The hot summer days are upon us—at least here in Texas&mdash;and in this issue of Cardiology Review we cover several sizzling topics.

Dr Eric Bates discusses the optimal revascularization strategy for patients with stable ischemic heart disease. He opines that as we move closer to patient-centered care, it is important to remember that all coronary revascularization decisions are complex and need to be individualized. Rather than continuing the debate on revascularization superiority, PCI and CABG should be viewed as complementary strategies and valued as equally important for stable ischemic heart disease treatment options.

Dr Alison Bailey reviews the role of rivaroxaban for the treatment of symptomatic pulmonary embolism. In the past few years, multiple new oral anticoagulants have been 

developed. Most of these drugs focus on directly inhibiting either Factor Xa (rivaroxaban, apixaban, edoxaban) or thrombin (dabigatran). Dr. Bailey concludes that there are multiple benefits associated with these drugs, including ease of  administration (oral versus intravenous or subcutaneous), no need for routine monitoring, and improved safety profiles (driven mostly by a reduction in major bleeding episodes). The major drawbacks include cost and the irreversible nature of most of these drugs. However, with currently expanding indications (prophylaxis and treatment of DVT and PE,  thromboembolism prophylaxis in AF) and the lack of enthusiasm for coumadin, these medicines are likely to gain a larger share of the antithrombotic market.

Dr O. Julian Booker discusses the impact of the progression of diastolic dysfunction on mortality in patients with normal ejection fraction and recommends that moderate or severe diastolic dysfunction should be treated by aggressive risk-factor modification. The increase in mortality associated with all levels of diastolic dysfunction extends the use of medical therapy for the treatment of even mild dysfunction, specifically the use of statins. Among other imaging modalities, Dr Mushabb ar Syed reviews CT angiography for safe discharge of patients with possible acute coronary syndromes, and states that based on the currently available evidence, a CCTA-based strategy is a reasonable alternative to traditional stress testing in patients with lowto intermediate-risk acute chest pain.

Dr Sunee t Mittal discusses optimal periprocedural anticoagulation strategy in patients undergoing catheter ablation of atrial fibrillation and suggests that available data provide support for the notion that ablation during continued therapeutic anticoagulation with warfarin is the optimal strategy in patients undergoing catheter ablation of AF.

Dr Michael Rich reflects on the status of vitamin D therapy in hypertension and kidney disease. He provides some practical advice to clinicians, stating that for those not at risk for osteoporosis, there is no evidence that taking vitamin D is beneficial; however, it’s probably not harmful at modest dosages such as 1000 to 2000 IU per day, and is therefore OK to take if desired. Dr Thomas Whayne discusses a novel therapy: a monoclonal antibody in patients with primary hypercholesterolemia. He concludes that the potential of this therapy is exciting and offers an additional, promising approach to possibly improve the lives of patients at risk for, or ravaged by, atherosclerotic disease. Finally, in our new section on diabetes and heart disease, Dr Peter Jones discusses our national obsession: namely, weight loss, and provides many insightful and practical suggestions for a healthy approach to this problem.

I hope that you will find these commentaries to be valuable and enjoyable. Also, the insightful compilation of current news and trends by our managing editor, Ms Jackie Syrop, should keep you updated on the latest happenings in the field of medicine. 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.

Articles

Editor's Page

Heat and Light

Vice Chairman, Department of Internal Medicine

Texas Tech University Health Sciences Center

Director, UCLA Cardiac Arrhythmia Center & EP

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)

Editorial Advisory Board

Cardiology Review Editorial Advisory Board

The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.

ulmonary embolism (PE) is a common disorder that requires prompt diagnosis and long-term treatment to reduce the associated morbidity and mortality. The mortality of untreated PE approaches 30%, with recurrent venous thromboembolism (VTE) being the most common cause of death.1

The incidence of PE has been increasing (from 62.3 to 112.3 per 100,000), likely due to improved diagnostic accuracy with the increased availability of computed tomographic pulmonary angiography. 2 The classical management of PE consists of initial therapy with a parenteral or subcutaneous anticoagulant such as  unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux for 5 days overlapping with an oral vitamin K antagonist (VKA) titrated to a goal international normalized ratio (INR) of 2.0 to 3.0.3 The time course of VKA therapy depends on clinical factors such as the inciting event and comorbid conditions, but is generally 3 to 12 months.

There are many challenges with maintenance VKA therapy; thus, there is great clinical interest in more convenient anticoagulants. Rivaroxaban is an oral direct Xa inhibitor that has been studied for the prophylaxis and treatment of deep vein thrombosis (DVT). In the United States, rivaroxaban is approved by the FDA for postoperative

DVT prophylaxis and thromboembolism prophylaxis in atrial fibrillation (AF). The EINSTEIN-PE trial evaluated the use of rivaroxaban alone versus standard therapy in patients with a pulmonary embolus.4

EINSTEIN-PE was a randomized, open-label, event-driven noninferiority trial that compared oral rivaroxaban with standard therapy of enoxaparin (LMWH) followed by  adjusted-dose VKA in patients diagnosed with acute, symptomatic PE. The primary efficacy outcome was symptomatic recurrent VTE; the principal safety outcome was

major or clinically relevant non-major bleeding. PE with or without DVT must have been objectively confirmed for the patient to be included in this trial. Prior trials of rivaroxaban monotherapy did not include patients with PE (DVT only), so a dose-confirmation phase was included within this trial to confirm therapeutic equality.

Patients were excluded if they had received therapeutic dosing of LMWH, UFH, or fondaparinux for more than 48 hours or more than 1 dose of a VKA before randomization; were treated with thrombectomy, vena cava filter, or fibrinolytic therapy for the current VTE episode; had contraindications to enoxaparin or VKA therapy; had significant renal (CrCl <30 mL/min) or hepatic disease; had evidence of active bleeding or contraindication to anticoagulant therapy because of a high risk of bleeding; had uncontrolled hypertension (>180/110 mm Hg); had anticipated concomitant use of a strong inhibitor of CYP3A4 or a CYP3A4 inducer; or had a life expectancy <3 months.

The treating physician determined the intended duration of anticoagulant treatment for each patient prior to randomization. Randomization was then

stratified according to country and the intended treatment duration (3, 6, or 12 months). Assignment to either rivaroxaban or standard therapy was then performed. The rivaroxaban group received an oral dose of 15 mg twice daily for 3 weeks followed by 20 mg once daily. The standard-therapy group received enoxaparin injections twice daily (at a dosage of 1 mg/kg body weight) in combination with a VKA (either warfarin or acenocoumarol). Enoxaparin was stopped when the INR was >2.0 for more than 2 consecutive days and the patient had received at least 5 days of enoxaparin therapy. The INR goal was 2.0 to 3.0 and was checked at least once per month. The duration of anticoagulation for patients in each group was based on the pre-randomization plan of care. Concomitant use of aspirin (≤100 mg daily), clopidogrel (≤75 mg daily), or

both was allowed if clinically indicated.

Between March 2007 and March 2011, 4832 patients were enrolled at 263 sites and followed for a mean of 260 days. The patients were well matched at baseline, with a mean age of 57 years and an intermediate extent of PE. Onefourth of the patients had a concurrent DVT and the majority of cases were unprovoked VTE (64%). For the standard therapy group, the median duration of enoxaparin therapy was 8 days, and 83% of the patients reached an INR

of 2.0 or greater by the end of enoxaparin therapy. The proportion of time spent with a therapeutic INR (2.0-3.0) was 62.7%, subtherapeutic INR (<2.0) was 15.5%, and supratherapeutic INR (>3.0) was 21.8%. In the rivaroxaban group, adherence to therapy was >80% in the majority of the patients.

The primary efficacy outcome of recurrent VTE occurred in 2.1% (50 patients) of the rivaroxaban group and 1.8% (44 patients) of the standard therapy group (hazard ratio [HR], 1.12; 95% confidence interval [CI], 0.75-1.68; P = 0.003 for noninferiority, P = 0.57 for superiority) (Figure). The principal safety outcome of first major or clinically relevant non-major bleeding episode occurred in 10.3% (249 patients) of the rivaroxaban group and 11.4% (274 patients) of the stand therapy group (HR, 0.90; 95% CI,

0.76-1.07; P = 0.23). Major bleeding occurred in 1.1% (26 patients) of the rivaroxaban group and 2.2% (52 patients) in the standard therapy group (HR, 0.49;

95% CI, 0.31-0.79, P = 0.003). Similar results were seen across all prespecifiedsubgroups.

In this study of patients with symptomatic PE, a single-drug regimen with oral rivaroxaban was not inferior to standard therapy of enoxaparin and a VKA for efficacy, and may have a better side-effect profile.

1. Carson JL, Kelley MA, Duff A, et al. The clinical course of pulmonary embolism. N Engl J Med. 1992;326:1240.

2. Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171:831.

3. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease. In: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed. American College

of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141;e419Se494S.

4. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297.

5. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients. In: Antithrombotic Therapy and Prevention of Thrombosis. 9th

ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(suppl);e278S-e325S.

6. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients. In: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed. American

College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(suppl):e227S-e77S.

7. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients. In: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2) (suppl):e195S-e226S.

8. The RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352.

9. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.

10. The ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363:2487-2498.

11. Van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ. Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest. 2006;129;1155-1166.

12. Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet. 2011;50:675-686.

13. Agnelli G, Gallus A, Goldhaber SZ, et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-

DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients with Acute Symptomatic Deep-Vein Thrombosis) study. Circulation. 2007;116:180-187.

New, Acceptable Options for Anticoagulation of VTEs

TE is a commonly encountered clinical problem. Recommendations for both prophylaxis and treatment differ based on baseline risk, clinical scenario, and bleeding risk, and can be quite complex.3,5-7 Until recently, initial parenteral anticoagulation with overlapping VKA therapy was the only option for treatment of VTE. There are many challenges with VKA therapy, including the slow onset of action, difficulty in maintaining therapeutic drug levels, and need for frequent blood monitoring, as well as the increased bleeding risk. Recently, several new oral anticoagulants have been introduced that appear to have acceptable side-effect profiles when used for the prophylaxis and treatment of VTE.8-10 The EINSTEIN-PE trial sought to evaluate the role of oral rivaroxaban monotherapy for symptomatic PE and compare outcomes of both efficacy and safety with the standard of care, LMWH plus a VKA.4

The desire for less cumbersome oral anticoagulants than VKAs has existed for many years. However, until recently there were no viable options. Warfarin is the  mostcommonly used VKA in clinical medicine and is a burden to both patients and health care providers. Its slow onset of action and narrow therapeutic window, combined with multiple food and drug interactions, necessitate frequent monitoring of blood levels and dose adjustments. Despite this, maintenance of the drug in a therapeutic range is difficult to achieve. In clinical trials, a therapeutic INR (2.0-3.0) is maintained only about 66% of the time and 57% of the time in clinical practice.11 This is problematic as both insufficient and excessive anticoagulation therapy significantly increases the risk of thrombotic and bleeding events, respectively. In the EINSTEIN-PE study, the INR was within the therapeutic range 62.7% of the time and >3.0 only 15.5% of the time, thus representing a “realworld” treatment group and comparable to therapeutic ranges seen in other contemporary trials. Adherence to rivaroxaban was high and drug discontinuation due to adverse events was low and similar in the rivaroxaban and standard therapy groups (4.6% and 3.8%, respectively). Rivaroxaban was not inferior to standard therapy for recurrent VTE, with a lower rate of major bleeding. The ease of administration and lack of monitoring with rivaroxaban, combined with a potentially improved riskbenefit profile, will make this therapy preferable to warfarin for many patients and health care providers.

This trial enrolled a broad spectrum of patients presenting with hemodynamically stable, symptomatic PE. A moderate proportion had concurrent DVT (25%) and

met the study definition of “extensive” anatomic disease (25%). There was no difference in treatment outcomes of recurrent VTE or bleeding for any of the prespecified subgroups, suggesting no need for either monitoring or dose adjustments in the majority of patients. Patients who met the criteria for thrombolytic therapy were not enrolled in this trial and thus this treatment should not be extrapolated to that group of patients.

The dose of rivaroxaban used in this trial deserves discussion: 15 mg twice daily for the first 3 weeks and then 20 mg daily thereafter. The authors wanted to provide intense anticoagulation initially, as it is known that inadequate anticoagulation for initial therapy of VTE leads to unacceptably high recurrence rates. Additionally, in phase 2 trials, pharmacokinetic data show that earlier steady-state levels, higher trough levels, and better thrombus regression at 3 weeks occurs when using twice-daily versus once-daily dosing of rivaroxaban.12,13 There did not appear to be any early hazard in bleeding risk with this more intensive anticoagulant regimen and, as stated earlier, noninferiority to standard therapy was proven.

One of the biggest clinical concerns with rivaroxaban (and other new anticoagulants) is the lack of a specific antidote or reversal agent. The half-life of rivaroxaban is 5 to 9 hours with a peak plasma level after 2 to 4 hours of drug ingestion. Obviously, cases of acute bleeding (ie, trauma or gastrointestinal hemorrhage) are the most  concerning. However, enoxaparin and other LMWHs have been widely used in clinical practice without a specific antidote in existence and have remained the standard of care without overwhelming complications. The biggest potential difference in oral rivaroxaban and LMWH will be the duration of therapy. Anticoagulant therapy for the

treatment of a PE or thromboprophylaxis for AF require much longer time periods than the typical use of LMWH for a few days while bridging to a longer-term therapy.

Whether a clinically significant bleeding risk ensues because of lack of reversibility with this new generation of anticoagulants remains to be seen.

The other concern with rivaroxaban (and other new anticoagulants) is the cost compared with warfarin. These medications generally cost the patient 5 to 100 times as

much as warfarin (depending on presence of insurance and amount of insurance copay). Economic analyses will be important to determine the true cost of warfarin anticoagulation when taking into consideration laboratory monitoring, person-time to adjust doses, medical costs of unintended supra- and sub-anticoagulation, and travel costs to the patient.

In the past few years, multiple new oral anticoagulants have been developed. Most of these drugs focus on directly inhibiting either Factor Xa (rivaroxaban, apixaban,

edoxaban) or thrombin (dabigatran). The benefits of these drugs include ease of administration (oral versus intravenous or subcutaneous), no need for routine monitoring, and improved safety profiles (driven mostly by a reduction in major bleeding episodes). The drawbacks include cost and the irreversible nature of most of these drugs. With currently expanding indications (prophylaxis and treatment of DVT and PE, thromboembolism prophylaxis in AF, acute coronary syndrome therapy) and the lack of enthusiasm for VKAs, these medicines are likely here to stay.

Alison L. Bailey, MD, is assistant professor of medicine and director of cardiac rehabilitation at the Gill Heart Institute, Division of Cardiovascular Medicine, at the University of Kentucky in Lexington. She is also associate director of the cardiovascular fellowship program. Dr Bailey received her MD from the University of Kentucky College of Medicine and completed her residency and fellowship at University of Kentucky Chandler Hospital. Her clinical interests include cardiovascular disease in women and cardiovascular disease prevention. Dr Bailey has been published in numerous peer-reviewed medical journals.

CME Reviews

Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism

The dangerous combination of heart disease, diabetes, and obesity is one that cardiologists confront on a daily basis. It represents a ticking time bomb for countless Americans who struggle to make better choices with their health.

Consider this: a staggering 65% of individuals with diabetes die from some form of heart disease or stroke, according to the American Heart Association. In fact, heart disease and stroke remain the number 1 cause of death and disability among patients with diabetes.

For many patients, genetic factors play a key role in determining risk factors for cardiovascular problems. F

or others, the personal choices they make every day can make a big difference in mitigating the risk of serious complications. After your patients are confronted with the statistics, or the “why” of  making changes for their health, they are going to ask, “How?” Providing you with an understanding of the very latest research— and giving you expert analyses that you can apply to your practice&mdash;is the mission of Cardiology Review.

For a complete update on the relationship between weight loss and heart health, you will not want to miss our special section on Diabetes and Health, which offers a close look at “The Skinny on Weight Loss,” by Peter H. Jones, MD, FACP, FNLA. In addition to examining the latest studies relating to cardiometabolic health, Dr Jones presents clear and practical strategies for discussing weight loss with your patients. These expert insights and applications of research are what you have come to expect in each issue of Cardiology Review.

As always, we also offer you the opportunity to receive CME credits based on the important topics, articles, and commentaries presented in the pages of Cardiology Review. The CME activity for this issue—and all issues of Cardiology Review&mdash;can be found online at www.cardiology-review.com.

Although serving as a front-line advocate for cardiometabolic and cardiovascular health can sometimes feel like a sisyphean task, Cardiology Review is here to provide the fresh perspective, expert opinions, current meeting coverage, and latest news you need to stay ahead of best practices—and make a difference.

President, Chairman, Chief Executive Officer

Letter from the Publisher

Making Healthy Living Manageable

he American Society of Hypertension (ASH) 27th Annual Scientific Meeting, held May 19-22, 2012, in New York City, was a scientific forum for clinical investigators and health care professionals treating hypertension to present research findings and advances in treatment. The presenters addressed emerging trends in research and new developments in the approach to treating patients with hypertension and its consequences. Cardiology Review highlights 4 studies presented at the ASH meeting.

“Clinical Inertia” Common for Hypertension Patients

linical inertia, the failure of the physician to adjust antihypertensive medication regimens within 30 days of a visit in which documented hypertension remained uncontrolled, is common, particularly among those at highest risk for poor outcomes, according to new data presented by Jeffrey Harman, PhD, of the University of Florida in Gainesville.

The study of large, multispecialty group practices showed that 59.4% of patients with hypertension experienced clinical inertia. More than half of the patients experienced

clinical inertia at least once during the study and 45% had uncontrolled hypertension at the end of the study.

The patients who were most likely to experience clinical inertia were older, obese, and Hispanic and had higher blood pressure at the start of the study, said Dr Harman.

“The patients who really need aggressive treatment are the ones who seem to be least likely to be getting it,” he noted. The importance of the problem was highlighted by the finding that patients who experienced inertia were more than 2.5 times as likely to have uncontrolled hypertension at the final office visit during the study. Dr Harman noted that the investigators were unable to assess whether the patients were already taking maximum doses of prescribed medications.

The data suggest that none of the physician characteristics assessed in the study— age, gender, specialty, years in practice, and patient volume&mdash;was associated with

clinical inertia, which suggests that it is a potential problem for all clinicians.

Dr Harman said that possible solutions to clinical inertia were increased physician education and building pop-up warnings or alerts into electronic medical records to remind physicians about the need to bring blood pressure under control.

Harman J, et al. Clinician and patient characteristics associated with clinical inertia

in blood pressure control. ASH 2012; Abstract PO-16.

Resistant Hypertension Associated With Greater Risks

atients with resistant hypertension have significantly higher risks of myocardial infarction (MI), heart failure, stroke, and end-stage renal disease but still

had a 19% lower risk of death through 3 years of follow-up, according to the

results of a study presented by John Sim, MD, of Kaiser Permanente Los Angeles

Medical Center. The reason for the finding of a U-shaped curve is unclear, Dr Sim

said, but the researchers are planning to examine whether greater health care utilization

among the resistant patients could explain the lower death rate. Medication

effects could also provide an explanation because patients with resistant hypertension were more likely to be taking diuretics, ß-blockers, ACE

inhibitors, and angiotensin receptor blockers.

Of 2.4 million adult members in the Kaiser health plan during the study period, 20.7% had hypertension. Resistant hypertension was defined as uncontrolled blood pressure (>140/90 mm Hg) despite the use of 3 antihypertensive medications or the use of 4 antihypertensive medications regardless of blood pressure levels. The study compared clinical outcomes between resistant and nonresistant hypertensives treated within the Kaiser Permanente health system, which has a closed pharmacy system, uniform care aided by a guideline based on Joint National Committee recommendations, low clinical inertia, and a high level of retention in the program.

After adjusting for older age and higher rates of obesity, chronic kidney disease, ischemic heart disease, congestive heart failure, cerebrovascular disease, and diabetes among the patients with resistant hypertension, there was 10% to 36% greater risk of heart failure, stroke, MI, and end-stage renal disease, but a 19% lower risk of dying during followup.

The study’s limitations included the use of single blood pressure values and a lack of information that would have allowed adjustment for pseudoresistant hypertension. The authors stressed the need for further research to better understand the findings.

Dr Sim reported receiving grant/research support from Novartis, sanofi-aventis, and Genzyme. Sim J, et al. Comparative outcomes in resistant hypertension (RH) versus non-RH: Kaiser Permanente Southern California cohort. ASH 2012; Abstract OR-9.

ulaglutide, an investigational glucagon-like peptide (GLP-1) agonist, significantly reduced systolic blood pressure in patients with type 2 diabetes mellitus who were taking oral antihyperglycemic medications. Keith Ferdinand, MD, of Tulane University in New Orleans, LA, presented data from a phase 2 trial of 775 adult patients showing that after 16 once-weekly injections of dulaglutide 1.5 mg, 24-hour ambulatory systolic blood pressure was an average of 2.8 mm Hg lower versus placebo (P <0.001), a difference that was sustained at the end of the 26-week treatment period (2.7 mm Hg; P = 0.002).

The study is the first large randomized trial to use ambulatory monitoring to assess the long-term effects of a GLP-1 agonist on blood pressure and heart rate. Patients had a mean age of 56 years and all had type 2 diabetes mellitus, a glycated hemoglobin level of 7% to 9.5%, were on a stable regimen of at least 1 oral antihyperglycemic medication, and had a mean clinic blood pressure greater than 90/60 mm Hg and less than140/90 mm Hg. Hypertensives had to be taking no more than 3  antihypertension medications.

A lower 0.75-mg dose of dulaglutide resulted in nonsignificant reductions of 1.1 and 1.7 mm Hg. There were slight (but nonsignificant) increases in heart rate with the higher dose. Dr Ferdinand said he and his colleagues did not believe at this point that the increases are clinically significant. Dulaglutide was well tolerated, with serious adverse event rates of 3.2% with placebo and 3.1% with the lower dulaglutide dose and 4.85% with the higher dose.

Four of the study’s coauthors are employed by Eli Lilly, which is developing dulaglutide.

Ferdinand K, et al. Long-term effects of dulaglutide, a novel GLP-1 agonist, on ambulatory blood pressure and heart rate in patients with type 2 diabetes. ASH 2012; Abstract LB-OR-04.

Spanish study suggests that the ambulatory blood pressure monitoring (ABPM) cutoff for the diagnosis of hypertension should be lower in women than in men. Ramon Hermida, PhD, of the University of Vigo in Spain, presented data showing that in a randomized trial of antihypertensive treatment, the ABPM cutoffs associated with an

increased risk of cardiovascular events in men were 135/85 mm Hg for daytime and 120/70 mm Hg for nighttime, which is consistent with current guidelines. However, the cutoffs associated with cardiovascular risk in women were 125/80 mm Hg for daytime and 110/65 mm Hg for nighttime, said Dr.Hermida. Thus, to equal the cardiovascular risk of a man with an awake systolic pressure of 135 mm Hg, a woman only needs to achieve a systolic pressure of 125 mm Hg.

For blood pressure readings of 125/75 mm Hg for daytime and 110/70 mm Hg for nighttime and higher, the risk for cardiovascular events increased more rapidly for women than for men. The findings suggest that the ABPM threshold for starting hypertension treatment should be lower in women even though the current guidelines have the same cutoff figures for both sexes, Dr Hermida noted.

The study included 1718 men and 1626 women with hypertension (mean age, 52.6 years) randomized to take all prescribed antihypertensives after waking up in the morning

or at least 1 of the medications at bedtime. Forty-eight-hour ABPM was performed at baseline and at least annually for every patient in the study. The occurrence of cardiovascular disease events, including cardiovascular mortality, myocardial infarction, coronary revascularization, stroke, and heart failure, was tracked through a median of 5.6 years.

Hermida R, et al. Gender differences in ambulatory blood pressure thresholds for diagnosis of hypertension based on cardiovascular outcomes. ASH 2012; Abstract FP-4.

Meeting Report

Meeting Report: American Society of Hypertension (ASH) 27th Annual Scientific Meeting

he FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 6 to 2 (with 1 abstention) against the approval of rivaroxaban (Xarelto) to reduce the risk of  secondary cardiovascular events in patients with acute coronary syndrome (ACS) in combination with standard antiplatelet therapy. Panel members were concerned about missing data in the ATLAS ACS 2 TIMI 51 trial of rivaroxaban. “The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the risk of bleeding and intracranial hemorrhage, but the studies were hindered by early patient withdrawals and missing data,” according to heartwire (www.theheart.org/article/1405663/print.do).

Rivaroxaban, a product of Bayer/Janssen, is already approved to reduce the risk of venous thromboembolism (VTE) in patients who have just undergone knee or hip replacement surgery and to reduce the risk of hemorrhagic and thrombotic stroke and blood clots in people with atrial fibrillation (AF) not caused by heart valve problems. Bayer/Janssen recently submitted data to the FDA to support its request for an expanded indication for rivaroxaban for treatment of VTE and long-term prevention of recurrent VTE.

• Pfizer has stopped promoting Lipitor in the United States. Lipitor’s patent expired in November 2011 but generic competition was limited to 1 company for the first 6 months. Pfizer had been subsidizing patients’ copayments for Lipitor as well as producing an authorized generic product marketed by Watson Pharmaceuticals.

However, the company is no longer negotiating new contracts to sell Lipitor to health plans and has stopped promoting the drug (www.theheart.org/ article/1396675/print.do).

• The FDA approved generic versions of Bristol-MyersSquibb’s clopidogrel bisulfate (Plavix) (www.fda.gov/newsevents/newsroom/pressannouncements/ucm304489.htm?source=govdelivery).

• The FDA issued a safety alert concerning Zithromax (azithromycin), saying it is aware of the study published in the New England Journal of Medicine on May 17, 2012, reporting a small increase in cardiovascular deaths, and in the risk of death from any cause, in persons treated with a 5-day course of azithromycin compared

with persons treated with amoxicillin, ciprofloxacin, or no drug. The agency is reviewing the results from the study and will communicate new information on azithromycin and this study or the potential risk of QT interval prolongation after the review is completed (www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm304503. htm).

Cardiologists Report Frustration in New Survey

 Medscape survey of 24,216 US physicians across 25 specialties conducted in February 2012 found that if they had to do it all over again, just 50% of cardiologists would choose cardiology as their specialty, and only 18% would choose the same practice setting. Less than half of respondents said they would choose a career in medicine—down from 65% in 2010.

The report showed that US cardiologists earned an average of $314,000 in 2011, with the highest earners those who worked in single-specialty group practices. Only 13% considered themselves wealthy, and 54% felt they were inadequately compensated. Nearly 40% said their income was no better than nonphysicians, and 50% said that although their income might place them in “the 1%,” they did not consider themselves rich because of expenses and debt.

Cardiologists were among the top earners in the survey, behind radiologists and orthopedic surgeons. While 16% of cardiologists earned more than $500,000 in 2011, 15% earned under $100,000; 1% reported earning more than $1 million. The highest-paid cardiologists are located in the north-central United States; cardiologists on the coasts earned less. Female cardiologists earned 32% less than their male counterparts, attributed largely to females working more part-time hours than males. Academic-based cardiologists earned the least of their colleagues in 2011, reporting average salaries of $192,000.

Cardiologists reported working long hours, with 40% spending more than 50 hours/week seeing patients and 11% spending more than 65 hours/week with patients.

Very few cardiologists work in alternative patient-care and payment models, with just 2% now involved in accountable care organizations (ACOs) and 9% planning to be involved in ACOs next year. Forty-three percent of cardiologists believe health care reform will have a negative effect on patient care.

Compensation was considered to be salary, bonuses, profit-sharing contributions for employed cardiologists, and earnings after tax-deductible business expenses

but before income tax for partners in hospitals/specialty clinics.

Among the 645 cardiologists who responded to the survey, 90% were male and 38% were younger than 45 years; 96% were board certified. To read the report, visit www.medscape.com/features/slideshow/compensation/2012/cardiology.

esearchers used skin cells from 2 men with advanced heart failure and induced them to differentiate into cardiomyocytes, which can be integrated with host cardiac tissue. Early tests in animals proved promising, but more work is needed before human trials can begin. “We have shown it’s possible to take skin cells from an elderly patient with advanced heart failure and end up with his own beating cells in a laboratory dish that are healthy and young,” said researcher Lior Gepstein.

he American Heart Association (AHA) recognizes that important scientific results do not always coincide with AHA Scientific Sessions in November. The Emerging 

Science Series presents 1-hour professionalquality webinars held 2 or 3 times yearly; each session has two 30-minute blocks of presentations of original research from late breaking clinical trials, trial updates, and late-breaking basic science. Live webinars will be viewable from computers or mobile phones. Theseries will be archived for on-demand viewing.

ET imaging was used to quantify amounts of denervated myocardium, thus identifying patients who would benefit from receiving implantable cardiac defibrillators (ICDs), according to University of Buffalo researcher John Canty Jr, MD. By imaging the heart’s ability to take up a radioactive tracer of norepinephrine, researchers were able to identify patients at higher risk of experiencing a sudden cardiac arrest. They found that when at least 38% of the heart was denervated there was a significant increase in risk of cardiac arrest.

he American Heart Association’s (AHA’s) Learn: Rapid STEMI ID is a self-directed online course that teaches health care professionals to use a 12-lead ECG, interpret ECGs for signs of ST-segment elevation myocardial infarction (STEMI), and activate a system of care for rapid reperfusion of an occluded coronary artery. The course supports the efforts of the AHA’s Mission: Lifeline, a national initiative to improve quality of care and outcomes in heart attack patients by improving health care systems’

readiness and response to STEMI patients.                                         

News & Trends

Vaidya A, Forman JP. Vitamin D and vascular disease: the current and future status of vitamin D therapy

in hypertension and kidney disease. Curr Hypertens Rep. 2012;14:111-119.

n the past decade, numerous observational studies have implicated vitamin D insufficiency and deficiency as risk factors for hypertension, cardiovascular disease, and kidney disease. Yet prospective randomized trials reported to date have failed to provide convincing evidence that vitamin D supplementation has salutary effects on relevant clinical outcomes. Vaidya and Forman review the putative mechanisms underlying the potential vascular and renal effects of vitamin D; findings from  observational studies examining the relationship between vitamin D, hypertension, and kidney disease; data from clinical trials; and future directions in vitamin D research and the role of vitamin D therapy in the prevention and treatment of cardiovascular and renal disease.1

Based on multiple studies in both laboratory animals and humans, several plausible mechanisms have been proposed whereby low levels of vitamin D might contribute to elevated blood pressure and chronic kidney disease (CKD). By far the best studied and welldocumented effect is that low vitamin D levels are associated with  increased activation of the renin-angiotensinsystem (RAS), including increased renin activation, increased circulating angiotensin II concentrations, and increased

RAS activity in cardiac and renal tissue. These effects contribute directly to elevations in blood pressure and left ventricular mass, as well as to renal injury. Conversely, these effects are attenuated by RAS inhibitors, vitamin D supplementation, or administration of vitamin D receptor (VDR) agonists.

Additional mechanisms that may contribute to the associations of vitamin D with vascular and renal pathology include vitamin D—mediated alterations in calcium flux in vascular smooth muscle cells, alterations in the effects of advanced glycation end products on endothelium, alterations in nitric oxide system activity, alterations in activity of inflammatory cytokines and other mediators of inflammation, and alterations in prostacyclin production. Studies in humans also indicate that higher vitamin D concentrations are associated with improved endothelial function, reduced oxidative stress, and increased circulating adipocytokine levels. Vitamin D may also inhibit renin gene expression, and there is evidence that VDR agonists inhibit transforming growth factor beta and extracellular signal-regulated protein kinase, implying anti-proliferative and/or anti-inflammatory renoprotective effects.

Cross-sectional and prospective observational studies examining the relationship between vitamin D and blood pressure have provided inconsistent findings. In several large prospective studies, including the Health Professionals’ Follow-up Study in men and both the Nurses’ Health Study and Michigan Bone Health and Metabolism

Study in women, lower vitamin D levels at baseline were associated with significantly higher rates of incident hypertension during follow-up periods ranging from 4 to 14 years.2-4 Conversely, the Tromso Study failed to find a significant relationship between baseline vitamin D levels and either blood pressure orincident hypertension during 14 years of follow-up.5

Observational studies evaluating the association between vitamin D and renal disease have also produced mixed results. In the Third National Health and Nutrition Examination Survey (NHANES III), a cross-sectional study of over 15,000 US adults, individuals in the lowest vitamin D quartile had a moderate but significantly higher prevalence of albuminuria than those in the highest quartile (odds ratio 1.37).6 Several small longitudinal studies have also shown an association between baseline

vitamin D levels and progression of kidney disease and proteinuria. Nonetheless, a meta-analysis of 22 studies of low to moderate quality, including 17 observational studies and 5 randomized trials, found no significant effect of vitamin D2 or D3 supplementation on either renal function or urinary albumin excretion.7

As previously reported by Vaidya and Forman and briefly summarized in the current review, there have been approximately 13 prospective randomized trials involving vitamin D therapy for which data on blood pressure are available.1,8 The largest of these studies, the Women’s Health Initiative, enrolled 36,252 subjects9; all other studies enrolled fewer than 500 subjects and more than half enrolled fewer than 100 subjects. The dose of vitamin D was highly variable and the followup duration ranged from 5 weeks to 7 years. Only 2 of the studies evaluated blood pressure as the primary end point in subjects free of antihypertensive therapy. Overall, 11 of the 13

studies found no effect of vitamin D therapy on blood pressure. Two studies reported a favorable effect, including 1 study in which blood pressure was the primary end point. In this study, 800 IU of vitamin D3 for 8 weeks was associated with a 7—mm Hg decline in systolic blood pressure compared with placebo among 148 older women with a mean baseline 25-(OH)-vitamin D level of 10 ng/mL.10 All studies reported to date are limited by small sample size, short follow-up, and/or insufficient dose of vitamin D to significantly affect serum levels.

As noted previously, a meta-analysis that included 5 low- to moderate-quality randomized trials failed to show a beneficial effect of vitamin D therapy on renal outcomes. On the other hand, 5 trials evaluating the effect of a VDR agonist (paricalcitol or calcitriol) on proteinuria consistently demonstrated a salubrious effect. These studies ranged in size from 10 to 281 subjects, and follow-up ranged from 1 month to 6 months; all subjects had baseline CKD stages 2 to 4. In the largest and most

recent study, paricalcitol 2 mcg/d for 6 months was associated with an 18% to 28% reduction in the urinary albuminto-creatinine ratio relative to placebo.11 A limitation of these studies, apart from small sample size and short duration, is that none evaluated renal function per se as the primary outcome.

Mechanistic studies in laboratory animals and humans provide strong support for a role for vitamin D in the regulation of vascular and renal function, as well as a clear basis for an association between vitamin D insufficiency and deficiency and hypertension, vascular disease, and kidney disease. However, observational studies and clinical trials in humans have been inconclusive. It is important to note that all randomized trials to date are beset with major limitations. It is therefore evident that additional mechanistic and clinical studies are essential in order to elucidate the role of vitamin D replacement therapy, VDR agonists, and increased sun exposure in the prevention and treatment of hypertension and kidney disease. In this regard, the ongoing Vitamin D and Omega-3 (VITAL) study, which is randomizing 20,000 US subjects to vitamin D3 2000 IU daily or placebo and to omega-3 fatty acids or placebo, should provide valuable insights.12

1. Vaidya A, Forman JP. Vitamin D and vascular disease: the current and future status of vitamin D therapy in hypertension and kidney disease. Curr Hypertens Rep. 2012;14:111-119.

2. Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension. 2007;49:1063-1069.

3. Forman JP, Curhan GC, Taylor EN. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension among young women. Hypertension. 2008;52:828-832.

4. Griffin FC, Gadegbeku CA, Sowers MR. Vitamin D and subsequent systolic hypertension among women. Am J Hypertens. 2010;24:316-321.

5. Jorde R, Figenschau Y, Emaus N, Hutchinson M, Grimnes G. Serum 25-hydroxyvitamin D levels are strongly related to systolic blood pressure but do not predict future hypertension. Hypertension. 2010;55:792-798.

6. deBoer IH, Ioannou GN, Kestenbaum B, Brunzell JD, Weiss NS. 25-Hydroxyvitamin D levels and albuminuria in the Third National Health and Nutrition Examination

Survey (NHANES III). Am J Kidney Dis. 2007;50:69-77.

7. Kandula P, Dobre M, Schold JD, Schreiber Jr MJ, Mehrotra R, Navaneethan SD. Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials. Clin J Am Soc Nephrol. 2011;6:50-62.

8. Vaidya A, Forman JP. Vitamin D and hypertension. Current evidence and future directions. Hypertension. 2010;56:774-779.

9. Margolis KL, Ray RM, Van Horn L, et al. Effect of calcium and vitamin D supplementation on blood pressure: the Women’s Health Initiative Randomized Trial. Hypertension. 2008;52:847-855.

10. Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen D. Effects of a shortterm vitamin D(3) and calcium supplementation on blood pressure and parathyroid

hormone levels in elderly women. J Clin Endocrinol Metab. 2001;86:1633-1637.

11. De Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL

study): a randomised controlled trial. Lancet. 2010;376:1543-1551.

12. Clinicaltrials.gov. Vitamin D and Omega-3 Trial (VITAL). http://clinicaltrials.gov/ct2/show/NCT01169259. Accessed April 9, 2012.

13. McGreevy C, Williams D. New insights about vitamin D and cardiovascular disease: a narrative review. Ann Intern Med. 2011;155:820-826.

14. Qaseem A, Snow V, Shekelle P, Hopkins R Jr, Forciea MA, Owens DK. Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;149:404-415.

15. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and metaanalysis. BMJ. 2011;342:d2040.

Current and Future Status of Vitamin D Therapy

ardly a week goes by without a new article in a major medical journal expounding on the dangers of vitamin D deficiency or extolling the virtues of vitamin D supplementation. Indeed, vitamin D deficiency has been linked not only to hypertension and cardiovascular disease, but also to diabetes, stroke, kidney disease, various forms of cancer, multiple sclerosis, dementia, pre-eclampsia, and even statin myopathy (not to mention the more prosaic disorders, osteoporosis and fractures). Conversely, vitamin D supplementation, usually in mega-dosages, is proposed as a potential panacea for all of these ills. But where is the evidence? Is this the vitamin

E, vitamin C, homocysteine, and hormone replacementtherapy story all over again?

One thing is clear: vitamin D insufficiency and deficiency are very common among American adults, affecting up to 75% of individuals.8 But is there even consensus on what constitutes insufficiency or deficiency? Not really, as insufficiency has been variously defined as <40 ng/ mL, <30 ng/mL, or <25 ng/mL, and deficiency has been defined as <20 ng/mL, <15 ng/mL, or <10 ng/mL. Given how arbitrary these definitions appear to be, it seems that some degree of skepticism is appropriate before accepting the claim that 75% of Americans are afflicted with hypovitaminosis D.

Fortunately, reviews like the one published in Current Hypertension Reports and another similar review by Mc-Greevy and Williams in the Annals of Internal Medicine

provide a more balanced view.1,13 Yes, there is good evidence that vitamin D plays a role in regulating the RAS and vascular function. And, yes, there is reasonable evidence that low vitamin D levels (however defined) may be associated with higher blood pressure and increased risk for vascular disease, kidney disease, and possibly other disorders. But there is no convincing evidence at this time that vitamin D replacement has a beneficial effect on any conditions other than rickets and osteoporosis (including prevention of hip fractures).

So how should the clinician translate current data on vitamin D into routine patient care? Should 25-(OH)-vitamin D levels be incorporated into patients’ cardiovascular risk profiles and assessed as part of standard chemistry batteries at regular intervals? Certainly not. However, it is reasonable and appropriate to check vitamin

D and possibly parathyroid hormone (PTH) levels in individuals at increased risk for osteoporosis, falls, and fractures, and to advocate supplemental vitamin D and calcium in accordance with current guidelines.14 Absent a routine vitamin D level, should all patients be advised to take vitamin D supplements (given that most

are likely to have “low” levels), and if so, how much? This is a difficult question. All patients should be encouraged to eat a balanced diet that contains sufficient

amounts of vitamin D from natural sources to meet or exceed the recommended daily allowance. Regular exercise and adequate sun exposure are also appropriate. But

based on the current lack of evidence to support vitamin D supplementation for the prevention or treatment of hypertension, cardiovascular disease, or kidney disease, routine vitamin D supplementation does not seem warranted. Indeed, there is evidence to suggest that vitamin D taken in conjunction with calcium may actually promote accelerated atherosclerosis.15 

What do I tell my patients who ask if they should take vitamin D? For individuals with or at risk for osteoporosis, the answer is “yes,” and I usually recommend a minimum of 2000 IU daily along with calcium and close follow-up by their primary care physician. For those not at risk for osteoporosis, I usually explain that there is no evidence that taking vitamin D is beneficial, but also that it’s probably not harmful at modest dosages, such as 1000 to 2000 IU per day, and that it is therefore OK to take it, if desired.

In conclusion, I completely concur with Vaidya and Forman’s call for additional research on vitamin D, and eagerly await the results of the VITAL study (unfortunately, probably some 5 years away), which will hopefully answer key questions not only about vitamin D, but also about omega-3 fatty acid supplementation.

Michael W. Rich, MD, is professor of medicine in the Cardiovascular Division of the Washington University School of Medicine in St. Louis, MO. He is also director of the Cardiac Rapid Evaluation Unit at Barnes- Jewish Hospital in St. Louis. He received his MD from the University of Illinois College of Medicine in Chicago, and did his internship, residency, and cardiology fellowship at the Jewish Hospital of St. Louis. Dr Rich’s main areas of interest are cardiovascular aging and cardiovascular disease in the elderly. He has published many papers, reviews, and book chapters related to heart failure and atrial fibrillation.

Current and Future Status of Vitamin D Therapy in Hypertension and Kidney Disease

Weintraub WS, Grau-Sepulveda MV, Weiss JM, et al. Comparative effectiveness of revascularization

strategies. N Engl J Med. 2012;366:1467-1476.

ercutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) for patients with stable ischemic heart disease (SIHD) are revascularization strategies that have been in competition for over 25 years. A dozen randomized trials have compared them for revascularization efficacy and many more observational

reports have evaluated the 2 types of procedures for revascularization effectiveness. It has previously been established that PCI does not reduce the risk of death or myocardial infarction (MI) compared with medical therapy, but that it is excellent at reducing angina pectoris and myocardial ischemia, and improving quality of life. Likewise, there is no survival advantage with CABG compared with medical therapy in patients with single- and double-vessel coronary artery disease (CAD) and in patients with normal left ventricular function. CABG  accomplishes the same goals as PCI and offers more durable benefit with less need for repeat revascularization

procedures, but is associated with the complications of major surgery, more hospital days, and a longer recovery period. CABG is superior to PCI in complex triple-vessel CAD, but PCI is a comparable strategy when focal triple-vessel CAD is present.1

A strong case can be made that the only revascularization intervention in patients with SIHD that prolongs life is an internal mammary graft to the left anterior descending artery. Conversely, it is quite possible that stents will prove to be superior to saphenous vein bypass grafts that degenerate after several years and lead to major clinical challenges. Whereas cardiac surgery has made important progress in reducing perioperative stroke and MI rates, interventional cardiology has made advances in treating chronic total occlusions, bifurcation lesions, and left main stenosis. And so the debate over efficacy and effectiveness continues into its third decade.

The American College of Cardiology Foundation (ACCF) and the Society for Thoracic Surgery (STS) have established important national data registries for PCI and CABG. The NHLBI-funded ASCERT (ACCF and STS Database Collaboration on the Comparative Effectiveness of Revascularization Strategies) study linked hospital data from the 2 registries collected from 2004 through 2007 to claims data from the Centers for Medicare & Medicaid Services to analyze long-term mortality, re-hospitalization,

June 2012

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Current and Future Status of Vitamin D Therapy in Hypertension and Kidney Disease

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