-aged men. Am J Clin Nutr. 2010;91:39-45.

10. Pan A, Bernstein AM, Schulze MB, et al. Red meat consumption and mortality: results from 2 prospective cohort studies. Arch Intern Med. 2012;172:555-563.

11. Bernstein AM, Sun Q, Hu FB, Stampfer MJ, Manson JE, Willett WC. Major dietary protein sources and risk of coronary heart disease in women. Circulation. 2010;122:876-883.

Why does this study’s findings differ from those of Willett et al in the Nurses’ Study? One theory to account for the difference that has been proposed by Willett et al is that the differences in the sources of protein (animal versus plant), types of carbohydrates consumed (highly refined starch and sugar), and the preparation and processing of the products might explain the conflicting findings.6 Certainly this has some merit. Recently, the report by Fung et al from the Nurses’ Health Study and the Health  Professionals Follow-up Study found that there was a statistically positive association between a low-carb diet of mainly animal protein and cardiovascular mortality, and a negative association between a low-carb diet of mainly vegetable origin and cardiovascular mortality.7

In other words, diets low in carbohydrates and high in animal protein increased cardiovascular events, and a low-carb/high vegetable protein diet decreased  cardiovascular events. Additionally, in the Health Professionals Follow-up Study, there was again an association between stroke and ischemic heart disease with diets low in carbohydrates and high in animal protein.8,9

In both studies, there was a statistically nonsignificant increase in cardiovascular mortality with the low-carb/high-protein diet. This is most likely due to combining into 1 group the diets high in both animal and vegetable protein. There have also been studies showing that an increase in red meat consumption appears to increase the risk of cardiovascular disease.10,11 Thus, the data appear to show that a long-term diet of low carb/high protein (high animal protein) increases cardiovascular disease. Unfortunately, this new study by the Lagiou group did not obtain information about the type of carbohydrate and protein—animal versus plant&mdash;that was consumed.5

Can this finding in young Swedish women be generalized to the US population? I think the answer is yes. Even though this particular study is done on a younger (30- 49 years of age), thinner population than is reflected in US studies (body mass index [BMI]>30 is only 5.7% of the whole cohort, while in the Nurses’ Study it was over

30%) and researchers assessed their diet only at enrollment, the findings are still applicable given similarities in dietary patterns in the 2 populations.

The great attraction to lowcarb/ high-protein diets is weight loss. The easy weight loss may lead people to adopt this type of diet for the long term to maintain weight loss. While the low-carb/ high—vegetable protein diet may have cardiovascular benefits,7-9 most patients who go on low-carb/high-protein diets elect to have diets high in

animal protein because they are often the cheapest and most easily accessible. Thus, what this study shows us is that even in this low-risk population of young, thin women, a diet low in carbohydrates and high in protein can increase the risk of cardiovascular disease long term. In the fight against obesity, where much confusion reigns among both patients and physicians about what diet to recommend and follow, we are reminded once again that a healthy diet is one of moderation.

Leslie Cho, MD, FACC, is Director of the Cleveland Clinic Women’s Cardiovascular Center. She is also Section Head of Preventive Cardiology and Rehabilitation in the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic. Dr Cho is board certified in interventional cardiology, cardiovascular medicine, and internal medicine, and specializes in heart disease in women.

Low-Carbohydrate/High- Protein Diet: The Good, the Bad, and the Ugly

As winter comes knocking on our doors, I hope you will find time to sit near a crackling fireplace with a hot cup of cocoa and enjoy your copy of Cardiology Review.

This issue of the journal discusses many important articles and viewpoints that I am sure you will find enjoyable and useful.

Dr Carol Chen discusses the role of coronary CT angiography (CCTA) versus standard evaluation in patients with acute chest pain. She suggests that in patients who are to undergo myocardial perfusion imaging testing, CCTA remains an option as an initial diagnostic procedure, with a favorable cost and radiation exposure profile. She goes on to say that by choosing the right patient and algorithm, CCTA could reduce overall hospital costs, and she cautions against the potential hazards of its inappropriate use in low-risk patients.

Dr Leslie Cho discusses pros and cons of a low-carbohydrate/ high-protein diet and reports that while the low-carb/ high-vegetable-protein diet may have cardiovascular benefits, most patients who go on low-carb/high-protein diets elect to have diets high in animal protein because they are often the cheapest and most easily accessible. Even in a low-risk population of young, thin women, a diet low in carbohydrates and high in animal protein can increase the risk of cardiovascular disease long term. We are reminded that in the fight against obesity, where much confusion reigns among both patients and physicians about what diet to recommend and follow, a healthy diet is a balanced diet and one of moderation. Also addressing lifestyle modifications, Dr Carolyn Hempel discusses structured and supervised exercise as a treatment for depression and as a means of improving clinical outcomes in heart failure (HF) patients, and suggests that current evidence justifies increased counseling and, potentially, administration of structured exercise programs for patients suffering from symptomatic HF— particularly patients with severe clinical depression.

Dr German Hernandez discusses chronic kidney disease (CKD) as a coronary heart disease risk equivalent. Based on data that patients with CKD are at high risk, he recommends consideration of lipid-lowering therapy in patients with more severe CKD (eGFR 15 mL/min/1.73 m2 to 44 mL/min/1.73 m2 or with severe proteinuria). Dr Niki Katsiki reviews the role of aspirin for the prevention of recurrent venous thromboembolism (VTE), and states that while aspirin seems promising in preventing

recurrent VTE, more trials are needed to address this issue. The ongoing ASPIRE trial will likely provide additional insight.

Dr Harold Lazar discusses endoscopic versus open vein-graft harvesting in patients undergoing coronary artery bypass grafting (CABG) and reports that despite some of the difficulties with endoscopic vein harvesting, it represents a major breakthrough in minimizing the morbidity associated with leg vein harvesting in CABG surgery. The decreased leg morbidity associated with this technique does not come at the expense of increased long-term mortality or myocardial infarctions, or result in an increased incidence of the need for repeat revascularization procedures.

Dr Saurav Chatterjee discuses new evidence and a recommendation against screening for CHD with resting or exercise ECG in asymptomatic, low-risk adults. He reports that there is no convincing evidence to recommend for or against such screening in high-risk individuals. Thus, future studies are urgently needed to identify patients in whom such screening may lead to significant reduction in CHD events and to identify tools for appropriate risk stratification.

Dr Diana Fancher touches on an important societal issue that is uppermost in many physicians’ minds: the implications of the Affordable Care Act (ACA). She points out that the ACA is the first US law to attempt comprehensive and systemic health care delivery reform, and hopes that both sides of the political aisle will be working together to assess, modify, and rework elements of the law. She quotes John E. McDonough, DrPH, of the Department of Health Policy and Management at the Harvard School of Public Health, who said, “Perhaps we will still get there, but there are many obstacles ahead.”

For our Diabetes and Health section, Dr Aparna Bhagavat reflects on insulin resistance and cardiovascular disease, and suggests that the main goal should be to reduce insulin resistance by recommending weight loss and increased physical activity—which should be stressed to patients in cardiology, primary care, and  endocrinology clinics. A significant proportion of time should be spent on educating patients to eat right and exercise rather than only increasing their oral medications

or insulin to achieve a better A1C using either nutritionists or diabetes nurse specialists.

In addition, Ms Jackie Syrop, our excellent managing editor, summarizes key presentations at ESC 2012 to help keep us all up-to-date on major recent cardiovascular trials.

I encourage you to share your insights, thoughts, and personal experiences on the topics touched upon in this issue. On a broader level, I would love to hear feedback on how we can make this journal even better. My goal continues to be to make you look forward to every issue of Cardiology Review.

Editor's Page

Getting Ready for Winter's Arrival

	President, Chairman, Chief Executive Officer

Along with exercising and quitting smoking, losing weight is likely one of the primary lifestyle modifications that cardiologists recommend to patients on a daily basis. Although perhaps not a surprise to these physicians, who are in the trenches in terms of trends in health care, new research suggests that the problem of obesity in America has reached alarming levels.

The new study, published in the International Journal of Obesity, shows that the rate of type III obesity (patients with a body mass index [BMI] of 40 kg/m2 or higher) increased by a staggering 70% between 2000 and 2010. The prevalence of BMIs greater than 50 kg/m2 increased even faster. Even after adjusting for self-reporting bias, the researchers estimated that in 2010, as many as 15.5 million American adults fell into the classification of type III obese.

If there is good news to be found in the report, it’s that the rate of growth appeared to be slowing somewhat from 2005 to 2012. This is small consolation, however, for health care professionals who see the negative effects of obesity every single day. Or for the health care system, which continues to be burdened by the direct and indirect costs of this serious health problem.

Although almost everyone can agree that obesity has long since reached epidemic levels in the United States, possible solutions to the problem stir endless debate. The recent approval of a new anti-obesity medication raises concerns about the long-term effectiveness of a “quick fix” that does not address underlying causes. Another tactic—attempts to pass a tax on sugary beverages in some cities&mdash;makes healthy choices a legislative issue and replaces personal responsibility with government oversight.

The obesity epidemic, in short, has no easy answer, but it starts with the individual making better choices for his or her health. Health care professionals have an important role to play by encouraging patients to make healthier choices, including improving one’s diet and getting more exercise. Although this is likely the advice that you are already giving, these new numbers reinforce the fact that empowering patients to take responsibility for their own health can’t come a moment too soon.

Letter from the Publisher

Obesity in America: More Than Just a Headwind?

In 1999, researchers announced the counterintuitive finding that overweight patients with certain chronic diseases have better survival odds than less obese counterparts, a phenomenon known as the “obesity paradox.” It has remained questionable as to whether losing weight might actually be the best advice for an overweight patient. Now a large study from Sweden finds that after a myocardial infarction, obese patients had better subsequent survival rates than those with normal body mass indices (BMIs) (The Atlantic, September 19, 2012).

The study evaluated whether the obesity paradox could be observed in 64,436 adults in a Swedish acute coronary syndrome registry. Researchers examined the relationship between BMI and mortality in these patients after dividing them into 9 BMI categories ranging from underweight (<18.5) to obese (>35) and controlling for potentially confounding variables. They evaluated the overall mortality of patients with significant stenosis in 1 or more coronary arteries over an average follow-up of 21 months.

Overweight patients (BMI 26.5-28) had the lowest risk of dying. Death risk decreased as BMI increased, until BMIs reached over 40, a point at which the risk of dying  increased. The pattern was consistent across different ages, sex, and treatment method. For patients treated with percutaneous coronary interventions, being underweight was associated with a 3 times greater risk of death than being overweight.

The authors caution that the study’s limitations prevent it from being an endorsement of the obesity paradox until causative factors are identified. The study will be published in the European Heart Journal.

Stress From Work Linked to Increased Heart Attack Risk

A new review published in Lancet finds that job stress can increase the risk of heart attack and death (ABC News, September 14, 2012). European researchers analyzed the results of 13 previous studies conducted between 1986 and 2006 that examined job stress as a risk factor for heart attack and death. A total of 200,000 patients were evaluated for an average of 7.5 years.

They concluded that people who have highly demanding jobs and little autonomy to make decisions are 23% more likely to have a heart attack. This held true regardless of gender, age, and socioeconomic status. The study did not definitively show a cause-and-effect relationship between job stress and heart attack and death, however.

Researchers suggest that the increase in job stress triggers a defensive “fight or flight” response that takes a toll on health. The hypothesis that work stress influences heart health is over 3 decades old, said lead study author Mika Kivimaki of University College London. But this latest study was able to investigate the theory with greater precision than has been previously possible.

The next question to answer is, now what do we do in light of the findings?

What Your Patients Are Reading

New Guidelines on Valve Disease Issued at ESC

The European Society of Cardiology (ESC), in conjunction with the European Association of Cardiothoracic Surgery, released new guidance on the treatment of valve disease. The previous guidelines were issued in 2007. The guideline’s writing group was led by Drs Alec Vahanian (Hôpital Bichat, Paris, France) and Ottavio Alfieri (S Raffaele University Hospital, Milan, Italy). They said the update was necessitated by advances in diagnostics, particularly, echocardiography; developments in surgical

valve repair; and the arrival of percutaneous valve replacement and repair techniques.

Among the new recommendations were a comprehensive review of echocardiographic criteria for defining severe valve regurgitation, indications for surgery in severe aortic regurgitation and aortic root disease, and giving transcatheter aortic-valve implementation (TAVI) a class IB recommendation in patients with symptomatic aortic stenosis who are not candidates for surgery.

The updated guidelines focus on acquired valve disease. According to Dr Vahanian, the heart-team approach—the involvement of a cardiologist, surgeon, and others in the patient’s workup&mdash;dominates the document because teamwork is crucial to the management of patients with valve disease. The new guidelines encourage the evaluation of patients with the entire heart team and moving toward less reliance on EuroSCOREs and STS scores. “Clinical judgment is more important than the scoring,” said Dr Vahanian.

Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). The Joint Task Force on the management of valvular heart disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2012; doi:10.1093/ eurheartj/ehs109. 

Merck Seeking FDA Approval for Vorapaxar in Prior MI Patients

Merck plans to pursue FDA approval for its antiplatelet agent vorapaxar for patients with prior myocardial infarction (MI) and no history of stroke or transient ischemic attack (TIA).1 The application for approval, to be made in 2013, will be based on data from a subgroup analysis of 17,779 patients in the TRA 2°P-TIMI 50 Trial, which was presented at the ESC 2012 Congress and published in Lancet.2

The trial found that in this carefully selected subgroup of patients, vorapaxar significantly reduced cardiovascular death/MI/stroke. There was an increase in moderate or severe bleeding, but intracranial hemorrhage was not different between groups. The investigators pointed out that the efficacy results are more favorable in prior-MI patients who were at low bleeding risk—those younger than 75 years, with no history of TIA or stroke, and with body weight over 60 kg (www.theheart.org/article/1438137/print.do).

1. Merck press release. “Merck provides update on cardiovascular development program.” April 26, 2012. www.merck.com/newsroom/news-release-archive/research-and-development/2012_0826.html.

2. Scirica BM, Bonaca MP, Braunwald E, et al, for the TRA 2°PTIMI 50 Steering Committee and Investigators. Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial. Lancet. 2012;doi:10.1016/S0140-6736(12)61269-0. 

Survey Finds Hospital Employment of Cardiologists Triples

A new survey by the American College of Cardiology (ACC) finds “a continuing trend toward hospital integration,” with hospital employment of cardiologists having almost tripled since the last census in 2007.

Of the nearly 6000 cardiology practices surveyed, more than 42% responded. Only 60% of practices are now physician owned, compared with 73% in 2007. Twenty-four percent are now hospital owned, up from 8% in 2007. Five years ago 59% of practitioners were employed by physician-owned private practices and 11% worked for

hospitals; now, 35% are employed by physician-owned practices and 35% work for hospitals.

According to the survey, of the practices that merged or integrated, 68% said the climate was better or about the same as before. The challenges cited are work flow management, hospital—practice alignment, reimbursement, Medicare cuts, and health IT implementation.

“The earlier we can get into a system that transitions the current fee-for-service…to one that is more sustainable, rewarding quality and decreasing waste, the better it will be for everyone—health care providers and patients,” said ACC president William Zoghbi, MD.

http://www.cardiosource.org/News-Media/Media-Center/News-Releases/2012/09/Leg-Conf.aspx

News & Trends

European Society of Cardiology (ESC) 2012 Congress 

Each year, the ESC Congress is the largest cardiology congress in Europe, with over 30,000 health care professionals in attendance from more than 150 countries. This

year’s Congress, held in Munich, Germany, August 25-29, featured over 4200 abstracts presented in 400 sessions. This year’s theme was “From Bench to Practice,” and

included a new universal definition of myocardial infarction updating the 2007 definition and key presentations of the studies summarized here: WOEST, PRAGUE-12, FAME 2, ATLAS ACS 2-TIMI 51, IABP-SHOCK II, and TRILOGY ACS.

WOEST: Clopidogrel, Not Aspirin, in Stent Patients on Oral Anticoagulants

Stent patients taking oral anticoagulation therapy should be treated with clopidogrel, not aspirin, according to results of the What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting (WOEST) trial, presented by Dr Willem Dewilde of TweeSteden Hospital, Tilburg, the Netherlands. The WOEST trial data showed a large reduction in overall Thrombolysis in Myocardial Infarction (TIMI) bleeding in patients on dual therapy with oral anticoagulants and clopidogrel (75 mg/d) compared with those on triple therapy with oral anticoagulants, clopidogrel, and aspirin (80 mg/d). Treatment was continued for 1 month after bare-metal stenting (35% of patients) and 1 year after placement of drug-eluting stents (65% of patients). There was 1 year of follow-up.

With only 573 patients, the study is small, but as the first randomized trial to address the issue, the trial’s results were considered to be very important and potentially “practice changing” and valuable because bleeding in patients on triple therapy is a prevalent problem. The results may prod guideline committees to examine the data and consider updates, it was suggested.

The oral anticoagulants studied were warfarin-type drugs, and thus the results cannot be extrapolated to the new anticoagulants.

Surgical Ablation With Maze Procedure Benefits AF Patients

Results of the PRAGUE-12 study show that when added to cardiac and/or valvular surgery in patients with atrial fibrillation (AF), surgical ablation results in significantly more patients being in normal sinus rhythm, compared with patients who underwent the surgery without the modified Maze ablation procedure.

Senior investigator Petr Widimsky, MD, DrSc, FESC, FACC, of Charles University, Prague, Czech Republic, reported that at 1 year 53.2% of patients with longstanding, persistent AF who underwent the Maze procedure in addition to surgery were in normal sinus rhythm, compared with 13.9% of patients who

had surgery alone. There was no difference in rates of sinus rhythm between the 2 treatment arms in patients with paroxysmal or persistent AF. There was no significant difference in the primary safety outcome— 30-day composite of death, myocardial infarction (MI), stroke, and renal failure.

PRAGUE-12 was published concurrently in the European Heart Journal.1 An editorial in the same issue of the journal said the study’s follow-up regimen was too weak and thus may have missed most of the AF recurrences, making the findings of very limited value.2

Dr Widimsky noted that the results are interesting and to some degree surprising, but agreed that more research is needed to answer the question of whether surgeons should consider the treatment of AF using the modified Maze procedure only in patients with longstanding, persistent AF.

1. Budera P, Straka Z, Osmancik P, et al. Comparison of cardiac surgery with left atrial surgical ablation vs cardiac surgery without atrial ablation in patients with coronary and/or valvular heart disease plus atrial fibrillation: final results of the PRAGUE-12 randomized multicenter study. Eur Heart J. 2012; doi:10.1093/eurheartj/ehs290. http://eurheartj.oxfordjournals.org.

2. Hindricks G, Piorkowski C. Surgical ablation after the PRAGUE-12 study: more questions than answers. Eur Heart J. 2012; doi:10.1093/eurheartj/ehs294.http://eurheartj.oxfordjournals.org.

ATLAS ACS 2-TIMI 51: Rivaroxaban Use inPatients With STEMI

In patients with a recent ST-segment elevation myocardial infarction (STEMI), treatment with a low dose of rivaroxaban offers an effective strategy to reduce thrombotic events, according to results of the ATLAS ACS 2-TIMI-51 trial, presented at the ESC 2012 Congress.

A twice-daily 2.5-mg dose of rivaroxaban reduced the risk of cardiovascular death, MI, or stroke, showing a mortality benefit.

The lower dose showed better results than the twice-daily 5-mg dosage. Compared with placebo, rivaroxaban increased the risk of major bleeding and intracranial hemorrhage, but there was no increase in fatal bleeding, researchers reported. Dr Jessica Mega, of Brigham & Women’s Hospital in Boston, MA, noted that long-term anticoagulant therapy has been of interest in the STEMI population, which was a pre-specified subgroup in the study.

ATLAS ACS 2-TIMI-51 compared the 2 doses of rivaroxaban with placebo in addition to standard therapy in 15,526 acute coronary syndrome (ACS) patients. The current analysis focused on the 7817 STEMI patients who underwent randomization to the twice-daily dose of either rivaroxaban 2.5 mg, 5 mg, or placebo. Data are presented as 2-year Kaplan-Meier event rates, and testing was based on the log-rank test stratified by the intention to use a thienopyridine.

No Survival Benefit of Balloon Pump in AMI with Shock

October 2012

Cardiology Review Editorial Advisory Board

Is CKD a Coronary Heart Disease Risk Equivalent?

Is Exercise the Missing Link in Treating Depression in Heart Failure?

Diabetes and Health: Going the Distance

Low-Carbohydrate/High- Protein Diet: The Good, the Bad, and the Ugly

Getting Ready for Winter's Arrival

Obesity in America: More Than Just a Headwind?

What Your Patients Are Reading

News & Trends

Meeting Report: European Society of Cardiology (ESC) 2012 Congress

Aspirin for the Prevention of Recurrent VTE

What's Ahead for the Affordable Care Act?

Coronary CT Angiography Versus Standard Evaluation in Acute Chest Pain

Recommendation Against Screening for CHD With Resting and Exercise ECG in Asymptomatic and Low-Risk Adults

Endoscopic Versus Open Vein-Graft Harvesting in Patients Undergoing CABG

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