December 2010 Vol. 16 No.

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From the publishers of The New England Journal of Medicine

CA RDI OLOGY
NEWS IN CONTEXT Dabigatran Is Approved for AFib
Will dabigatran replace warfarin?

On October 19, 2010, dabigatran (Pradaxa; an oral thrombin inhibitor) was approved by the FDA (http://viajwat.ch/bHYWi5) to lower risk for thrombus and stroke in patients with atrial fibrillation (AF). Unlike warfarin, dabigatran is given in fixed twice-daily doses and does not require international normalized ratio (INR) monitoring. The approval comes on the heels of the RE-LY trial, in which >18,000 people were randomized to one of two twice-daily doses of dabigatran (110 mg or 150 mg) or to dose-adjusted warfarin and were followed for a median of 2 years (JW Cardiol Oct 2009, p. 82, and N Engl J Med 2009; 361:1139). In RE-LY, risk for systemic embolism or stroke was 1.7% in the warfarin group, 1.5% in the 110-mg group, and significantly lower 1.1% in the 150-mg

group. The rate of major bleeding was significantly lower in the 110-mg group (2.7% annually) than in the warfarin group (3.4%) or in the 150-mg group (3.1%). Dyspepsia was almost twice as common with dabigatran as with warfarin, and the rate of myocardial infarction (MI) was higher in both dabigatran groups (0.5% annually for warfarin vs. 0.7% in both dabigatran groups).
COMMENT

The FDAs action gives physicians an alternative to warfarin in patients with AF who are at excess risk for stroke. Interestingly, only the 75-mg and 150-mg capsules were approved for this indication. Dabigatran should not be used in patients with renal dysfunction, severe heart-valve disorders, liver disease, recent stroke, or other conditions that raise risk for hemorrhage; data for other indications, such as mechanical valves, are lacking. MI risk should be monitored closely. Dabigatran also should not be given to pregnant women or patients with clinically significant dyspepsia.

But who should be treated with dabigatran instead of warfarin? Some experts suggest that we have little reason to switch patients with stable INRs who are doing well on warfarin, especially because the yearly cost of dabigatran likely will be thousands of dollars, whereas generic warfarin now is available at some U.S. pharmacies for pennies a day. Of course, the costs of INR monitoring are also relevant, although these might be less important to patients than out-of-pocket drug costs. Only time will tell to what extent dabigatran displaces warfarin and to what extent other emerging alternatives to warfarin (e.g., oral factor Xa inhibitors, such as rivaroxaban) will compete with dabigatran. But, in the meantime, anticipate frank discussions with and many questions from patients about the pros and cons of this new drug.
Kirsten E. Fleischmann, MD, MPH, Journal Watch General Medicine

SUMMARY & COMMENT Warfarin, Aspirin, and Clopidogrel in AFib

Any combination raises risk for bleeding without lowering risk for ischemic stroke.

CONTENTS
NEWS IN CONTEXT

Dabigatran Is Approved for AFib .............................. 93

SUMMARY & COMMENT

Fondaparinux for Treatment of Supercial Venous Thrombosis............................. 97 More Work on Weight Loss....................................... 97 New Perspectives on an Old Problem: Tailoring Treatment for Hypertension ................... 99 Vascular Events After Invasive Dental Procedures ................................... 99 Blood Transfusions in Cardiac Surgery: Too Much, Too Soon? ............................................ 100
DRUG WATCH

Warfarin, Aspirin, and Clopidogrel in AFib ............. 93 More Controversy over Clopidogrel ........................ 94 Ten-Year Findings from a Randomized ................... 95 Comparison of CAD Therapies Does a Gene Expression Test Help Identify Patients with Obstructive CAD? ............................ 95 Chest Compression-Only CPR by Lay Rescuers Increases Survival.......................... 96 Testosterone Replacement for Women with Chronic HF ......................................... 96 Preventing DVT After Stroke: Thigh-High vs. Below-Knee Stockings ................ 96

Label Change for Saquinavir ..................................... 95

FEATURE

Many patients with new-onset atrial fibrillation (AF) receive anticoagulation with warfarin, but many have coexisting vascular disease that requires platelet inhibition. Combinations of warfarin, aspirin, and clopidogrel often are used and even endorsed in some practice guidelines, but their safety and benefit are not fully characterized. Danish investigators used national registries to identify 119,000 patients who survived first hospitalizations for AF. Nearly 83,000 were discharged on warfarin, aspirin,

Individualized Strategies for the Use of Antihypertensive Drugs........................................... 98

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EDITOR-IN-CHIEF Harlan M. Krumholz, MD, SM, Harold H. Hines, Jr., Professor of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven EXECUTIVE EDITOR Kristin L. Odmark Massachusetts Medical Society DEPUTY EDITOR Howard C. Herrmann, MD, Professor of Medicine, Director, Interventional Cardiology and Cardiac Catheterization Laboratories, University of Pennsylvania Medical Center, Philadelphia ASSOCIATE EDITORS JoAnne M. Foody, MD, Director, Cardiovascular Wellness Center, Brigham and Womens Hospital, Boston Joel M. Gore, MD, Edward Budnitz Professor of Cardiovascular Medicine, University of Massachusetts, Worcester Mark S. Link, MD, Associate Professor of Medicine, New England Medical Center and Tufts University School of Medicine, Boston Frederick A. Masoudi, MD, MSPH, Division of Cardiology, Denver Health Medical Center and Associate Professor of Medicine, University of Colorado at Denver Beat J. Meyer, MD, Associate Professor of Cardiology, University of Bern; Chief, Division of Cardiology, Lindenhofspital, Bern, Switzerland CONTRIBUTING EDITORS William T. Abraham, MD, Professor of Medicine, Chief, Division of Cardiovascular Medicine, The Ohio State University Heart Center, Columbus Hugh Calkins, MD, Professor of Medicine and Director of Electrophysiology, The Johns Hopkins Hospital, Baltimore FOUNDING EDITOR Kim A. Eagle, MD, Albion Walter Hewlett Professor of Internal Medicine and Chief of Clinical Cardiology, Division of Cardiology, University of Michigan Medical Center, Ann Arbor MASSACHUSETTS MEDICAL SOCIETY Christopher R. Lynch, Vice President for Publishing; Alberta L. Fitzpatrick, Publisher Betty Barrer, Christine Sadlowski, Sharon S. Salinger, Staff Editors; Martin Jukovsky, Copy Editor; Misty Horten, Layout; Matthew ORourke, Director, Editorial and Product Development; Robert Dall, Editorial Director; Art Wilschek, Christine Miller, Lew Wetzel, Advertising Sales; William Paige, Publishing Services; Bette Clancy, Customer Service Published 12 times a year. Subscription rates per year: $119 (U.S.), C$166.67 (Canada), US$165 (Intl); Residents/Students/Nurses/PAs: $69 (U.S.), C$96.19 (Canada), US$80 (Intl); Institutions: $219 (U.S.), C$256.19 (Canada), US$230 (Intl); individual print only: $89 (U.S.). Prices do not include GST, HST, or VAT. In Canada remit to: Massachusetts Medical Society C/O #B9162, P.O. Box 9100, Postal Station F, Toronto, Ontario, M4Y 3A5. All others remit to: Journal Watch Cardiology, P.O. Box 9085, Waltham, MA 02454-9085 or call 1-800-843-6356. E-mail inquiries or comments via the Contact Us page at JWatch.org. Information on our conflict-of-interest policy can be found at JWatch.org/misc/conflict.dtl

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clopidogrel, or combinations thereof most commonly with warfarin alone (42.9%), aspirin alone (40.0%), or warfarin plus aspirin (15.5%). In analyses adjusted for age, sex, comorbidity, and concomitant medical therapies, risk for fatal or serious nonfatal bleeding was 3.7-fold higher in patients who received triple therapy (warfarin plus aspirin plus clopidogrel) versus warfarin alone, 3.1-fold higher in patients who received warfarin plus clopidogrel, and 1.7- to 1.8-fold higher in patients who received aspirin plus clopidogrel or aspirin plus warfarin. No benefit was noted for triple therapy or warfarin plus clopidogrel in lowering risk for ischemic stroke.
COMMENT

pharmacodynamic response to clopidogrel has generated controversy over dosing, the concomitant use of proton pump inhibitors (JW Cardiol Nov 2010, p. 92, and N Engl J Med 2010; 363:1909), and the need for functional or genetic testing. In this collaborative meta-analysis, data were pooled from nine genetic studies including 9685 ACS patients; median study follow-ups ranged from 30 days to about 1 year. One reduced-function CYP2C19 allele was identified in 26%, and two reduced-function alleles in 2%, of patients. Incidence of the composite of death, myocardial infarction, and ischemic stroke during follow-up was significantly increased by 57% in patients with at least one reduced-function allele (26% in those with one allele, 76% in those with two), compared with those with no reduced-function alleles. In 5894 stent recipients from six studies, the risk for stent thrombosis was significantly increased in patients with at least one reduced-function allele (hazard ratio, 2.81 overall; 2.67 with one allele; and 3.97 with two alleles).
COMMENT

These results show that adding platelet inhibition to warfarin a common practice significantly raised risk for fatal and serious bleeding. Warfarin plus clopidogrel and triple therapy are particularly risky combinations. These data argue for much greater care in the use of platelet inhibition with warfarin even when a strong indication exists to use both. For example, in a patient with a mechanical prosthetic valve or AF with high risk for stroke who requires antiplatelet therapy for stenting, bare-metal (rather than drug-eluting) stents should be considered preferentially to shorten the length of time that the patient receives triple therapy.
Thomas L. Schwenk, MD, and Kirsten E. Fleischmann, MD, MPH, Journal Watch General Medicine
Hansen ML et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010 Sep 13; 170:1433.

More Controversy over Clopidogrel

A meta-analysis supports the association of reduced-function CYP2C19 risk alleles with adverse ACS.

This meta-analysis demonstrates an increased risk for cardiovascular events, including stent thrombosis, in patients with even one reduced-function allele for clopidogrel activation, a variant present in about 30% of the population. These findings support an FDA boxed warning issued in March 2010, but logistical and practical barriers remain obstacles to genetic testing. If future studies demonstrate that medication adjustment based on these tests improves outcomes, functional platelet testing and newer antiplatelet agents might play a greater role than genetic testing in the management of ACS and in percutaneous coronary intervention.
Howard C. Herrmann, MD
Mega JL et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: A meta-analysis. JAMA 2010 Oct 27; 304:1821. Fuster V and Sweeny JM. Clopidogrel and the reduced-function CYP2C19 genetic variant: A limited piece of the overall therapeutic puzzle. JAMA 2010 Oct 27; 304:1839.

Clopidogrel prevents stent thrombosis and cardiovascular events in patients with acute coronary syndromes (ACS) by inhibiting the adenosine diphosphate P2Y12 platelet receptor. Variability in patients

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Ten-Year Findings from a Randomized Comparison of CAD Therapies

Compared with medical therapy, revascularization improved some outcomes in patients with stable multivessel disease.

DRUG WATCH Label Change for Saquinavir

The new label outlines an increased risk for abnormal heart rhythms when saquinavir is used with ritonavir.

In the Brazilian single-center MASS II trial, 611 patients with multivessel coronary artery disease (CAD), stable angina, and preserved left ventricular function were randomized to medical therapy (MT), percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG). At 5-year follow-up, mortality was similar in all three groups. The MASS II authors now report results at an average follow-up of 11.4 years. The primary endpoint was a composite of total mortality, Q-wave myocardial infarction (MI), and refractory angina requiring revascularization. A primary endpoint occurred in significantly fewer CABG patients (33%) than PCI or MT patients (42% and 59%, respectively). Cardiac mortality was lower in the CABG and PCI groups (11% and 14%, respectively) than in the MT group (21%); overall mortality remained similar in all three groups. Compared with patients assigned to CABG, larger proportions of patients assigned to PCI or MT had additional revascularization (about 40% vs. 7%) and nonfatal MI (13%21% vs. 10%). Subgroup analyses (sex, age, presence of diabetes, etc.) produced similar results. About 60% of patients in the CABG and PCI groups were free of angina, compared with about 40% in the MT group. Stroke incidence was slightly but nonsignificantly higher in the CABG group than in the other two groups.
COMMENT

On October 21, 2010, the FDA announced that the label for saquinavir will now carry a warning of an increased risk for cardiac problems when the drug is used in combination with ritonavir. Taken together, these drugs can cause prolongation of the QT and PR intervals, potentially leading to serious arrhythmias, such as torsades de pointes and complete heart block. Patients with underlying heart conditions or problems with their heart rate or rhythm are at particularly elevated risk.

An electrocardiogram (ECG) should be performed before ritonavirboosted saquinavir is initiated. Ongoing ECG monitoring may be appropriate in some patients. A similar warning was added to the label of lopinavir/ritonavir in 2009.
U.S. Food and Drug Administration (FDA). FDA Drug Safety Communication: Invirase (saquinavir) labels now contain updated risk information on abnormal heart rhythms. Oct 21, 2010.

ists emphasize, future trials should stratify patients based on extent of ischemia in addition to symptoms.
Howard C. Herrmann, MD
Hueb W et al. Ten-year follow-up survival of the medicine, angioplasty, or surgery study (MASS II): A randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease. Circulation 2010 Sep 7; 122:949. Williams DO et al. Is optimal medical therapy optimal therapy for multivessel coronary artery disease?: Optimal management of multivessel coronary artery disease. Circulation 2010 Sep 7; 122:943.

of obstructive CAD. The authors used the Diamond-Forrester risk score, based on age, sex, and chest pain type, to evaluate the additive value of the gene expression score. In the validation cohort, obstructive CAD was present in 192 patients and absent in 334 patients. The area under the ROC curve for the algorithm was 0.70 (P<0.001). Compared with the DiamondForrester risk score alone, adding the gene expression score modestly but significantly improved the prediction of obstructive CAD; however, the net improvement in risk reclassification was only 20%.
COMMENT

Does a Gene Expression Test Help Identify Patients with Obstructive CAD?
Not yet.

Although this study is underpowered for survival endpoints, it has longer follow-up data than any other randomized study of multivessel CAD treatments in the stent era. Compared with MT, both CABG and PCI reduced cardiac mortality, and CABG reduced rates of MI, additional revascularization, and angina. The extent of disease in the MASS II patients was considerably greater than in the COURAGE trial (JW Cardiol May 2007, p. 37, and N Engl J Med 2007; 356:1503), a possible explanation for the greater benefit observed with revascularization in MASS II. Finally, as editorial-

Diagnosing obstructive coronary artery disease (CAD) without the use of invasive procedures or exposure to radiation and contrast agents remains a clinical challenge. In a multicenter, prospective trial, investigators used gene expression testing to analyze blood samples from nondiabetic patients scheduled to undergo coronary angiography. Risk for obstructive CAD (defined as atherosclerotic plaque causing 50% stenosis in one or more major coronary arteries) was scored according to an algorithm developed by the study sponsor. The primary endpoint was the area under the receiver-operating characteristics (ROC) curve for the algorithms prediction

Although this genetic algorithm was significantly associated with obstructive CAD in high-risk patients, its usefulness in clinical settings is unclear, because it does not substantially improve upon knowledge of clinical factors in estimating a patients risk. The small size of the cohort, the exclusion of diabetic patients, and the fact that all patients were already suspected of having CAD further limit interpretation of the findings. Joel M. Gore, MD
Rosenberg S et al. Multicenter validation of the diagnostic accuracy of a blood-based gene expression test for assessing obstructive coronary artery disease in nondiabetic patients. Ann Intern Med 2010 Oct 5; 153:425. Arnett DK. Gene expression algorithm for prevalent coronary artery disease: A first step in a long journey. Ann Intern Med 2010 Oct 5; 153:473.

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Chest Compression-Only CPR by Lay Rescuers Increases Survival

A statewide public education and training program in Arizona yielded impressive results.

Guidelines now recommend that untrained bystanders provide compression-only CPR for adults.
John A. Marx, MD, FAAEM, Journal Watch Emergency Medicine
Bobrow BJ et al. Chest compressiononly CPR by lay rescuers and survival from out-of-hospital cardiac arrest. JAMA 2010 Oct 6; 304:1447.

In 2005, Arizona initiated a multifaceted public education program promoting compression-only bystander cardiopulmonary resuscitation (CPR) that included direct training of more than 30,000 people and a media campaign. In a prospective, observational cohort study of adults (18 years) with out-of-hospital cardiac arrest in Arizona from 2005 through 2009, researchers compared survival in those who received conventional bystander CPR with survival in those who received compression-only bystander CPR. Of 4415 patients (67% men; mean age, 65), 66% received no CPR, 15% received conventional CPR, and 19% received compression-only CPR. The rate of bystander CPR increased significantly from 28% in 2005 to 40% in 2009, and the proportion of CPR that was compression-only CPR increased significantly from 20% to 76%. Rates of survival to discharge the primary outcome were 5% with no CPR, 8% with conventional CPR, and 13% with compression-only CPR. Rates of survival with good neurological status were 3%, 5%, and 8%, respectively. In multivariate analysis adjusted for potential confounders, compression-only CPR was independently associated with increased survival compared with conventional CPR (odds ratio, 1.60). Overall survival increased significantly from 4% in 2005 to 10% in 2009.
COMMENT

Testosterone Replacement for Women with Chronic HF

Findings from a small study showed some improvements in functional measures.

used in men has beneficial effects on functional capacity and metabolic status in older women with systolic HF. Whether the functional improvements resulted from improved skeletal muscle performance or increased hematocrit is not clear. Moreover, because the study was small and dropout substantial, many additional questions including the safety of androgen replacement and its effects on a broader range of outcomes must be addressed before this therapy can be considered for clinical use.
Frederick A. Masoudi, MD, MSPH
Iellamo F et al. Testosterone therapy in women with chronic heart failure: A pilot double-blind, randomized, placebo-controlled study. J Am Coll Cardiol 2010 Oct 12; 56:1310.

Heart failure (HF), although considered primarily a condition of cardiac function, is also characterized by numerous noncardiac disturbances, including impaired skeletal and muscular function and metabolic disorders such as low androgen levels and impaired insulin sensitivity. Low testosterone levels in HF patients are associated with functional impairment, and in small studies including only men, testosterone replacement produced improvements in functional capacity and insulin sensitivity. However, until now, the effects of testosterone replacement in women with HF had not been studied. Investigators randomized 36 postmenopausal women (mean age, 68) with clinically stable left ventricular (LV) systolic function but New York Heart Association class III symptoms to receive, in a 2:1 ratio, transdermal testosterone (300 g) or placebo twice weekly for 24 weeks. At 6 months, testosterone recipients showed significant improvements in 6-minute walking distance (mean increase, 96.6 meters); insulin resistance, as measured by the homeostasis model; and hematocrit (mean increase, 3.1%). Testosterone recipients also had significantly better leg muscle strength (measured by dynamometerdetermined isometric and isokinetic effort) but no change in LV ejection fraction. Four testosterone recipients dropped out within the first 2 months for reasons reportedly unrelated to therapy, and four additional patients (2 each in the testosterone and placebo groups) dropped out between 3 and 6 months.
COMMENT

Preventing DVT After Stroke: Thigh-High vs. Below-Knee Stockings

Thigh-high stockings were more effective than below-knee stockings, but neither provided more than a modest benefit.

Graduated compression stockings reduce pooling of blood in the deep veins and are frequently used alone or together with anticoagulation to decrease the risk for deep venous thrombosis (DVT). Investigators recently conducted a multinational, multicenter trial among immobilized, hospitalized stroke patients to determine whether below-knee stockings are as effective as thigh-high stockings. The stockings used in the study were manufacturer-supplied. A total of 3114 patients were randomized to receive thigh-high or below-knee stockings to wear while they were hospitalized. Ultrasonography of the lower extremity was performed between 7 and 10 days after enrollment. A second scan, if practical, was done 25 to 30 days after enrollment. The primary outcome was symptomatic or asymptomatic DVT in the popliteal or femoral veins, detected by scan. Seventy-five percent of the patients in both groups wore the stockings for 30 days or until they were discharged, died, or regained their mobility. The primary outcome occurred in 6.3% of patients who received thigh-high stockings and 8.8% of those who received below-knee stockings (absolute difference, 2.5%). The difference

Bystander CPR is known to enhance the likelihood of survival, yet it is attempted in fewer than 30% of out-of-hospital cardiac arrests in the U.S. This study demonstrates that a widespread education campaign increased bystander CPR in general and compression-only CPR a method more appealing to bystanders specifically. Moreover, compression-only CPR improved survival compared with conventional CPR, likely because it avoids the diminished forward blood flow caused by interruption of chest compressions and the reduced cardiac venous return associated with positive pressure ventilation. Of note, the recently released 2010 American Heart Association

This randomized trial provides some evidence that testosterone replacement in doses much smaller than those typically

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in DVT rate was largely caused by a reduction in proximal DVTs. Antithrombotic use, time from stroke onset to randomization, and leg weakness showed no significant effect on the primary outcome.
COMMENT

The finding that in stroke patients, belowknee compression stockings did not prevent DVT as well as thigh-high stockings raises a concern for other patient groups who receive such interventions. The event rates with thigh-high stockings in this study were higher than would be expected with anticoagulation. For patients who have contraindications to anticoagulation treatment and use below-knee stockings for DVT prophylaxis, the present findings should prompt a change to thigh-high stockings. Joel M. Gore, MD
The CLOTS (Clots in Legs Or sTockings after Stroke) Trial Collaboration. Thigh-length versus below-knee stockings for deep venous thrombosis prophylaxis after stroke: A randomized trial. Ann Intern Med 2010 Nov 2; 153:553. Kearon C and ODonnell M. Should patients with stroke wear compression stockings to prevent venous thromboembolism? Ann Intern Med 2010 Nov 2; 153:610.

In this randomized trial among patients with superficial venous thrombosis, lowdose fondaparinux lowered the incidence of DVT and PE but had no effect on mortality. Given the negligible rate of adverse events, the temptation might exist to initiate treatment in all patients with superficial venous thrombosis. However, 88 patients would need to be treated for approximately 45 days to prevent a single DVT or PE with no effect on mortality. Furthermore, these researchers did not examine whether watchful waiting and reassessment would have captured patients at risk for progression. As noted in an accompanying editorial, routine use of fondaparinux cannot be justified until cost-effectiveness and quality-of-life studies show a benefit.
Jamaluddin Moloo, MD, MPH, Journal Watch General Medicine
Decousus H et al. Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med 2010 Sep 23; 363:1222. Goldman L and Ginsberg J. Superficial phlebitis and phase 3.5 trials. N Engl J Med 2010 Sep 23; 363:1278.

In another study, 130 severely obese people (mean age, 47; mean body-mass index, 44 kg/m2 ) received a diet intervention that provided regular group, individual, and telephone contacts, free liquid and packaged meals for the initial months, and pedometers and other exercise aids. Participants were randomized to receive an exercise intervention for the entire 1-year study or to receive it beginning at month 6. At 1-year follow-up, both groups lost roughly 10 kg to 12 kg and had similarly small but statistically significant improvements in various cardiometabolic risk factors.
COMMENT

Fondaparinux for Treatment of Superficial Venous Thrombosis

Anticoagulation was effective, but the proportion of people who benefited was very small.

More Work on Weight Loss

Both commercial weight-loss programs and intensive lifestyle modification show significant, although small, benefits.

Does the modest, albeit statistically significant, weight loss achieved with these very intensive behavioral interventions (including free food) justify their cost? The commercial weight- loss program used in the commercial-program study has an estimated 2-year cost of nearly US$14,000 thats about $920 per average pound lost in the intervention groups. In comparison, bariatric surgery, according to an editorialist, costs as much as $29,000, with greater weight loss but higher risk. Adherence to these structured interventions in routine community practice likely would be much lower than it was in these studies, even with free food.
Thomas L. Schwenk, MD, Journal Watch General Medicine
Rock CL et al. Effect of a free prepared meal and incentivized weight loss program on weight loss and weight loss maintenance in obese and overweight women: A randomized controlled trial. JAMA 2010 Oct 27; 304:1803. Goodpaster BH et al. Effects of diet and physical activity interventions on weight loss and cardiometabolic risk factors in severely obese adults: A randomized trial. JAMA 2010 Oct 27; 304:1795. Wing RR. Treatment options for obesity: Do commercial weight loss programs have a role? JAMA 2010 Oct 27; 304:1837.

Most guidelines do not recommend anticoagulation for treating patients with uncomplicated superficial venous thrombosis. In this international manufacturer-funded double-blind trial, 3002 patients with superficial venous thrombosis were randomized to daily fondaparinux (Arixtra, a factor Xa inhibitor; 2.5 mg) or placebo for 45 days. Exclusion criteria included location of thrombosis within 3 cm of the saphenofemoral junction or history of cancer or thrombosis. During 77 days of follow-up, 4 fondaparinux recipients (0.3%) and 19 placebo recipients (1.3%) developed deep venous thrombosis (DVT); no fondaparinux recipients and 6 placebo patients (0.4%) developed pulmonary embolisms (PEs). The incidence of death was 0.1% in each group, and one patient in each group experienced major bleeding.

Two studies add to efforts to combat the obesity epidemic. In one study, researchers randomized 442 overweight or obese women (mean age, 44; mean weight, 92 kg) to usual care or to enrollment in a commercial weightloss program; this program provided them with free low-fat, reduced-calorie, packaged, prepared meals and with weekly counseling either in person or by telephone and access to the programs website and message boards. Women in the commercial program could transition to regular foods as desired. Control-group participants received two counseling sessions with nutrition professionals, written materials, and monthly telephone or e-mail follow-up. In an intent-to-treat analysis at 2 years, the in-person and by-telephone intervention groups lost a mean of 7.4 kg and 6.2 kg, compared with 2.0 kg for the control group.

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FEATURE

Individualized Strategies for the Use of Antihypertensive Drugs

Two new paradigms illustrate how incorporating patient-specific factors might improve the odds of successful blood pressure control.

A recent series of articles in the American Journal of Hypertension (see following page and Am J Hypertens 2010; 23:1014) reflects the growing consensus that decisions regarding hypertension treatment should be individualized and that algorithms for individual treatment approaches should be developed and tested. In two accompanying editorials, Morris Brown and Curt Furberg propose treatment strategies based on the findings of the studies.
A PATIENT-BASED APPROACH

A PATHOPHYSIOLOGY-BASED APPROACH

Focusing on heterogeneity in the response of individual patients to various antihypertensive drugs, Brown describes how various patient-specific characteristics such as ethnicity and plasma renin reactivity (PRA) relate to the probable pathophysiologic mechanisms of hypertension, depicted as a spectrum with pure volume overload (which responds very favorably to volume-depleting agents such as diuretics and calcium-channel blockers) at one end and pure vasoconstriction (which responds better to angiotensin-converting enzyme [ACE] inhibitors, angiotensin-receptor blockers [ARBs], and new direct renin inhibitors such as aliskiren) at the other end. Browns proposed treatment approach amounts to something like this: Use the patients age and ethnicity to estimate where he or she is likely to lie on the spectrum of hypertensive pathophysiology. Base initial therapy on the patients probable location on the spectrum: calcium-channel blocker or diuretic for older patients and nonwhites; ACE inhibitor or ARB for younger, white patients. Add-on therapy depends on response to initial therapy and the patients probable location on the spectrum (e.g., an older, black patient who doesnt respond to a diuretic might do better with a calcium-channel blocker than with a PRA inhibitor as an add-on). If a two-drug combination doesnt work, add a third agent: If the patient is already on a calcium-channel blocker and diuretic, add an ACE inhibitor or ARB, and if the patient is on either an ACE inhibitor or ARB plus either a calciumchannel blocker or a diuretic, add the volume-depleting agent that he or she is not on. If a three-drug combination doesnt work, measure the PRA level: If the level is normal, add an alpha-blocker; if the level is high, add a beta-blocker; if the level is low, change the diuretic drug or dose. Also reconsider whether the hypertension is secondary to a renovascular or endocrine condition.

Furberg supports categorizing hypertension based on the pathophysiologic underpinnings of the disease, as initially proposed by Laragh several decades ago (Am J Med 1973; 55:261): (1) low-renin hypertension (approximately one-third of all hypertensives), effectively treated with volume-depleting agents; (2) medium- or high-renin hypertension (more than one third of all hypertensives), effectively treated with PRA inhibitors; (3) resistant hypertension, which requires a combination of three or more drugs; or (4) secondary hypertension. Furbergs proposed treatment approach amounts to something like this: Measure the PRA level before initiating therapy. If the PRA level is low, start with a diuretic; if the PRA level is high, start with an ACE inhibitor or ARB. If that doesnt work, measure PRA again and add or subtract therapy as appropriate. If three or more drugs dont work, reconsider whether the hypertension is secondary.

COMMON GROUND

Both of these strategies suggest that management of resistant hypertension can be improved by carefully evaluating whether the failure of blood pressure control results from sodium volume excess (low PRA), insufficiently blocked renin levels (high PRA), or a combination of both (medium PRA), and tailoring therapy accordingly. The approaches differ primarily in the use of PRA measures to determine initial and add-on therapy. Whether either strategy will improve control rates and clinical outcomes remains to be determined in large clinical trials. Nonetheless, both exemplify a rational, physiologic approach to tailoring therapy for individual patients, particularly those with difficult-to-control hypertension.
JoAnne M. Foody, MD
Brown MJ. Heterogeneity of blood pressure response to therapy. Am J Hypertens 2010 Sep; 23:926. Furberg CD. Renin-guided treatment of hypertension: Time for action. Am J Hypertens 2010 Sep; 23:929.

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New Perspectives on an Old Problem: Tailoring Treatment for Hypertension

Three studies lay the groundwork for moving beyond a cookbook approach to drug therapy.

Despite the availability of several antihypertensive drug classes and numerous individual agents, hypertension remains poorly controlled in many patients. Improving control rates will require tailoring of therapy to individual patient factors. In a recent issue of the American Journal of Hypertension, three studies address the heterogeneity of response to various antihypertensive drugs, and two editorialists use the findings to propose novel treatment paradigms. Two studies highlight inter-individual responses to treatment. Turner and colleagues found that measures of plasma renin activity (PRA) predicted patient responses to atenolol or hydrochlorothiazide, both as monotherapy and as add-on therapy, independently of patient age, race, and pretreatment blood pressure (BP). Alderman and colleagues assessed the frequency of paradoxical pressor responses (BP increases 10 mm Hg) in patients during initial monotherapy with various antihypertensive drugs. Patients were stratified by tertile of baseline PRA. Pressor responses occurred with all drug classes. The likelihood of a pressor response was significantly higher with an angiotensin-converting enzyme (ACE) inhibitor or beta-blocker than with a diuretic or calcium-channel blocker, but only in patients in the low and middle PRA tertiles. In a third study, researchers compared responses of white, black, and south Asian ASCOT participants randomized to initial therapy with atenolol or amlodipine; if needed, patients subsequently received a thiazide diuretic (added to atenolol) or perindopril (added to amlodipine). Atenolol monotherapy was significantly less effective in blacks than in whites and south Asians. The addition of perindopril to amlodipine was also significantly less effective in blacks than in whites and south Asians, whereas the addition of a diuretic to atenolol was not associated with any significant difference in response among the three groups. In separate editorials, Brown and Furberg outlined different strategies for individualizing the care of patients with

hypertension. Browns approach begins by assessing the individuals probable location on the spectrum of hypertension pathophysiology (volume overload to vasoconstriction), whereas Furbergs approach begins by categorizing the hypertension as one of four types, based largely on PRA measurement. For a more detailed description of these two strategies, see Individualized Strategies for the Use of Antihypertensive Drugs (previous page).
COMMENT

Current treatment guidelines make no real distinction between different types of hypertension pathophysiology. This one size fits all approach to hypertension therapy probably leads to an overuse of drugs and has been associated with poor outcomes. By sharpening our focus on the clinical predictors of response to various drugs, the present studies bring us closer to tailored approaches to hypertension management. The algorithms proposed by editorialists are intriguing, but we cannot know whether they will improve control rates and, more important, patient outcomes without careful clinical testing.
JoAnne M. Foody, MD
Turner ST et al. Plasma renin activity predicts blood pressure responses to -blocker and thiazide diuretic as monotherapy and add-on therapy for hypertension. Am J Hypertens 2010 Sep; 23:1014. Alderman MH et al. Pressor responses to antihypertensive drug types. Am J Hypertens 2010 Sep; 23:1031. Gupta AK et al. on behalf of ASCOT investigators. Ethnic differences in blood pressure response to first and second-line antihypertensive therapies in patients randomized in the ASCOT trial. Am J Hypertens 2010 Sep; 23:1023. Brown MJ. Heterogeneity of blood pressure response to therapy. Am J Hypertens 2010 Sep; 23:926. Furberg CD. Renin-guided treatment of hypertension: Time for action. Am J Hypertens 2010 Sep; 23:929.

Of 20,369 adults (median age, 67.3) with at least one primary hospital discharge diagnosis of myocardial infarction (MI) or ischemic stroke, 1152 had undergone at least one invasive dental procedure. In this cohort (ischemic stroke, 629; MI, 504; both, 19), the mean duration of observation was 4.2 years. The rate of vascular events was significantly increased in the first 4 weeks and gradually declined within 6 months after invasive dental procedures, compared with other periods. None of the vascular events occurred on the day of the dental procedure. Excluding patients with diabetes, hypertension, or coronary artery disease did not affect the results.
COMMENT

These findings challenge the assumption that patients undergoing invasive dental procedures are at low risk for cardiovascular events. As editorialists note, most of the events occurred in women, and 30% occurred in patients younger than 50. The short-term risk of dental procedures must be weighed against the long-term cardiovascular benefits of alleviating periodontal disease. No direct evidence from this study suggests that inflammation is a causative mechanism in vascular events that occur after dental procedures. However, clinicians would be prudent to heed guideline recommendations to continue aspirin therapy during and immediately after minor surgical procedures. Joel M. Gore, MD
Minassian C et al. Invasive dental treatment and risk for vascular events: A self-controlled case series. Ann Intern Med 2010 Oct 19; 153:499. Weitz H and Merli G. Invasive dental treatment and risk for vascular events: Have we bitten off more than we can chew? Ann Intern Med 2010 Oct 19; 153:542.

Vascular Events After Invasive Dental Procedures

A case-series analysis bolsters recommendations to continue aspirin therapy during minor surgery.

Periodontal disease is a known risk factor for cardiovascular events, but might an association exist between therapeutic dental procedures and acute vascular events? To find out, investigators conducted a selfcontrolled case-series analysis of Medicaid claims data from 2002 through 2006.

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JOURNAL WATCH SUBSCRIBERS HAVE 10 FREE CREDITS! This is one of four questions in a recent Journal Watch Online CME exam. from Ten-Year Findings from a Randomized Comparison of CAD Therapies (p. 95) Which of the following statements does not describe a finding from a single-center randomized trial of medical therapy (MT), PCI, or CABG in patients with stable multivessel CAD? A. Overall mortality was similar in all three groups. B. The MI rate was lowest in the CABG group. C. Cardiac mortality was lowest in the MT group. D. Angina incidence was lower in the PCI and CABG groups than in the MT group. Category: Cardiovascular Diseases Exam Title: Stable Coronary Artery Disease Posted Date: Nov 16 2010 View this exam and others at http://cme.jwatch.org User name and password are required. CME FACULTY Kelly Anne Spratt, DO, FACC, Section Editor, Cardiology

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CARDIOLOGY

Vol. 16
COMMENT

No. 12

Blood Transfusions in Cardiac Surgery: Too Much, Too Soon?

Findings from two studies underline the need for a more cautious transfusion strategy.

According to published guidelines based on clinical experience, perioperative blood transfusions are not beneficial when hemoglobin levels are >10 g/dL. However, other factors such as comorbid conditions and discrete organ ischemia complicate the establishment of clear indications for transfusion. Two new studies address distinct but related aspects of this issue. In the Transfusion Requirements After Cardiac Surgery (TRACS) trial, 502 patients who underwent cardiac surgery with cardiopulmonary bypass between February 9, 2009, and February 1, 2010, at a single cardiac surgery referral center in So Paolo, Brazil, were randomized to one of two perioperative red blood cell (RBC) transfusion strategies: liberal transfusion to maintain a hematocrit of 30% (hemoglobin level, 10 g/dL), or conservative transfusion to maintain a hematocrit of 24% (hemoglobin level, 8 g/dL).

Transfusion rates were relatively high in both groups (78% and 47% in the liberal and conservative groups, respectively; P<0.001). The primary outcome, a composite of 30-day mortality and severe inhospital complications, did not differ significantly between the two groups. Bennett-Guerrero and colleagues analyzed data from the Society for Thoracic Surgery Adult Cardiac Surgery Database (ACSD) on >100,000 patients undergoing coronary artery bypass grafting with cardiopulmonary bypass in 2008 at 798 centers across the U.S. Perioperative transfusion rates varied substantially; in 408 sites performing at least 100 on-pump procedures, the rate of RBC transfusion ranged from 7.8% to 92.8%. After adjustment for patientspecific risk factors, transfusion rates varied significantly by geographic location, academic status, and hospital volume. However, these factors combined explained only 11.1% of between-hospital variation in RBC use, and case mix explained only 20.1% of the variation. Mortality rates were not associated with hospital-specific RBC transfusion rates.

Despite some study limitations, the TRACS findings showed that patients do as well with a conservative transfusion strategy as with a more liberal one. The ACSD findings indicate that between-hospital variability in transfusion rates remains high and independent of several patient- and hospital-specific factors. The absence of differences in mortality among centers with varying transfusion rates strongly suggests inappropriate transfusions, but current guidelines seem ineffective at reducing these variations. As editorialists note, more restrictive policies of blood transfusion in cardiac surgery should be developed and instituted at individual sites and regionally. Beat J. Meyer, MD
Hajjar LA et al. Transfusion requirements after cardiac surgery: The TRACS randomized controlled trial. JAMA 2010 Oct 13; 304:1559. Bennett-Guerrero E et al. Variation in use of blood transfusion in coronary artery bypass graft surgery. JAMA 2010 Oct 13; 304:1568. Shander AS and Goodnough LT. Blood transfusion as a quality indicator in cardiac surgery. JAMA 2010 Oct 13; 304:1610.