Eric R. Bates, MD review Miedema MD, Newell MC, Duval S, et al. Causes of delay and associated mortality in patients transferred with ST-segment-elevation myocardial 

infarction. Circulation. 2011;124:1636-1644.

otal ischemic time is the most important determinant of clinical outcome in patients with ST-elevation myocardial infarction (STEMI) treated with reperfusion therapy. Measuring the door-to-balloon time has been successfully used to reduce in-hospital system delays for primary percutaneous coronary intervention (P-PCI). In the United States, over 90% of direct-admit patients not excluded for extenuating clinical circumstances are now treated at PCI centers with door-to-balloon times within 90 minutes, the treatment goal established by clinical guidelines1 and performance measures.

 This represents a major improvement in treatment delays that were documented only a few years ago.

 The next challenge in reperfusion therapy is improving time to treatment in patients presenting to hospitals without PCI capability who must undergo interhospital transfer for P-PCI.

The recently released American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACCF/AHA/SCAI) PCI Guidelines again endorse P-PCI as the preferred reperfusion strategy, with a P-PCI goal of 90 minutes for first-medical-contact-to-balloon time at hospitals that have PCI capability.

 Note that the concept of “first medical contact” is meant to encourage the use of the prehospital ECG to make the STEMI diagnosis earlier and start the system response to STEMI before the patient reaches the door of the emergency department (ED). This metric is also meant to be a hospital-quality metric measured over the course of a year, to be used to identify logistical delays that prolong time to treatment. It is not meant to be used to make treatment decisions on whether P-PCI or fibrinolytic therapy should be chosen as the reperfusion strategy for an individual patient.

It is important to recognize the challenges that prolong door-to-balloon times in patients presenting to hospitals without PCI capability and the superiority of P-PCI as a treatment option when treatment delays are minimized. Nevertheless, the goal for first-medical-contact to-balloon time for interhospital transfer patients has recently been increased from 90 to 120 minutes.

The aim is to encourage hospitals to develop more efficient regional STEMI systems rather than to discourage them by challenging them with an unrealistic treatment goal. It is not meant to erode the gains that have been made in the in-hospital system of care by pulling back from the 90-minute target for direct admits to PCI centers, but rather to promote a more organized prehospital system of care to increase patient access to P-PCI.

Miedema et al report on the frequency, magnitude, and clinical impact of specific delays in their superb regional system designed for the rapid transfer of STEMI patients for P-PCI from 31 referral hospitals. Their study population included 2034 patients treated between March 2003 and December 2009. The goal was to achieve a referral hospital door-indoor- out (DIDO) time within 45 minutes, an interhospital transfer time within 45 minutes, and a PCI center door-to-balloon time within 30 minutes, for a total hospital door-to-balloon time within 120 minutes.

The study included 11 hospitals within 60 miles of the PCI center and 20 hospitals 60 to 120 miles away. The diagnosis was made by the ED physician; a single phone call activated the system. Standardized protocols and a predetermined transfer plan were established at each site. Patients bypassed the PCI center ED and were directly admitted to the cardiac catheterization laboratory for P-PCI.

The most common reasons for delay at the referral hospital were delays awaiting transport and ED delays. DIDO times greater than 45 minutes occurred in 64% of referral hospitals. The longest ED delays occurred in patients with nondiagnostic initial ECGs or investigations for diagnoses other than STEMI. Transport delays were noted in 12.6% of transfers due to weather or distance, but were not associated with increased mortality risk. Delays at the PCI center (15.7% of patients) were most commonly due to catheterization laboratory team delays and complex procedures.

Older patients and nonsmokers, and those with diabetes or cardiogenic shock, had the longest delays. As expected, patients with cardiogenic shock and/or cardiac arrest had the highest mortality rates. The overall in-hospital mortality rate was 5.4% and the 1-year mortality rate was 9.9%. Compared with patients treated within 120 minutes, patients treated later than within 120 minutes had increased hospital mortality (6.4% vs 4.1%; P = 0.023) and a trend for increased 1-year mortality (10.2% vs 8.8%; P = 0.29).

1. Levine G, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. J Am Coll Cardiol. doi:10.1016/j.jacc.2011.08.007. http: //content.onlinejacc.org/cgi/content/full/j. jacc.2011.08.007. Published 2011. Accessed November 16, 2011.

2. Krumholz HM, Anderson JL, Bachelder BL, et al. ACC/AHA 2008 performance measures for adults with ST-elevation and non-ST-elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Performance Measures (Writing Committee to develop performance measures for ST-elevation and non- ST-elevation myocardial infarction): developed in collaboration with the American Academy of Family Physicians and the American College of Emergency Physicians: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, Society for Cardiovascular Angiography and Interventions, and Society of Hospital Medicine. Circulation. 2008;118:2596-2648.

3. Krumholz HM, Bradley EH, Nallamothu BK, et al. A campaign to improve timeliness of primary percutaneous coronary intervention: Door-to-Balloon: An Alliance for Quality. JACC Cardiovasc Interv. 2008;1:97-104.

4. Nallamothu BK, Bates ER, Herrin J, et al. Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the United States: National Registry of Myocardial Infarction (NRMI)-3/4 analysis. Circulation. 2005;111:761-767.

5. American Heart Association. Mission: Lifeline. http://www.heart.org/HEARTORG/ HealthcareResearch/MissionLifeline- HomePage/Mission-Lifeline-Home-Page_ UCM_305495_SubHomePage.jsp. Accessed November 17, 2011.

Meeting the Challenge of Tomely STEMI Transfer

his study presents the first description of the frequency and magnitude of treatment delays in a regional STEMI system of transfer for P-PCI. Several years ago, only 4% of transfer patients were treated within 90 minutes and only 16% were treated within 120 minutes.4 With great emphasis on decreasing logistical delays in time to treatment, these investigators were able to treat 30% of patients within 90 minutes and 66% within 120 minutes, an impressive accomplishment given some long-distance transfers. The results for the transfers within 60 miles were even more impressive: 43% treated within 90 minutes and 79% treated within 120 minutes. Longer delays were measured with transport distances 60 to 120 miles: 12% treated with 90 minutes and 47% treated within 120 minutes.

Nevertheless, treatment delays still occurred frequently, most commonly at the referral hospital. The authors suggest that delays awaiting transport may be reduced by establishing standard transfer protocols and increasing the availability of transport vehicles. ED delays may be improved with continued clinical systems improvement and feedback/quality improvement with a DIDO goal of 30 minutes when there are no delays in awaiting arrival of the ambulance or helicopter.

The ideal transfer strategy for patients with STEMI is direct transport to a PCI center, bypassing hospitals without PCI capability, with prehospital diagnosis and notification of the cardiac catheterization laboratory. However, only 50% of patients use emergency medical services and some of them are required to transport to the nearest hospital. Therefore, all hospitals without PCI capability need to develop and participate in a regional STEMI transfer system to increase timely access to P-PCI. The results of this report demonstrate that median referral hospital door-to-balloon times within 120 minutes should be obtainable for hospitals without PCI capability in urban or suburban locations. Whereas many rural hospitals may also be able to achieve these treatment goals, others will need to adopt fibrinolytic therapy as the initial reperfusion strategy, with a door-toneedle goal within 30 minutes if they cannot consistently meet the P-PCI target. Current guidelines encourage transfer of patients receiving fibrinolytic therapy to PCI centers so that coronary angiography with intent to perform PCI can be accomplished within 24 hours of symptom onset.1 Developing an excellent regional STEMI transfer system can be achieved through participation in the AHA’s Mission: Lifeline program.

Eric R. Bates, MD, is professor of internal medicine at the University of Michigan. Dr Bates graduated from the University of Michigan Medical School, where he trained in internal medicine and cardiology. He is vice-chair for the 2011 ACCF/AHA Guideline for Percutaneous Coronary Intervention Writing Committee, and chair for the program committee of the American Heart Association Council on Clinical Cardiology. He is also chair of the Mission: Lifeline Science Task Force. 

Articles

CME Reviews

Causes of Delay and Associated Mortality in Patients Transferred With STEMI 

Hochholzer W, Wiviott DS, Antman EM, et al. Predictors of bleeding and time dependence of association of bleeding with mortality: insights from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). Circulation. 2011;123:2681-2689.

he association between bleeding events and late mortality in patients with ACS is well established. 

This observation has led to increased awareness of balancing ischemic benefit and bleeding risk in the assessment of new antithrombotic therapies. Prasugrel is a P2Y12 inhibitor that is more potent than clopidogrel and virtually abolishes the individual variability in the response to antiplatelet therapy observed with clopidogrel. Prasugrel has received a Class I indication in both the American and European ACS 2011 guidelines.

This new analysis of the TRITONTIMI 38 trial focusing on bleeding complications confirms the major impact of serious bleeding on mortality and provides insights on the type of bleeding complications that occurred in the trial and their predisposing factors. 

The TRITON-TIMI 38 study randomized 13,608 patients with moderate- to high-risk acute coronary syndromes (ACS), both ST-elevation myocardial infarction (STEMI) and non-ST-elevation ACS, to aspirin and prasugrel (a 60-mg loading dose and a 10-mg/d maintenance dose) versus aspirin and clopidogrel (a 300-mg loading dose and a 75-mg/d maintenance dose).

 All patients were scheduled for percutaneous coronary intervention (PCI). Major clinical events were assessed at a mean follow-up of 14.5 months.

The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke. The key safety end point was major bleeding. The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio [HR] for prasugrel vs clopidogrel, 0.81; 95% confidence interval [CI], 0.73-0.90; P <0.001). There was also a significant reduction in the prasugrel group in the rates of MI (9.7% for clopidogrel vs 7.4% for prasugrel; P <0.001), urgent target- vessel revascularization (3.7% vs 2.5%; P <0.001), and stent thrombosis (2.4% vs 1.1%; P <0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (HR, 1.32; 95% CI, 1.03-1.68; P = 0.03). The rate of life-threatening bleeding was also greater in the prasugrel group (1.4% vs 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs 0.9%; HR, 1.25; P = 0.23) and fatal bleeding (0.4% vs 0.1%; P = 0.002).

The aim of the current analysis,4 which included 13,420 patients, was to identify baseline characteristics that independently predicted bleeding events and to determine how bleeding events impacted mortality in the TRITON-TIMI 38 trial. A total of 534 patients (4.0%) experienced a serious bleeding event. The variables with the highest strength of association with a serious bleeding event included female sex (HR, 1.77), the use of glycoprotein IIb/IIIa receptor inhibitor (HR, 1.59), duration of intervention, age, assignment to prasugrel (HR, 1.34) admission diagnosis of STEMI (HR, 1.35), femoral access for angiography and intervention (HR, 1.60), creatinine clearance, hypercholesterolemia, and arterial hypertension.

Fatal serious bleeding occurred in 21 patients (0.3%) treated with prasugrel and in 6 patients (0.1%) treated with clopidogrel (HR, 3.50; 95% CI, 1.41- 8.68; P = 0.01). This excess of serious bleeding on prasugrel occurred in both instrumented/traumatic and spontaneous bleeding, and was driven mainly by a higher incidence of bleeding from surgical sites (other than coronary artery bypass grafting [CABG]) (HR, 5.05; 95% CI, 1.46-17.45; P = 0.01) and gastrointestinal bleeding (HR, 1.32; 95% CI, 0.99-1.77; P = 0.05). Transfusions related to bleeding were more frequent in patients assigned to prasugrel (HR, 1.33; 95% CI, 1.07- 1.67; P = 0.01). Minimal bleeding was also more frequent in patients assigned to prasugrel (HR, 1.48; 95% CI, 1.29-1.71; P <0.001), largely related to puncture site bleeding and epistaxis. No differences were detected in the 2 groups with respect to intracranial bleeding (numerically higher in the clopidogrel group) and access side bleeding (numerically higher in the prasugrel group).

Subgroups of patients with higher risk of serious bleeding were identified— namely, patients with a history of stroke or transient ischemic attack (TIA) (HR, 1.58; 95% CI, 1.10-2.29; P = 0.01), age ≥75 years (HR, 2.58; 95% CI, 2.13-3.13; P <0.001), and body weight <60 kg (HR, 2.30; 95% CI, 1.74-3.05; P <0.001).

In patients with a history of stroke or TIA, the increased rate of serious bleeding was driven mainly by a higher rate of intracranial bleeding events (6 of 20 serious bleeding events with prasugrel). Serious bleeding was significantly associated with mortality (adjusted HR, 5.84).

However, according to the analyses performed, the impact of instrumented or traumatic serious bleeding on mortality was of short duration (ie, less than a week). Serious spontaneous bleeding tended to have a longer impact on mortality, with an HR significantly elevated for approximately 1 month but becoming nonsignificant thereafter.

The authors summarized the results of this analysis with 5 major findings:

(1) Only a limited number of variables were found to be independently associated with serious bleeding in the entire cohort. Those most strongly associated with the risk of bleeding were female sex and advanced age, together with procedural characteristics.

(2) Although prasugrel was independently associated with a higher risk of serious bleeding than clopidogrel, the strength of this association was less than the above-named clinical factors.

(3) Assignment to prasugrel was principally associated with a higher frequency of serious gastrointestinal bleeding, bleeding at surgical sites, and more frequent non-serious nasal and vascular access site bleeding.

(4) Blood transfusion for bleeding was not an independent predictor for mortality after full adjustment for all available variables and bleeding.

(5) The impact of bleeding events on mortality was greatest within the first few days. However, its impact on mortality waned rapidly and the HR was not significantly different from 1.0 after 40 days.

1. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114:774-782.

2. Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123:2022-2060.

3. Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC) [published online ahead of print August 26, 2011]. Eur Heart J.

4. Hochholzer W, Wiviott SD, Antman EM, et al. Predictors of bleeding and time dependence of association of bleeding with mortality: insights from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-- Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). Circulation. 2011;123(23):2681-2689.

5. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.

6. Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial. Lancet. 2011;377:1409-1420.

7. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045-1057.

8. Chin CT, Roe MT, Fox KA, et al. Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-STsegment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial. Am Heart J. 2010;160:16-22 e11.

9. Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): doubleblind, randomised controlled trial. Lancet. 2009;373:723-731.

10. Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel- Thrombolysis in Myocardial Infarction 38. Circulation. 2008;118:1626-1636.

Predictiors and Impact of Bleeding Complications 

he most impressive finding of this study is the strong association serious bleeding events have with mortality (HR, 5.84). The authors underscored the fact that the impact of serious bleeding on mortality was not more significant after 40 days. However, the clinical relevance of this observation remains limited.

This study identified independent predictors of serious bleeding, which included female sex, use of glycoprotein IIb/IIIa receptor inhibitors, duration of intervention, age, assignment to prasugrel, admission diagnosis of STEMI, femoral access for angiography, creatinine clearance, hypercholesterolemia, and arterial hypertension. With respect to prasugrel, the increased risk of bleeding was principally associated with a higher frequency of serious gastrointestinal bleeding, bleeding at surgical sites, and more frequent non-serious nasal and vascular access site bleeding. Patients in the prasugrel group received more frequent blood transfusions than those assigned to clopidogrel. However, in contrast to previous findings, in TRITONTIMI 38, blood transfusion did not independently predict mortality. How should those findings influence our clinical practice? First of all, we should be more restrictive in the administration of glycoprotein IIb/IIIa receptor inhibitors in patients treated with prasugrel. The use of those agents should be limited to patients at high ischemic risk (ie, STEMI patients with an occlusion of a major epicardial vessel and sizable thrombus burden on angiography) who at the same time are not at increased bleeding risk. Second, the use of a transradial approach should be favored in patients treated with prasugrel. The benefit of the transradial approach versus the transfemoral one in terms of reduction of access site bleeding and access site complications is now supported by a randomized trial.6 More centers in Europe have “converted” to the transradial approach. At my center, the University Hospital of Geneva, the rate of PCI by transradial approach rose from less than 5% in 2007 to 73% in 2010.

TRITON-TIMI 38 indentified 3 groups of patients with increased bleeding risk with prasugrel: patients with history of stroke or TIA, ≥75 years, and body weight <60 kg. Based on the increased rate of intracranial bleeding observed in patients with prior TIA/ stroke treated with prasugrel, the administration of the drug at 10 mg/day over several months should be considered contraindicated. For patients aged ≥75 years or with body weight <60 kg, other drugs such as ticagrelor should be considered.

 There are no clinical data yet available for prasugrel 5 mg/day; however, the efficacy and safety of this dosage is currently being investigated in the TRILOGY trial.

It is worth remembering that for 2 main categories of patients the benefit-risk ratio of prasugrel appears particularly favorable: STEMI and diabetic patients. In STEMI, allocation to prasugrel in TRITON-TIMI 38 was associated not only with a reduction in the primary end point of cardiovascular death, MI, or stroke, but also with significant reduction in mortality in the absence of an increase in non-CABG TIMI major bleedings.9 In diabetic patients the benefit of prasugrel was impressive with respect to the primary end point (12.2% in the prasugrel group and 17.0% in the clopidogrel group; HR, 0.70; P <0.001) and no increase in non-CABG major bleeding was observed.10

Marco Roffi, FE SC, FA CC, is associate professor of medicine and director of the Interventional Cardiology Unit at the University Hospital of Geneva, in Geneva, Switzerland. He received his Swiss board certification in internal medicine and trained in general and interventional cardiology at the University Hospital of Berne. His fellowship in coronary, peripheral, and carotid interventions was at the Cleveland Clinic. Dr Roffi is chairman of the Scientific Program Committee of the European Association of Percutaneous Cardiovascular Intervention (EAPCI) and a member of the Program Committee of EuroPCR. He has coauthored over 120 publications, 34 book chapters, and edited 3 books. His clinical and research fields of interest include ACS, anti-platelet therapy, CAD in diabetes, and carotid and peripheral interventions.

Predictors and Impact of Bleeding Complications in Patients With ACS Undergoing PCI 

Groenveld HF, Crijns HJGM, Van den Berg MP, et al. The effect of rate control on quality of life in patients with permanent atrial fibrillation. J Am Coll Cardiol. 

espite a decade of important clinical trial data on the management of atrial fibrillation (AF), no other arrhythmia continues to present so many clinical challenges. While the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) and the Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure (AF-CHF) “rate control versus rhythm control” trials showed that the rate control approach was not an inferior strategy, 

 these studies left many unanswered questions for both approaches.

Rate control appears simple and possibly easier to achieve than rhythm control; however, the exact definition of what constitutes optimal “rate control” has been contentious. This question was taken up by the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient versus Strict Rate Control II) trial investigators, who evaluated a historically defined “strict” rate control versus a more “lenient” rate control in patients with permanent AF.

Strict rate control required a target heart rate <80 beats/minute at rest, and <110 beats/minute during moderate exercise, while lenient rate control allowed the target resting heart rate <110 beats/ minute. In a randomized study of 614 patients with permanent AF, with a minimum of 2 years of follow-up, the composite primary outcome, defined in the trial as death from cardiovascular causes, hospitalization for heart failure, stroke, systemic embolism or bleeding, and lifethreatening arrhythmic events, showed that the lenient rate control approach was non-inferior.

Indeed, the primary outcome was lower in the lenient rate control group (12.9%) than in the strict rate control group (14.9%). The frequency of symptoms and adverse events was similar in both groups. These findings have been incorporated in the most recent American Heart Association/American College of Cardiology4 and European Society of Cardiology5 guideline updates on AF (Figure).

The Dutch group that carried out the RACE II study has recently also reported on the effect of the different rate control approaches on remodeling6 and quality of life (QOL)7 in patients with permanent AF. Perhaps surprisingly, there were no differences in changes in left atrial size or left ventricular end-diastolic diameter between the 2 groups. This finding will address a concern raised by many that lenient rate control would more likely result in tachycardia-mediated cardiomyopathy. Recently, these investigators have published a detailed analysis of the effect of the different approaches to rate control on QOL in patients with AF, which is the focus of this report.

In this analysis of the RACE II trial data, the authors studied a total of 437 patients with permanent AF randomized to the lenient (n = 230) or strict (n = 207) rate control for whom QOL data was available. Rate control was achieved with β-blockers, nondihydropyridine calcium-channel blockers, and digoxin, alone or in combination, until the target heart rate was achieved. Medication usage was recorded at the end of the dose-adjustment period. The minimum follow-up was 2 years (median, 3 years). QOL was measured with the Medical Outcomes Study 36-item Short Form Health Survey (SF-36), the University of Toronto AF Severity Scale (AF severity scale), and the Multidimensional Fatigue Inventory-20 (MFI-20) questionnaires, administered at baseline, 12 months, and at the end of the study.

The baseline characteristics were similar in the 2 groups: mean age of 68 years, 66% male, mean duration of AF of 18 (6-58) months, and a resting heartbeat of 95±12 per minute. Hypertension was present in 60%, coronary artery disease in 19%, chronic obstructive pulmonary disease in 13%, and diabetes in 9%, while 8.5% had a prior heart failure hospitalization. The mean ejection fraction was 53%. Fifty-eight percent of the patients had symptoms, most commonly dyspnea (37%), fatigue (31%) and palpitations (24%); 42% of the patients were asymptomatic. The rate control drugs used were β-blocker alone (33%), β-blocker with verapamil/diltiazem or digoxin (28%), verapamil/diltiazem with digoxin (8.5%), sotalol or amiodarone (3.4%), no drug (6%), and other combinations in the remainder.

While both groups had a mean baseline heart rate of 95+12 beats/min at baseline, 79% of the strict control group achieved a heart rate <80 beats/min at the end of the dose-adjustment period, compared with 2% of the lenient control group. However, it should be noted that the resting heart rate averaged 85 beats/ min in the lenient control group and 75 beats/min in the strict control group at 1 year, 2 years, and at the end of the study. There were almost 9 times more patient clinic visits in the strict control group (684) than in the lenient control group (75), yet only 67% of the strict control group achieved the target heart rates.

At 12 months of follow-up and at the end of the study, there were no differences in any of the SF-36 subscales between the lenient and strict control groups. Additionally, there was no relationship with heart rates at baseline, at end-of-dose adjustment period, or at the end of the study. There were also no differences in the AF severity scale or the MFI-20 scale from baseline to 12 months of follow-up to end of the study. Heart rate reduction was not related to improvements or worsening of QOL in any of the study measurements.

Worsening of the SF-36 subscales were associated with symptoms at the end of study, older age, diabetes, lower left ventricular ejection fraction, thicker septum, hospitalization for heart failure, β-blocker use, an arrhythmic event during the study, major bleeding, and female sex. Symptoms at the end of the study were also associated with worsening in the AF severity scale and worsening on the MFI-20 scale. In summary, changes in QOL were related to age, symptoms at baseline and at the end of the study, severity of underlying disease, and female sex.

1. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002; 347:1825-1833.

2. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008;358:2667-2677.

3. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010;362:1363-1373.

4. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation. 2011;123:1144-1150.

5. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369- 2429.

6. Smit MD, Crijns HJ, Tijssen JG, et al. Effect of lenient versus strict rate control on cardiac remodeling in patients with atrial fibrillation data of the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) study. J Am Coll Cardiol. 2011;58:942-949.

7. Groenveld HF, Crijns HJ, Van den Berg MP, et al. The effect of rate control on quality of life in patients with permanent atrial fibrillation data from the RACE II (RAte Control Efficacy in permanent atrial fibrillation II) study. J Am Coll Cardiol. 2011;58:1795-1803.

8. Jenkins LS, Brodsky M, Schron E, et al. Quality of life in atrial fibrillation: the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J. 2005;149:112-120.

9. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med. 2005;352:1861-1872.

10. Cooper HA, Bloomfield DA, Bush DE, et al. Relation between achieved heart rate and outcomes in patients with atrial fibrillation (from the Atrial Fibrillation Follow-up Investigation of Rhythm Management [AFFIRM] study). Am J Cardiol. 2004;93:1247-1253. 

and AF-CHF2 trials, there was no statistically significant difference in QOL for rate control compared with rhythm control, although the Sotalol Amiodarone Atrial Fibrillation Efficacy (SAFET) trial9 did find that sinus rhythm was associated with improved QOL, irrespective of treatment assignment. Additional analysis of the AFFIRM data showed no correlation between resting heart rate or heart rate with moderate exercise and QOL.

In the RACE II trial patient cohort there was no difference in overall QOL measurements between the strict and lenient rate control groups; symptoms, age, sex, and underlying heart disease, but not the amount of rate control, influenced QOL. This study did find that presence of symptoms was related to QOL and changes in QOL over time, but the type of rate control did not affect how symptoms changed over time.

First, it should be noted that 42% of the patients did not have any symptoms. This may indicate a selection bias in patients assigned to rate control in the first place, but will limit the impact of the different rate control strategies on QOL outcomes. Interestingly, the most common symptoms were dyspnea and fatigue rather than palpitations, suggesting the underlying heart disease rather than the rate may be the critical factor in defining symptoms. Additionally, patients with permanent AF are known to have fewer symptoms compared with patients with paroxysmal AF, in whom palpitations are the most common symptom. Second, it is possible that side effects such as fatigue seen with higher doses of β-blockers used in the strict rate control group may have offset any potential QOL benefit from the lower rate. Third, the ultimate difference of only 10 beats/min on average between the 2 groups may not have been large enough to have an effect on QOL measurements. Finally, it should also be noted that RACE II was a non-inferiority study and was not powered to detect differences in the primary clinical end point noted above; hence, it may not have the power to detect QOL differences.

If a strict rate control strategy is chosen, a Holter monitor should be considered to assess for pauses and bradycardia, while an exercise test may be useful to assess heart rate with exercise. If the lenient rate control strategy is chosen, then left ventricular function should be monitored, as this will raise concerns of possible tachycardiamediated cardiomyopathy developing over the long term. However, despite the finding in the remodeling sub-study of RACE II also recently reported,6 there are no longterm data on the effects of the more lenient strategy on ventricular function; hence, the possibility of tachycardia- mediated cardiomyopathy remains a concern in the long term. Lenient rate control would be expected to be more convenient for many patients, requiring fewer office visits and testing. The choice of rate control drugs will depend on underlying conditions such as heart failure or COPD, age, and the heart rate target.

The results of this trial will apply to patients with permanent AF who are relatively asymptomatic, but not those with newly diagnosed or paroxysmal AF who are highly symptomatic, where rhythm control is the option likely to be desired by the patient. Thus neither the present data nor other studies in the literature support the conventional and arbitrary definition of strict rate control in AF.

It is still possible that for highly symptomatic patients, strict rate control may have a beneficial effect on QOL. While the choice of rate control versus rhythm control is one that should be individualized, this is also true for the choice of lenient versus strict rate control.

Noel G. Boyle, MD, PhD, is professor of medicine, director of the Cardiac EP Fellowship Program, and co-director of the Cardiac Arrhythmia Center at the Ronald Reagan UCLA Medical Center in Los Angeles, California. He earned his medical degree and PhD at Trinity College Dublin School of Medicine, Dublin, Ireland, and completed an internship in St James’s Hospital, Dublin, and residency in Internal Medicine at the Medical College of Wisconsin. His fellowships in cardiology and cardiac electrophysiology were at Beth Israel Hospital and Harvard Medical School, Boston, MA. His research interests include mechanisms and management of atrial fibrillation, atrial fibrillation in heart failure, and management of ventricular tachycardia. He is a Fellow of the American College of Cardiology, the European Society of Cardiology, the Heart Rhythm Society, and the Royal College of Physicians of Ireland. Noel G. Boyle, MD, PhD The authors studied a total of 437 patients with permanent AF randomized to the lenient (n = 230) or strict (n = 207) rate control for whom QOL data was available. review

Effect of Rate Control on QOL in Patient With Permanent AF 

Gregory S. Pokrywka, MD, FA CP, FN LA, NCMP

Jena et al, “Malpractice risk according to physician specialty,” N Engl J Med. doi:10.1056/ NEJMsa1012370. February 2012 | Cardiology Review 33 FEATURE | Malpractice 

Risk review Jena AB, Seabury S, Lakdawalla D, Chandra A. Malpractice risk according to physician specialty. N Engl J Med. 2011;365:629-636.

alpractice risk is a daily concern for all physicians, yet surprisingly little is known about the differences between medical specialties with respect to the annual incidence of claims, size of payments, and cumulative career incidence of claims. The few studies that exist are limited by their use of older data, limited geographic coverage, reliance on self-reports, small sample sizes, low response rates to surveys, limited physician specialty information, and lack of payment size data. Although the National Practitioner Data Bank includes most US cases in which a plaintiff was payed on behalf of a licensed health care provider, it does not report physician specialty and does not record data on cases that do not result in a payment.

The authors were funded by the RAND Institute of Civil Justice and the National Institute on Aging. They examined physician-level data from a large physician- owned professional liability insurer covering physicians in all 50 states and the District of Columbia. The data are relatively current and large, covering closed malpractice claims for 40,916 physicians from 1991 to 2005 (233,738 physician-years of coverage). Physicians between the ages of 30 and 70 years were included in the study; the average age of physicians in all specialties was 49.0 years (range, 43.2 for emergency medicine to 53.0 for gynecology). Data on sex and race were not available.

Twenty-four specialties with at least 200 physicians each were identified; physicians in other, smaller specialties were grouped together in an “other specialty” category. California was overrepresented in this data (39.3% of the physicians), but after a reweighting process this share dropped to only 12.2%. Mean and median payments reflected indemnity payments made at jury verdicts or settlement with the claimant, and an outlier group of payments in excess of $1 million was identified. Data were separated into 3 time periods, 1991-1995, 1996-2000, and 2001-2003. “High-risk” and “low-risk” specialties were defined as the 5 specialties with the highest and lowest proportions of physicians with a claim in each category. Physician age data was used to calculate an annual rate of facing a claim, and was categorized by physician age and specialty. This model assumed that the probability of being sued was unrelated to the duration of coverage by this insurer, and that the probability of being sued at a given age was independent of being sued at an earlier age.

A total of 7.4% of all physicians annually had a malpractice claim, with significant variability across specialties: from 2.6% in psychiatry to 19.1% in neurosurgery. Annually, 1.6% of physicians made an indemnity payment, but the specialties in which physicians were most likely to face claims were not always the specialties in which indemnity claims occurred most often. The proportion of physicians with a claim was not well correlated with the payment rate, which was the number of physicians with a payment divided by the number with a claim (Pearson’s correlation, 0.17; P = 0.42). As an example, gynecology had the 12th highest claim rate, yet had the highest payment rate of >38%. With respect to time periods, differences in overall and paid claims were stable between low-risk and high-risk specialties. However, the annual claim rate in low-risk specialties actually decreased between 1991 and 1995 and 2001 and 2003. Average payment did not correlate well with claim rate (Pearson’s correlation, 0.13; P = 0.52), a finding the authors say suggests that the factors influencing the likelihood of a claim are independent of the factors that drive the size of the payment. Outlier awards (>$1 million) were infrequent, accounting for less than 1% of all payments, with obstetrics and gynecology accounting for the most payments. By age 65, a high percentage of physicians will face a claim (75% of those in low-risk specialties and 99% of those in high-risk specialties); the risk of indemnity payments at age 65 is 19% and 71%, respectively (Figure). Significant heterogeneity existed among specialty-specific projections of career malpractice risk.

his analysis of a large malpractice claims database demonstrates substantial heterogeneity across physician specialties in all risk parameters examined. Almost all high-risk specialty physicians will have a claim during their careers, but a substantial minority will not have to make a claims payment. A surprising finding is that specialties in which the largest proportion of physicians faced a claim were not necessarily those with the highest average payment size. Also important is the finding that a high percentage of claims do not result in payments to the plaintiff. Given that physician concern varies much less considerably across states than the objective measures of malpractice risk according to state, what accounts for this disparity?

Cardiologists and internists are in the middle of the pack in terms of the proportion of physicians facing claims annually, both coming in slightly higher than the average for all physicians. The rate of claims with indemnity payments is slightly less for cardiologists than for internists and all physicians, perhaps a surprising result in light of the increased amount of life-threatening and acute care rendered by cardiologists relative to the other specialties. This further illustrates the study’s conclusion that the forces that apparently drive claims differ from those that drive payments. Median physician indemnity payments to plaintiffs are higher for internists than for cardiologists, again illustrating this point.

Despite the soundness of study design and interesting analysis of this data, its insights are of little use in the busy clinician’s practice, other than as a vindication for the perceived high risk of medical malpractice we all face daily. As the authors point out, physicians can protect themselves from indemnity payments with malpractice insurance, but there is no protection from the time lost, stress, lost income, additional labor, and damage to reputation that result from a claim. Being the best doctors we can be, technically and in our interactions with patients and family, is our charge every day. It cannot be overemphasized how important it is to listen to our patients and respect them—2 of the best ways we can all prevent malpractice claims.

Gregory S. Pokrywka, MD, FACP, FNLA , NCMP, is assistant professor of medicine at Johns Hopkins University School of Medicine and director of the Baltimore Lipid Center, which he formed in 2001. He received his medical degree from Maryland Medical School and was chief resident at Mercy Hospital in Baltimore. He is a boardcertified internist, diplomate of the American Board of Clinical Lipidology, and a fellow of the National Lipid Association. Dr Pokrywka is also a certified menopause practitioner and board member of the South East Lipid Association. Dr. Pokrywka participates enthusiastically in the Go Red for Women and WomenHeart campaigns to fight heart disease in women.

Malpractice Risk According to Physician Specialty 

 Eplerenone Reduced Death and Risk of Hospitalization in Patients With Systolic Heart Failure and Mild Symptoms

The EMPHASIS-HF trial showed that the aldosterone antagonist eplerenone produced large reductions in both the risk of death and the risk of hospitalization compared with placebo in patients with systolic heart failure (HF) and mild symptoms. The trial randomized 2737 patients with NYHA class II HF and an ejection fraction of no more than 35% to receive either eplerenone up to 50 mg/d or placebo in addition to recommended therapy. The results showed a 37% reduction in the primary end point of the composite of death from cardiovascular causes or hospitalizations for HF. The trial was halted early because of the drug’s significant benefits. The study was published in The New England Journal of Medicine; http://www.ncbi.nlm.nih.gov/pubmed/21073363

 The FDA Approved Rivaroxaban for Prevention of Stroke in Atrial Fibrillation

On November 4, 2011, the US Food and Drug Administration approved rivaroxaban (Xarelto) to reduce the risk of stroke in people with nonvalvular atrial fibrillation (AF). Rivaroxaban is the first oral direct factor Xa inhibitor approved in the United States. Rivaroxaban was previously approved to reduce the risk of blood clots, deep vein thrombosis, and pulmonary embolism following knee or hip replacement surgery. It is marketed by Janssen Pharmaceuticals. www.fda.gov/newsevents/newsroom/pressannouncements/ucm 278646.htm

 PARTNER Cohort A Trial Shows TAVI Is Noninferior to Surgery

 The PARTNER Cohort A trial, which compared transcatheter- aortic valve implantation (TAVI) with surgical aortic valve replacement (AVR) for severe aortic stenosis, showed that the new catheter-based procedure is as good as surgery in surgery-eligible patients in terms of all-cause mortality. The results of the trial were presented at the American College of Cardiology 2011 Scientific Sessions. At 30 days, deaths were numerically lower in the TAVI group, but not statistically different. By the first year, deaths in both groups were nearly identical and met the definition of noninferiority. PARTNER Cohort A researchers concluded that TAVI is an acceptable alternative to AVR in selected high-risk operable patients. The study was published in The New England Journal of Medicine; http://www.nejm.org/doi/full/10.1056/NEJMoa11035100

 STICH Trial Substudy Suggests Myocardial Viability Testing Didn’t Impact Treatment Effectiveness

 A substudy of the Surgical Treatment for Ischemic Heart Failure (STICH) trial—a randomized comparison of medical therapy with or without bypass surgery for ischemic heart disease in patients with left ventricular (LV) systolic dysfunction&mdash; suggests that assessment of myocardial viability alone should not be the deciding factor in selecting the best therapy for patients with ischemic heart disease and LV dysfunction. Substantial viable myocardium evident in baseline imaging studies had no independent effect on all-cause mortality over 5 years, and viability did not influence the relative effectiveness of the 2 treatments, either for all-cause mortality or cardiovascular mortality and cardiovascular hospitalization. This study was published in The New England Journal of Medicine; http://www.ncbi.nlm.nih.gov/pubmed/21463153

Lipitor’s Patent Expired in 2011; Plavix’s Patent Expires in 2012

The patent on Pfizer’s blockbuster drug Lipitor (atorvastatin calcium) expired on November 30, 2011. The world’s biggest selling drug to date, Lipitor was still generating sales of almost $8 billion per year in the United States when it lost patent protection. How will the availability of generic Lipitor affect physicians’ prescribing behavior? Two generic HHS versions of atorvastatin are now available: one is made by Ranbaxy Laboratories, and the second is Watson’s authorized generic. Six months from the date of patent expiry, however, multiple generic versions of Lipitor will be allowed onto the market. As the data filters in with regard to Lipitor generics, a second big drug—sanofi-aventis/Bristol-Myers Squibb’s Plavix (clopidogrel bisulfate)&mdash;will lose patent protection on May 17, 2012. Bloomberg Businessweek, December 19, 2011

For the first time, the US Department of Health and Human Services has publicly overruled the FDA’s decision to approve a medication. On December 7, 2011, Secretary Kathleen Sebelius overruled the FDA’s decision to approve the application for over-the-counter (OTC) sale without age restrictions of Plan B One-Step, a single-dose emergency contraceptive tablet of the progestin levonorgestrel. The action has generated a great deal of controversy about whether the HHS decision was based on politics or science. The safety and efficacy of the emergency use of levonorgestrel has been well documented Top 10 Stories in Cardiology Top 10 Stories in Cardiology Debabrata Mukherjee, MD, MS,FACC, and Jackie Syrop, Managing Editor February 2012 | Cardiology Review 39 and was reviewed twice by the FDA—once in 2006 before Plan B was granted “behind the counter” status (permitting its sale without prescription to women 17 years or older, but requiring a prescription for those 16 years or younger) and in its most recent review for OTC use without age restrictions. doi:10.1056/NEJMp1114439

Supreme Court Will Review Constitutionality of the Affordable Care Act’s Medicaid Expansion Mandate

 The US Supreme Court’s upcoming review of the constitutionality of the Affordable Care Act’s (ACA) individual mandate to obtain health insurance will also examine the constitutionality of the ACA’s Medicaid expansion provision—the Act’s requirement that starting in 2014, state Medicaid plans cover all persons under 65 years of age with individual or family incomes up to 133% of the federal poverty level. Medicaid has not previously set a baseline income level for mandatory eligibility for adults. When fully phased in, the ACA will provide 90% federal matching funds for newly eligible beneficiaries. To remain eligible for any federal Medicaid matching funds, states are obliged to accept these new requirements. At the same time, traditional Medicaid will no longer be a possible option for states because the current federal support will stop in 2014. Florida’s lawsuit challenging the ACA’s mandatory Medicaid expansion requirements centers on the US Constitution’s Taxing and Spending Clause. Stay tuned. doi:10.1056/NEJMp1113416

 MI FREEE Trial: Access to Free Heart Meds Reduces MIs, Heart Failure

Results of the Post-Myocardial Infarction Free Rx Event and Ecomonic Evaluation (MI FREEE) study, funded by Aetna, revealed that patients who had suffered heart attacks, and whose entire costs for heart medications were covered by Aetna, had lower rates of rehospitalization for MI and heart failure (HF) than patients who had co-pays for these prescriptions. While there was no reduction in the rate of revascularization procedures, Aetna’s costs decreased despite the expense of completely covering heart medications, because the company spent less to treat subsequent health problems. Patients who received free medications also were more likely to take them as directed. Patients saved more than 25% on their overall out-of-pocket health care costs and payed fewer co-pays because their health had improved. Aetna said it will begin offering a benefit plan that will allow MI survivors to get some medications at no cost, or reduced cost, beginning in 2013 (see page 10).

The Centers for Medicare and Medicaid Services (CMS) Recovery Audit Contractors (RACs) have successfully used random audits to recoup billions in reimbursement payments resulting from fraud, abuse, and error, and to avoid what CMS terms the “pay and chase” scenario. In November 2011, CMS announced a new pilot program taking effect on January 1, 2012, with the goal of reducing improper payments by $50 billion and halving payment errors: RACs in certain high-volume or high-population states will begin pre-payment audits of many cardiovascular (and orthopedic) procedure claims prior to paying providers. The new process affects all procedures in certain cardiovascular diagnosis-related groups (DRGs) in 11 states (Florida, California, Michigan, Texas, New York, Louisiana, Illinois, Pennsylvania, Ohio, North Carolina, Montana) that have high CMS fraud rates or high claims volumes for short inpatient hospital stays. Submission of a claim under any of these DRGs will trigger a mandatory review prior to payment by Medicare. The program expires on December 31, 2014. Cardiology organizations have expressed concerns about the program disrupting care and placing burdens on providers and patients. www.theheart.org/article/1325457.do https://www.cms.gov/CERT/05_RAC_Prepay_Demo.asp

An Australian study found that overeating and salt are the 2 biggest threats to health and contributors to increased risk of stroke, and the overall quality of a person’s diet and the balance between caloric intake and expenditure are more important factors in stroke risk than the actual foods and nutrients consumed. Dr Graeme J. Hankey reviewed studies on the link between nutrition or diet and the risk of stroke published between 1970 and 2011. Between 1970 and 2008 the incidence of stroke in high-income countries fell by 42%—most likely because of reduced smoking and more attention to hypertension and high cholesterol&mdash;but in poorer nations, the incidence of stroke increased by more than 100%. The rise in stroke incidence coincided with food and lifestyle changes associated with urbanization and industrialization. Further research is needed to improve the quality of the evidence about nutrients, foods, and dietary patterns with stroke risk, and the role of exercise and how it affects nutrition or stroke risk. The study was published in Lancet Neurology; www.thelancet.com/ journals/laneur/article/PIIS1474-4422(11)70265-4/abstract

Overview

Year 2011 in Review: Top 10 Stories in Cardiology 

tatins are already widely used to lower cholesterol and reduce the risk of heart disease and death from cardiac events. Now there’s evidence that taking statins may help prevent deaths from influenza. A recent study in the 

 found that among more than 3000 older adults hospitalized with influenza in 2007-2008, those who were taking statins before or during their hospitalizations were 41% less likely to die from the flu over 30 days compared with those who did not use statins.

The absolute risk of death was 3.9% in the patients taking statins and 5.5% in those not taking statins. Even after adjusting for age, race, underlying health conditions, and flu vaccination status as well as antiviral drugs that patients received, statins’ benefit persisted.

Study coauthor Ann Thomas, MD, MPH, a physician at the Oregon Public Health Division, said that there is not yet enough evidence to justify statins becoming the standard of care for people hospitalized with the flu, but the findings should be investigated in a clinical trial to confirm the observed association.

Other factors could be responsible for the study’s findings, cautioned Jeffry Kwong, MD, a scientist at the Institute for Clinical Evaluative Science in Toronto who studied statins and the flu. Dr Kwong said people who take statins are inherently different from people who don’t take them, and may be more likely to take care of themselves in general and to be healthier overall, compared with those who don’t take medications for health.

Heart Attack Screening Guidelines for Student Athletes Not Being Followed 

f Washington State is an example of what goes on in the other 49 states, fewer than 6% of US doctors are fully following national guidelines for assessing the risk of sudden cardiac death in high school athletes. National guidelines concerning sudden cardiac death screening exams during high school sports physicals have been unchanged since 1996, when the American Heart Association (AHA) published a 12-point sudden cardiac death screening guideline, which was reaffirmed in 2007.

According to lead researcher Nicolas Madsen, MD, MPH, of the Seattle Children’s Hospital and the University of Washington School of Medicine, many doctors and athletic directors are not even aware the guidelines exist. He presented the study’s findings at the AHA’s Scientific Sessions 2011.

The study surveyed 1113 family doctors and pediatricians and 317 high school athletic directors in Washington state. Less than half of doctors and only 6% of athletic directors said they were aware of the screening guidelines, and none of the athletic directors said their schools required physicals to comply with the guidelines, which include 8 medical history questions and 4 physical exam elements, including checking blood pressure and listening to the heart.

Studies suggest that out of more than 7 million US high school athletes, 1 of every 30,000 to 50,000 athletes dies annually from out-of-hospital sudden cardiac arrest.

What Your Patients Are Reading

What Your Patients are Reading 

Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with Aatrial fibrillation (ARISTOTLE). N Engl J Med. 2011;365:981-992.

	Last year brought the FDA’s approval of dabigatran for this indication and, more recently, rivaroxaban. The latest investigational anticoagulant drug seek- ing approval for the AF indication is apixiban, an oral direct factor Xa inhib- itor. Here we review the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.

nticoagulants are mainstays of had a high risk of bleeding (includ- therapy in patients with atrial ing uncontrolled hypertension, recent fibrillation (AF) for the preven- stroke, or requirement for dual antition of embolic stroke. Until recently, oral options were limited to chronic warfarin. Given the difficulties of controlling patients on vitamin K antago- nists, the cardiology community has ea- gerly awaited the development of newer entities.

The ARISTOTLE trial was a randomized, double-blinded study comparing apixaban with warfarin for the preven- tion of stroke or systemic embolism in patients with nonvalvular atrial AF or flutter. In addition to AF or flutter, all patients had at least 1 additional risk factor for stroke, including previous stroke, transient ischemic attack (TIA), systemic embolism, symptomatic heart failure in the last 3 months, left ventricular ejection fraction ≤40%, age ≥75 years, diabetes mellitus, or hypertension.

Patients were excluded if they had another indication for anticoagulation, platelet therapy), or had severe renal or hepatic dysfunction. A total of 18,201 patients were enrolled from December 2006 to April 2010 and were followed for a mean of 1.8 years.

Patients were randomized to receive apixaban 5 mg twice daily or warfarin adjusted to target an international normalized ratio (INR) of 2.0 to 3.0. Pa- tients in the apixaban group who were ≥80 years of age, weighed ≤60 kg, or had serum creatinine (SCr) ≥1.5 mg/dL received 2.5 mg twice daily (n = 428). The study groups were well matched at baseline, with a mean age of 70 years and a mean CHADS2 score of 2.1. Pa- tient comorbidities included history of stroke or TIA (19%), hypertension (88%), diabetes (25%), heart failure (35.5%), history of myocardial infarc- tion (MI) (14%), and moderate or se- vere renal dysfunction (16.5%).

For those randomized to warfarin, the mean time spent in the therapeutic INR range of 2 to 3 was 66%. Rates of drug discontinuation were statistically higher for warfarin (27.5%) than for apixaban (25.3%), mostly attributed to a difference in the number of adverse drug events, though an equal propor- tion of discontinuations (44%) were due to adverse events or death for each group.

Apixaban was found to be superior to warfarin for the primary efficacy outcome of stroke or systemic embo- lism prevention, yielding a number needed to treat (NNT) of 303 for 1 year to prevent 1 event (1.27% vs 1.60%; P = 0.01). Likewise, apixaban was superior to warfarin for the pri- mary safety outcome of major bleed- ing (according to International Soci- ety on Thrombosis and Haemostasis [ISTH] criteria), with rates of 2.13% and 3.09% per year, respectively (P <0.001; NNT = 104).

Amid demonstration of superiority in clinical and safety end points, a com- bined net clinical outcome analysis was performed. Apixaban (6.13%) was su- perior to warfarin (7.20%) for the pre- vention of stroke, systemic embolism, death, or major bleeding, corresponding to an NNT of 93 (hazard ratio, 0.85; P <0.001).

Among pre-specified subgroups, no significant differences were observed for rates of stroke or systemic embolism, though P >0.10 was set as the level of significance for these interactions. Perti- nent subgroups included 2.5 mg or 5 mg apixaban twice daily versus warfarin. Although not statistically different from the 5-mg dose, the apixaban 2.5-mg dose versus warfarin confidence interval was wide and crossed 1.00; however, with only 831 patients enrolled in this dosing arm, it was likely underpowered to draw meaningful conclusions.

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in pa- tients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in non- valvular atrial fibrillation. N Engl J Med. 2011;365:883-891.

3. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806-817.

n order to understand the potential clinical implications of the ARISTOTLE trial, findings must be interpreted both alone and in light of available data supporting the use of other novel anticoagulants. The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) and ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trials evaluated other oral antico- agulants (dabigatran and rivaroxaban, respectively) for prevention of stroke or systemic embolism in patients with nonvalvular AF or flutter.

 Since a direct head-to- head comparison of these drugs has not been conducted and is unlikely, the trial designs, study populations, and results must be compared in order to determine the best therapeutic choice for a patient (pending FDA approval of apixaban, of course).

The study design of ARISTOTLE and the trial evaluating rivaroxaban in AF (ROCKET AF) were both double- blinded and randomized. However, the trial evaluating dabigatran in AF (RE-LY) was unblinded. The dabigatran trial did enroll a patient population that was more 14 Cardiology Review | February 2012 Anticoagulants similar to ARISTOTLE (similar age and baseline stroke risk), while the rivaroxaban study included patients of both greater age and risk of embolism. This difference is reflected in the higher rates of stroke and systemic embolism observed in ROCKET AF regardless of treatment assignment. Definitions for bleeding events were similar between trials.

Without direct comparison of these agents, and with differences in patient populations and study designs, it is hard to infer which agent would be superior. However, the results of ARISTOTLE showed apixaban to be superior with regard to both efficacy and safety. In the RE-LY trial, dabigatran 150 mg twice daily (the FDA-approved dose) was also found to be superior to warfarin for prevention of stroke, but this dose was associated with no difference in major bleeding. In ROCKET AF, no statis- tical difference was observed between rivaroxaban and warfarin for rates of stroke or systemic embolism (intent- to-treat population) or major bleeding. These differences may have been due to the higher stroke risk of patients enrolled in ROCKET AF, although no significant interaction based on CHADS

ARISTOTLE was the only trial to demonstrate a significant reduction in mortality and MI versus warfarin. Dabigatran 150 mg twice daily was associated with a nonsignificant lower rate of mortality but a significantly higher rate of MI than warfarin, while rivaroxaban demonstrated nonsignificant lower rates of both mortality and MI. On the other hand, both rivaroxaban and dabigatran 150 mg twice daily significantly lowered the rates of ischemic stroke versus warfarin, while the reduction with apixaban was nonsignificant. It is important to note that none of the trials was powered to detect differ- ences in these secondary outcomes. All 3 drugs significantly lowered the risk of intracranial bleeds compared with warfarin; however, dabigatran 150 mg twice daily and rivaroxaban were both associated with significantly higher rates of gastrointestinal bleeding.

Apixaban has an additional therapeutic niche based on the results of the AVERROES trial (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fi- brillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment), which compared apixaban to aspirin for prevention of stroke and systemic embolic in patients with AF deemed unsuitable for Vitamin K antagonist therapy.

 In clinical practice, patients with AF considered unsuitable candidates for warfarin therapy, often due to concerns for bleeding, may be started on aspirin to provide some protection against embolic events.

This trial was stopped early due to the significant superiority of apixaban over aspirin in preventing embolic events. This benefit was demonstrated against both high (≥162 mg) and low-dose aspirin (<162 mg) subgroups. More significantly, rates of major bleeding were no different between apixaban and aspirin, though a nonsig- nificant higher rate of bleeding was observed with apixaban versus low-dose aspirin.

Despite the theoretical advantages of apixaban over dabigatran and rivaroxaban, it is not currently approved for use in the United States. Furthermore, while the lower doses of apixaban and rivaroxaban were studied in clinical trials for patients with renal dysfunction, the lower recommended dose of dabigatran (see the Table) in patients with renal dysfunction has not yet been stud- ied in comparison with warfarin. Other factors affecting drug selection are summarized in the Table. All three agents provide a lifestyle advantage over warfarin due to decreased clinic or doctor’s office visits for therapeutic monitoring as well as lack of dietary restrictions for patients. However, these agents will also be significantly more expensive than warfarin for years to come, and are not reversible in the setting of a bleed. Though they each have a shorter half-life than warfarin, no antidote comparable to Vitamin K for warfarin is available for any of these agents. Thus, switching to a newer agent may be unnecessary for patients whose INR is well controlled and who have tolerated warfarin therapy for years.

ARISTOTLE was the first trial to demonstrate the combined benefit of increased efficacy and safety versus warfarin and a significant decrease in mortality. Apixaban was superior to warfarin for the prevention of stroke or systemic embolism in patients with nonvalvular AF and also decreased rates of major bleeding and mortality. Pending FDA approval, it will represent yet another option for a patient population that has been committed to warfarin for many decades past.

Jennifer G. Bekker, PharmD, is a cardiology pharmacy Specialty Resident at University of Kentucky Health-Care Pharmacy Services and Jack and Linda Gill Heart Institute in Lexington, KY. She wrote this article in collaboration with Sara D. Brouse, PharmD, FCCP, BCPS-AQ Cardiology, Clinical Pharmacy Specialist Cardiology at University of Kentucky HealthCare Pharmacy Services and Jack and Linda Gill Heart Institute, Lexington, KY, and Editorial Board member Tracy e. MaCaulay, PharmD, BCPS-AQ Cardiology, Clinical Pharmacy Specialist-Cardiology, PGY2 Residency Program Director-Cardiology, and Adjunct Assistant Professor at University of Kentucky HealthCare, Department of Pharmacy Services and Division of Cardiovascular Medicine, Lexington, KY. February 2012

Apixaban vs Warfarin in Patients With Atrial Fibrillation: Where Does ARISTOTLE Fit In?

Haukka J, Niskanen L, Partonen T, Lonnqvist J, Tiihonen J. Statin usage and all-cause and disease-specific mortality in a nationwide study. Pharmacoepidemiol Drug Safety 2011. doi:10.1002/pds/2255.

tatins have proved to be a remarkable preventive cardiovas- cular therapy. The Cholesterol Treatment Trialists’ (CTT) Collaborative Group has shown that statin treatment is better than placebo, and that more-intensive treatment is bet- ter than less-intensive treatment for all cardiovascular outcomes (fatal and nonfatal myocardial infarction, coro- nary revascularization, and stroke).

 For every 1 mmol/L (39 mg/dL) reduction in low-density lipoprotein (LDL) cholesterol, there is a 20% to 25% reduction in major cardiovas- cular events as well as a significant reduction in all-cause mortality.

 It is important to note that the CTT meta- analysis included subjects from randomized clinical trials (RCTs), which is a different situation from the real- world clinical setting in which we all practice.

The real-world setting lacks both the inherent motivation found in RCT patients and the dedicated clinical trial personnel who focus on the techniques of medication compliance, adherence, and follow-up, which together can produce a long-term compliance rate of >80%. Therefore, efforts have been made to analyze whether the use of pharmacy records and medical claims/ national medical databases can deter- mine whether varying levels of adherence to statin treatment result in different levels of outcomes benefit (as hard end points, hospitalizations, health care costs, etc). An example of just such an analysis, in a Finnish population, is presented in the study by Haukka et al.

The authors used a Finnish nationwide database for a record-linkage study to evaluate the association of statin use with all-cause and disease-specific mortality. The study population of statin users included all residents of Finland who had filled at least 1 prescription of a statin between 1997 and 2005. A control group was chosen, to match the statin users, from the general Finnish population who had not purchased a statin between 1997 and 2005. Adherence to statin use was determined as the proportion of days covered by statin therapy over the follow-up pe- riod, and 7 adherence thresholds were defined: 20%, 30%, 40%, 50%, 60%, 70%, and 80%. The mean length of follow-up was 4.4 years.

Data for mortality differences between statin users and nonusers by follow-up periods is shown in the table. All-cause mortality was lower in the statin users at the beginning of the follow-up period and persisted over time, but did not fall further. While there was no difference in CHD mortality between the groups at the start of follow-up, a significant benefit became evident for statin users after 1 year. When levels of adherence to statin use was considered, there was no effect on all-cause mortality or non-CHD mortality; however, there was a linear dose-response relationship between increasing statin adherence and decreasing CHD mortality.

The limitations of this study, and others like it, include the possibility of selection bias, as well as the “healthy adherer” effect, such that people who adhere to statin treatment might not only adopt healthier lifestyles but also show greater adherence to other med- ications that can beneficially affect outcomes. This study also had limited ability to assess individual risk factors that contribute to mortality, and, it should be noted, had no information about baseline and follow-up lipid values. This limits the applicability of the results to patients who are clinically determined to be at different levels of baseline CHD risk, and prevents linking the outcomes to the on-treat- ment levels of cholesterol achieved. The authors’ main conclusion was that there was no association between all-cause mortality and statin use, and that non-CHD mortality, especially cancer and suicide, was also not as- sociated with statin use. Most impor- tant, there was a significant reduction in CHD mortality with statin use, and this reduction was linearly proportional to increasing statin adherence.

1. Cholesterol Treatment Trialists’ (CTT) Collaboration, et al. Efficacy and safety of more intensive lowering of LDL cholester- ol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681.

2. Marelli C, Gunnarsson C, Ross S, et al. Statins and risk of cancer: a retrospective cohort analysis of 45,857 matched pairs from an electronic medical records data- base of 11 million adult Americans. J Am Coll Cardiol. 2011;58:530-537.

3. Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, Perri D. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol. 2008;52:1769-1781.

4. Ray KK, Sesbasai SR, Erqou S, et al. Statins and all-cause mortality in high- risk primary prevention: a meta-analysis of 11 randomized controlled trials involv- ing 65,229 participants. Arch Intern Med. 2010;170(12):1024-1031.

5. Ruokoniemi P, Korhonen NM, Helin- Salmivaara A, et al. Statin adherence and the risk of major coronary events in pa- tients with diabetes: a nested case-control study. Br J Clin Pharmacol. 2011;71:766- 776.

6. Pittman DG, Chen W, Bowlin SJ, Foody JM. Adherence to statins, subsequent healthcare costs, and cardiovascular hospi- talizations. Am J Cardiol. 2011;107:1662- 1666. February 2012

his study was performed to evaluate, in a “real- world” cohort of subjects, whether adherence to statin treatment had any beneficial, or even detri- mental, effect on all-cause or disease-specific mortality. The results are certainly not surprising for the benefit on CHD death, but are surprising for the lack of effect on all-cause mortality.

There has never been evidence from previously pub- lished meta-analyses of RCTs that statin treatment has a detrimental effect on non-CHD mortality, especially cancer-specific mortality.

To the contrary, these meta- analyses suggest reductions in not only CHD mortality but also all-cause mortality in both primary and sec- ondary patient populations.

 An important finding ments. Should we focus only on telling them about the health and/or cost benefits of statin use, for instance, and minimize, or even ignore, the potential side effects such as myalgias, Recent data using health claims databases has also shown that adherence to statins reduces cardiovascular hospitalizations and total health care costs.... from this study is that in a population that is not in a con- trolled trial setting, a greater adherence to statin use reduces CHD mortality with- out any trade-off in non-CHD mortality. It could be reason- ably anticipated that if these patients were followed for longer than 4.4 years, the reduction in CHD death observed (without a change in non-CHD death) would result in a reduction in all-cause mortality.

Recent date using health claims databases has also shown that adherence to statins reduces cardiovascular hospitalizations and total health care costs, and that better statin adherence in patients with type 2 diabetes predicts reduced major corinary events. 

 Adherence to and persistence with treatments for chronic asympotomatic medical conditions such as hypertension and dyslipimedia are not as optimal as we would like, despite clinically proven benefecial outcomes.

As clinicans, we struggle with finding the best method to encourage our patients to persist with drug tretments. Should we focus only on telling them about the health and/or cost benefits of statin us, for instance, and minimize, or even ignore, the potential side effects such as myalgias, weakness, and hepatic transaminitis, to name a few? What data can we show patients that will convince them that the long-term adher- ence to therapy has overwhelming ben- efit? Real-world da- tabase information, such as this study, can be both reassur- ing and motivating.

For our at-risk patients who can tolerate statins, even with manageable short- term side effects, this study confirms that long-term drug persistence provides one of the single most powerful methods to decrease CHD death, with no trade-off on death from other causes.

Peter H. Jones, MD, FACP, FNLA, is medical director of the Weight Management Center at the Methodist Diabetes and Metabolism Institute in Houston, Texas, and associate professor of medicine in the Center for Cardiovascular Disease Prevention at Methodist DeBakey Heart and Vascular Center at The Baylor College of Medicine. Dr Jones received his MD at The Baylor College of Medicine as the Michael E. DeBakey Scholar, where he also completed his internal medicine residency. He is board certified in internal medicine and clinical lipidology and is a fellow of the American College of Physicians and of the National Lipid Association (NLA). He was a board member of the NLA, and served as secretary and president of that organization. He is currently a board member of the American Board of Clinical Lipidology.

Statin Usage and All-Cause and Disease-Specific Mortality in a Nationwide Study

Driscoll A, Beauchamp A, Lyubomirsky G, Demos L, McNeil J, Tonkin A. Suboptimal man- agement of cardiovascular risk factors in coronary heart disease patients in primary care occurs particularly in women [published online ahead of print June 1, 2011]. Intern Med J. doi:10.1111/j.1445-5994.2011.02534.x.

here have been numerous studies showing the benefit of cho- lesterol lowering, blood pressure control, and healthy lifestyle in primary and secondary prevention of cardiovascular disease. Yet in study after study, conducted in different popu- lations over many years, it has been shown that cardiovascular risk factors are undertreated.

As all developed countries struggle with rising health care costs and grow- ing elderly populations, it is crucial that we understand why our patients are being undertreated, and how to make changes in practice so that all patients who are at risk are treated optimally. The study by Driscoll et al sought to compare how well female patients with coronary heart disease (CHD) are controlled for their risk factors in a primary care setting in Australia by comparing their management with that recommended in guidelines and that provided to male patients.

The authors used a chronic disease management program (mdCare, developed by Merck, Sharp, and Dohme Australia) that is available to general practitioners (GPs) in Australia to compare management of patients with CHD. Of the 6000 GPs approached, 1258 were enrolled in the study. Each practitioner then searched his or her electronic databases and consecutively extracted 100 patients with a diagnosis of preexisting CHD. The patients were contacted to assess risk factors; after the assessment, the GP reviewed the assessment and ordered relevant diagnostic tests.

Once results were obtained, an in- dividualized patient assessment report was generated automatically using the 

Following a review of the reports by the GP, a management plan was developed using a template provided by an 

Care coordinator. The plan was finalized in conjunction with the patient and included a selection of health issues with goals, actions, medications, and allied health refferals as appropriate. 

The study focused on risk factors at the time of enrollment. Patients were recruited over a 12-month period between January 2006 and January 2007. The guideline used for cholesterol control incoporated low density lipoprotein (LDL) cholesterol <100 mg/dL and LDL <77 mg/dL, and HDL >38 mg/dL which is the Australian and New Zealand 2005 guideline.

Most GPs participating in this study were more likely to be older, male, and have their practice in a rural setting compared with the total GP population in Australia. Of the 12,509 patients in the study, 7242 were male and 5267 were female. As in other studies, female patients were older; however, unlike in other studies, this study found that men had more cardiovascular comorbidities such as hyperlipidemia, peripheral artery disease, and diabetes, compared with women; women had higher levels of hypertension. More-over, men were more likey to have had a hospital readmission for CHD within the previous 6 months (74% vs 56%, P <0.0001). Men were more likey to smoke, drink alcohol, have a sedentary lifestyle, and eat a diet higher in salt and fat. However, women were more likely to have higher blood pressure than their male counterparts, as well as higher total cholesterol and higher LDL (Figure).

As seen in other studies, Driscoll et al found that women were less likely to be prescribed pharmacotherapy.

 For example, women were less likely to be taking aspirin (80% vs 71%, P <0.0001), lipid-lowering medications (71% vs 66%, P <0.0001), or antihypertensive medications (62% vs 58%, P <0.0001). The study also found that total cholesterol levels were outside the recommended range in 57% of men and 76% of women with CHD, and among those receiving lipid-lowering medication, a majority of patients were not controlled (53% of men and 72% of women). These patients were selected by the GPs to be enrolled in this study. If the study had been done in a randomly selected patient group, the control rate would be even lower.

On a positive note, both men and women had well-controlled blood pressure. In both groups, the mean systolic and diastolic blood pressure was below 140/80 mm Hg.

1. Jneid H, Fonarow GC, Cannon CP, et al. Sex differences in medical care and early death after acute myocardial infarction. Circulation. 2008;118(25):2803-2810.

2. Vittinghoff E, Shlipak MG, Varosy PD, et al. Risk factors and secondary preven- tion in women with heart disease: the Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 2003;138(2):81-89.

3. Driscoll A, Beauchamp A, Lyubomirsky G, et al. Suboptimal management of car- diovascular risk factors in coronary heart disease patients in primary care occurs par- ticularly in women. Intern Med J. 2011; doi:10.1111/j.1445-5994.2011.02534.x.

4. Stafford RS. Aspirin use is low among United States outpatients with coronary artery disease. Circulation. 2000;101(10):1097-1101.

5. Bhatt DL, Steg PG, Ohman EM, et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA. 2006;295(2):180-189.

February 2012

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