UPDATE Update in Cardiology: Evidence Published in 2014 Daniel A. Steinhaus, MD, and Peter J. Zimetbaum, MD
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his update summarizes key articles in cardiovascular disease published in 2014. We selected these articles for their novelty, potential effects on clinical practice, and general interest for physicians in internal medicine practice. New studies of antiplatelet therapy helped guide both primary and secondary prevention of coronary artery disease. Ongoing research has established the benefits of colchicine in the treatment of recurrent pericarditis. New guidelines for the management of atrial fibrillation were also practice-changing. Novel medical therapies are anticipated for heart failure (neprilysin inhibition) and hyperlipidemia (anti– proprotein convertase subtilisin/kexin type 9). However, new therapies for heart failure with preserved systolic function remain controversial. Researchers made notable advances in structural heart disease, especially with expanded results from transcatheter aortic valve replacement and investigation of the effectiveness of percutaneous left atrial appendage closure devices.
the difference in all-cause mortality was no longer statistically significant. Cautions: These results apply only to patients who did not have an adverse event while receiving dual antiplatelet therapy during the first 12 months of treatment. Although imbalanced randomization appears to explain the increase in all-cause mortality with dual antiplatelet therapy, concerns remain. Implications: Dual antiplatelet therapy protects against major adverse cardiac events beyond 1 year in patients with drug-eluting stents, but with an increased risk for bleeding.
Low-Dose Aspirin Has No Benefit in Primary Prevention of Cardiovascular Mortality in Low-Risk Patients Ikeda Y, Shimada K, Teramoto T, et al. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial. JAMA. 2014;312:2510-20. [PMID: 25401325] doi:10.1001/jama.2014.15690
Background: Drug-eluting stents require a longer period of dual antiplatelet therapy to prevent stent thrombosis than do bare metal stents, and current guidelines recommend 12 months. Observational studies suggest additional benefit from even longer therapy, and the optimal duration is uncertain. Findings: In the Dual Antiplatelet Therapy Study, 9961 patients who had drug-eluting stents and had been receiving dual antiplatelet therapy for 1 year without adverse drug events were randomly assigned for an additional 18 months to placebo or to aspirin with a thienopyridine. Patients receiving dual antiplatelet therapy had fewer major adverse cardiac events than patients receiving placebo (4.3% vs. 5.3%), and they had reductions in the frequencies of myocardial infarction (hazard ratio, 0.47) and stent thrombosis (hazard ratio, 0.29). However, the risk for all-cause mortality was increased (2% vs. 1.5%), primarily from deaths related to bleeding (11 vs. 3) and cancer (31 vs. 14). After adjustment for the increased number of patients with a history of cancer who received dual antiplatelet therapy,
Background: In patients with known cardiovascular disease, aspirin reduces the risk for myocardial infarction, stroke, and vascular death. In patients without known cardiovascular disease, aspirin reduces the risk for a first myocardial infarction but has no effect on stroke or cardiovascular death. Because aspirin increases the risk for bleeding, it is important to balance aspirin's benefits and harms. However, how to do this for people at low risk for adverse cardiovascular events is uncertain. Findings: The Japanese Primary Prevention Project randomly assigned more than 14 000 patients (aged 60 to 85 years) with hypertension, dyslipidemia, or diabetes recruited from a primary care setting to receive aspirin, 100 mg daily, or no aspirin. The primary outcome was a composite of death from cardiovascular causes, nonfatal stroke, and nonfatal myocardial infarction. The study was stopped early when the median follow-up time was 5 years and monitors determined that prolonging the study could not find aspirin beneficial. There was no significant difference in the primary endpoint (5-year event rate, 2.77% for aspirin vs. 2.96% for no aspirin; hazard ratio, 0.94; P = 0.54). Aspirin did significantly reduce the risk for nonfatal myocardial infarction (5-year event rate, 0.3% vs. 0.6%; hazard ratio, 0.53; P = 0.02) or transient ischemic event (5-year event rate, 0.26% vs. 0.49%; hazard ratio, 0.57; P = 0.04), but aspirin also significantly increased the risk for extracranial hemorrhage necessitating transfusion or hospitalization (5-year event rate, 0.86% vs. 0.51%; hazard ratio, 1.85; P = 0.004). Cautions: This study examined only patients at low risk for cardiovascular events. The Japanese patients in this
Ann Intern Med. 2015;162:W86-W90. doi:10.7326/M15-0272 For author affiliations, see end of text. This article was published online first at www.annals.org on 30 April 2015.
Annals of Internal Medicine
Coronary Artery Disease Dual Antiplatelet Therapy Protects Against Ischemic Events Beyond 1 Year Mauri L, Kereiakes DJ, Yeh RW, et al; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371:2155-66. [PMID: 25399658] doi:10.1056/NEJMoa1409312
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study had different characteristics from those of primary care patients in many other countries. Implications: Aspirin is unlikely to benefit people without known cardiovascular disease who are at low risk for cardiovascular death.
Pericarditis Colchicine Reduces the Recurrence of Pericarditis Imazio M, Belli R, Brucato A, et al. Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial. Lancet. 2014;383:2232-7. [PMID: 24694983] doi:10.1016/S0140-6736(13)62709-9
Background: Pericarditis recurs in as many as 30% of patients after acute pericarditis. Colchicine effectively treats acute pericarditis and prevents first recurrences of pericarditis, and nonrandomized trials suggest that colchicine may prevent multiple recurrences of pericarditis. Findings: In this double-blind trial conducted at 4 general hospitals in northern Italy, 240 patients with 2 or more recurrences of pericarditis received conventional therapy—nonsteroidal anti-inflammatory drugs or corticosteroids with a proton-pump inhibitor—and were randomly assigned to 6 months of placebo or colchicine (0.5 mg daily for patients weighing ≤70 kg and 0.5 mg twice daily for patients weighing >70 kg). Compared with patients receiving placebo, fewer patients receiving colchicine had recurrent pericarditis during a mean follow-up of 20 months (21.6% vs. 42.5%). This difference persisted when colchicine was compared with placebo, irrespective of the type of concurrent nonsteroidal anti-inflammatory drugs (aspirin, ibuprofen, or indomethacin), but statistical significance was lost when colchicine was compared with placebo for patients taking corticosteroids (36.8% vs. 52.2%). Colchicine was effective in patients with idiopathic pericarditis but not in patients with nonidiopathic pericarditis, such as the post– cardiac injury syndrome and pericarditis related to connective tissue disease. The frequency of adverse events was similar in the different groups. Cautions: The utility of adjunctive treatment with nonsteroidal anti-inflammatory drugs and corticosteroids remains unclear. Implications: Colchicine appears to be safe and effective for preventing recurrent pericarditis.
Atrial Fibrillation Guidelines for Atrial Fibrillation Management Change January CT, Wann LS, Alpert JS, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the man-
agement of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:e1-76. [PMID: 24685669] doi:10.1016/j.jacc.2014.03.022
Background: The previous American Heart Association, American College of Cardiology, and Heart Rhythm Society guidelines for atrial fibrillation were published in 2006 and updated in 2011. Findings: Major changes to the guidelines include replacing the CHADS2 score (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack) with the CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, sex category) for deciding which patients with nonvalvular atrial fibrillation should receive anticoagulation to prevent stroke. In addition, the guidelines now provide a stronger recommendation (class I) that anticoagulation should be based on the patient's risk for thromboembolism without consideration of the pattern or duration of atrial fibrillation. Patients with a CHA2DS2-VASc score of 2 or greater should receive anticoagulation with warfarin, dabigatran, rivaroxaban, or apixaban, although aspirin can still be considered for those with a CHA2DS2-VASc score of 1. Only warfarin should be used in patients with a mechanical valve; no specific guidance is given for a patient with a bioprosthetic valve. Catheter ablation is recommended for patients with symptomatic paroxysmal atrial fibrillation in whom antiarrhythmic medications have failed or who cannot tolerate these medications. Catheter ablation should be considered as initial rhythm-control therapy only for those who have had a full assessment of the risks and benefits of treatment options. Cautions: To address the needs of individual patients, physicians must modify these recommendations for patient type. Implications: The new guidelines recommend change in some established ways of managing patients with atrial fibrillation.
Heart Failure Angiotensin–Neprilysin Inhibition Improves Outcomes in Heart Failure McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:9931004. [PMID: 25176015] doi:10.1056/NEJMoa1409077
Background: Neprilysin is a neutral endopeptidase that degrades several endogenous vasoactive peptides, including the natriuretic peptides. Inhibition of neprilysin helps offset the neurohormonal dysregulation that occurs in heart failure. Prior trials of a neprilysin inhibitor combined with an angiotensin-converting enzyme in-
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Update in Cardiology
hibitor for the treatment of heart failure found an association with angioedema and failed to show benefit. Findings: The PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) study was an industry-supported, randomized, double-blind trial that compared enalapril, which is known to benefit patients with heart failure, against a combination of sacubitril (a neprilysin inhibitor) with valsartan (an angiotensin-receptor blocker). The trial enrolled 8442 patients with symptomatic heart failure and an ejection fraction of 40% or greater and excluded those with severe renal insufficiency and hyperkalemia. The trial was stopped early at a median follow-up of 27 months because the results met prespecified rules for determining that the combination drug was superior to enalapril for preventing a composite outcome of death from cardiovascular causes or first hospitalization for heart failure (21.8% vs. 26.5%; P < 0.001). The combination drug was also better for preventing cardiovascular death (13.3% vs. 16.5%), death from any cause (17% vs. 19.8%), and progression of heart failure symptoms. Use of the combination drug was discontinued less frequently for an adverse event than was use of enalapril (10.7% vs. 12.3%), and the combination drug was associated with lower rates of hyperkalemia, cough, and worsening of renal insufficiency. The frequency of angioedema was similar between groups, and no airway compromise occurred in either group. Cautions: The combination drug was associated with a higher rate of symptomatic hypotension. Implications: For patients with heart failure and a reduced ejection fraction, the combination of a neprilysin inhibitor with an angiotensin-receptor blocker reduced rates of total mortality, cardiovascular death, and heart failure hospitalization compared with standard therapy.
vated natriuretic peptide level in the preceding 60 days were randomly assigned to spironolactone or placebo. Patients were excluded if they had baseline hyperkalemia (potassium level ≥5.0 mmol/L) or renal insufficiency (estimated glomerular filtration rate 2.5 mg/dL [>221 μmol/L]). The median ejection fraction was 56%, and most patients had New York Heart Association class II or III symptoms. When compared with the placebo group, the spironolactone group experienced a statistically nonsignificant reduction in the primary composite endpoint of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization (18.6% vs. 20.4%; hazard ratio, 0.89; P = 0.14), but the reduction was statistically significant for the subgroup of spironolactone recipients with elevated natriuretic peptide levels (hazard ratio, 0.65; P = 0.003). Cautions: Patients enrolled in the United States, Canada, Brazil, and Argentina had a significant reduction in the primary outcome (27.3% vs. 31.8%), but those enrolled in Russia and Georgia did not (9.3% vs. 8.4%), possibly because of an unexpectedly low event rate in the placebo group. Implications: This study failed to find a benefit for spironolactone in patients with heart failure and preserved ejection fraction, but regional differences complicate how the results should be interpreted.
Spironolactone Has Uncertain Benefit in Heart Failure With Preserved Ejection Fraction
Koren MJ, Lundqvist P, Bolognese M, et al; MENDEL-2 Investigators. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2531-40. [PMID: 24691094] doi:10.1016/j.jacc.2014.03.018
Pitt B, Pfeffer MA, Assmann SF, et al; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383-92. [PMID: 24716680] doi: 10.1056/NEJMoa1313731
Background: Despite improvement in the treatment of patients with heart failure and a reduced ejection fraction, therapy for heart failure with preserved ejection fraction remains largely empiric. Mineralocorticoidreceptor antagonists reduce overall mortality and heart failure hospitalizations for patients with heart failure and a reduced ejection fraction (relative risk reduction, 25% to 30%), and they improve echocardiographic measures of diastolic function. Findings: In the international TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial, 3445 patients age 50 years or older with an ejection fraction of 45% or greater, hospitalization for heart failure in the past year, or an ele-
Hyperlipidemia Antibodies Against PCSK9 Decrease Low-Density Lipoprotein Cholesterol Levels Blom DJ, Hala T, Bolognese M, et al; DESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809-19. [PMID: 24678979] doi:10.1056/NEJMoa1316222
Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63: 2541-8. [PMID: 24694531 doi: 10.1016/j.jacc.2014.03.019
Background: The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the hepatic low-density lipoprotein (LDL) receptor. Evolocumab is a human monoclonal antibody that inhibits PCSK9. The GAUSS-2 (Goal Achievement after Utilizing an AntiPCSK9 Antibody in Statin Intolerant Subjects-2), MENDEL-2 (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2), and DESCARTES (Durable Effect of PCSK9 Antibody Compared with Placebo Study) trials studied whether evo-
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locumab could reduce LDL cholesterol levels in patients with hyperlipidemia. Findings: GAUSS-2 and MENDEL-2 were 12-week, double-blind trials that randomly assigned patients to evolocumab or placebo with or without ezetimibe. GAUSS-2 studied 307 patients previously intolerant of statins, and MENDEL-2 studied 614 patients previously or currently treated with statins. In both trials, evolocumab reduced LDL cholesterol by 53% to 57% compared with placebo and 37% to 40% compared with ezetimibe. In GAUSS-2, fewer evolocumab recipients had muscle-related adverse effects than ezetimibe recipients (12% vs. 23%). DESCARTES was a 52-week, double-blind trial of evolocumab versus placebo. After 4 to 12 weeks of traditional treatment to decrease lipids (various combinations of diet, atorvastatin, and ezetimibe), 901 patients with LDL cholesterol levels greater than 75 mg/dL (>1.94 mmol/L) were randomly assigned to evolocumab or placebo and followed for 52 weeks. The overall reduction in LDL cholesterol was 57% for evolocumab compared with placebo. Slightly more adverse events (nasopharyngitis, upper respiratory tract infection, back pain) occurred in the evolocumab group. Cautions: These trials did not study long-term results or clinical outcomes. The U.S. Food and Drug Administration (FDA) has expressed concern about possible neurocognitive adverse effects from aggressive lowering of LDL cholesterol. Implications: Therapy with human monoclonal antibody directed against PCSK9 decreases LDL cholesterol levels in patients not taking statins, those intolerant of statins, and those receiving appropriate traditional therapy. Whether these effects lead to more favorable clinical outcomes remains uncertain.
Structural Heart Disease Transcatheter Aortic Valve Replacement Improves Survival Compared With Surgery in Patients With Severe Aortic Stenosis and High Surgical Risk Adams DH, Popma JJ, Reardon MJ, et al; U.S. CoreValve Clinical Investigators. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med. 2014;370:1790-8. [PMID: 24678937] doi:10.1056/NEJMoa1400590 Popma JJ, Adams DH, Reardon MJ, et al; CoreValve United States Clinical Investigators. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol. 2014;63:1972-81. [PMID: 24657695] doi: 10.1016/j.jacc.2014.02.556
Background: Transcatheter aortic valve replacement with the Sapien balloon-expandable system (Edwards, Irvine, California) was approved in the United States in 2011 for patients whose condition is inoperable or who have a greater than 8% risk for 30-day mortality after surgery to replace the aortic valve. Approval was based
on a randomized trial that demonstrated noninferiority of the system compared with surgery. Patients with the system had more major vascular complications, but surgical patients had more major bleeding and atrial fibrillation. The FDA has also approved a different system that uses the CoreValve self-expanding transcatheter aortic valve, on the basis of a prospective nonrandomized study. Findings: The U.S. CoreValve High Risk Study randomly assigned 795 patients with an estimated postsurgery mortality greater than 15% to receive a self-expanding transcatheter aortic valve or to undergo open aortic valve surgery. Compared with the open surgery group, fewer patients in the group that received a transcatheter aortic valve experienced the primary endpoint of death from any cause at 1 year (14.2% vs. 19.1%; P = 0.04 for superiority). Both groups experienced similar improvements in symptoms. The transcatheter aortic valve group had a higher rate of major vascular complications and permanent pacemaker placement and a nonsignificantly lower incidence of stroke. Cautions: The patients in this trial were not as high risk as those in the randomized trial of the balloonexpandable system. Implications: Transcatheter aortic valve replacement with the self-expanding system appears to be superior to open surgery in patients with a high risk for death after surgery.
Percutaneous Left Atrial Appendage Closure May Be Similar to Warfarin for Preventing Thromboembolism in Atrial Fibrillation Holmes DR Jr, Kar S, Price MJ, et al. Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol. 2014;64:112. [PMID: 24998121] doi:10.1016/j.jacc.2014.04.029 Reddy VY, Sievert H, Halperin J, et al; PROTECT AF Steering Committee and Investigators. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA. 2014;312:1988-98. [PMID: 25399274] doi:10.1001/jama.2014.15192
Background: The Watchman device (Boston Scientific, Marlborough, Massachusetts) is a percutaneous left atrial appendage closure device currently under evaluation by the FDA for prevention of thromboembolism in patients with nonvalvular atrial fibrillation. Findings: PROTECT AF (WATCHMAN Left Atrial Appendage Closure Device for Embolic PROTECTion in Patients with Atrial Fibrillation) was an unblinded clinical trial that randomly assigned 707 patients (CHADS2 score of at least 1 and no contraindication for long-term warfarin therapy) to warfarin alone or to left atrial appendage closure with aspirin and warfarin; in the latter group, warfarin was administered until transesophageal echocardiography confirmed minimal peridevice flow and no thrombus, after which aspirin alone was continued. Most patients stopped warfarin at 45 days (348 of 401 patients). At a mean follow-up of 3.8 years, fewer patients in the device group than in the warfarin group experienced the primary endpoint, which was a
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UPDATE composite of stroke, systemic embolism, or cardiovascular death (8.4% vs. 13.9%; hazard ratio, 0.61; P = 0.04). The rates of ischemic stroke were similar (1.4 vs. 1.1 per 100 patient-years). The primary safety endpoint was also similar with early periprocedural complications from device implantation balanced by an accumulation of complications from long-term anticoagulation. The PREVAIL (Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trial randomly assigned 407 patients (CHADS2 score of 2 or a score of 1 plus another risk factor) to continued warfarin therapy or to left atrial closure with discontinuation of warfarin use. At 18 months, patients in the device group, when compared with patients in the warfarin group, had similar rates of events in the co–primary composite endpoint of cardiovascular or unexplained death, stroke, or systemic embolism (6.4% vs. 6.3%), but these results did not meet the prespecified criteria for noninferiority. However, study outcomes did meet prespecified noninferiority criteria for the other co–primary outcome, which was stroke or systemic embolism from greater than 7 days to 18 months. Cautions: Neither trial studied non–vitamin K oral anticoagulants, which decrease embolic and hemorrhagic stroke risk compared with warfarin. In addition, in the PROTECT AF trial the rate of bleeding during warfarin therapy was higher than in most other modern anticoagulation trials. In the PREVAIL trial, ischemic strokes
Update in Cardiology
continue to occur as more long-term information accumulates. Implications: The FDA is evaluating the role of the percutaneous left atrial appendage closure device to prevent thromboembolism in patients with nonvalvular atrial fibrillation. From Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. Disclosures: Disclosures can be viewed at www.acponline
.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15 -0272. Requests for Single Reprints: Peter Zimetbaum, MD, Beth Israel Deaconess Medical Center, 185 Pilgrim Road, Baker 4, Boston, MA 02215; e-mail, [email protected]. Current Author Addresses: Drs. Steinhaus and Zimetbaum:
Beth Israel Deaconess Medical Center, 185 Pilgrim Road, Baker 4, Boston, MA 02215. Author Contributions: Conception and design: D.A. Steinhaus, P.J. Zimetbaum. Analysis and interpretation of the data: D.A. Steinhaus. Drafting of the article: D.A. Steinhaus, P.J. Zimetbaum. Critical revision of the article for important intellectual content: D.A. Steinhaus, P.J. Zimetbaum. Final approval of the article: D.A. Steinhaus, P.J. Zimetbaum. Collection and assembly of data: D.A. Steinhaus.
W90 Annals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015
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www.annals.org
T
his update summarizes key articles in cardiovascular disease published in 2014. We selected these articles for their novelty, potential effects on clinical practice, and general interest for physicians in internal medicine practice. New studies of antiplatelet therapy helped guide both primary and secondary prevention of coronary artery disease. Ongoing research has established the benefits of colchicine in the treatment of recurrent pericarditis. New guidelines for the management of atrial fibrillation were also practice-changing. Novel medical therapies are anticipated for heart failure (neprilysin inhibition) and hyperlipidemia (anti– proprotein convertase subtilisin/kexin type 9). However, new therapies for heart failure with preserved systolic function remain controversial. Researchers made notable advances in structural heart disease, especially with expanded results from transcatheter aortic valve replacement and investigation of the effectiveness of percutaneous left atrial appendage closure devices.
the difference in all-cause mortality was no longer statistically significant. Cautions: These results apply only to patients who did not have an adverse event while receiving dual antiplatelet therapy during the first 12 months of treatment. Although imbalanced randomization appears to explain the increase in all-cause mortality with dual antiplatelet therapy, concerns remain. Implications: Dual antiplatelet therapy protects against major adverse cardiac events beyond 1 year in patients with drug-eluting stents, but with an increased risk for bleeding.
Low-Dose Aspirin Has No Benefit in Primary Prevention of Cardiovascular Mortality in Low-Risk Patients Ikeda Y, Shimada K, Teramoto T, et al. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial. JAMA. 2014;312:2510-20. [PMID: 25401325] doi:10.1001/jama.2014.15690
Background: Drug-eluting stents require a longer period of dual antiplatelet therapy to prevent stent thrombosis than do bare metal stents, and current guidelines recommend 12 months. Observational studies suggest additional benefit from even longer therapy, and the optimal duration is uncertain. Findings: In the Dual Antiplatelet Therapy Study, 9961 patients who had drug-eluting stents and had been receiving dual antiplatelet therapy for 1 year without adverse drug events were randomly assigned for an additional 18 months to placebo or to aspirin with a thienopyridine. Patients receiving dual antiplatelet therapy had fewer major adverse cardiac events than patients receiving placebo (4.3% vs. 5.3%), and they had reductions in the frequencies of myocardial infarction (hazard ratio, 0.47) and stent thrombosis (hazard ratio, 0.29). However, the risk for all-cause mortality was increased (2% vs. 1.5%), primarily from deaths related to bleeding (11 vs. 3) and cancer (31 vs. 14). After adjustment for the increased number of patients with a history of cancer who received dual antiplatelet therapy,
Background: In patients with known cardiovascular disease, aspirin reduces the risk for myocardial infarction, stroke, and vascular death. In patients without known cardiovascular disease, aspirin reduces the risk for a first myocardial infarction but has no effect on stroke or cardiovascular death. Because aspirin increases the risk for bleeding, it is important to balance aspirin's benefits and harms. However, how to do this for people at low risk for adverse cardiovascular events is uncertain. Findings: The Japanese Primary Prevention Project randomly assigned more than 14 000 patients (aged 60 to 85 years) with hypertension, dyslipidemia, or diabetes recruited from a primary care setting to receive aspirin, 100 mg daily, or no aspirin. The primary outcome was a composite of death from cardiovascular causes, nonfatal stroke, and nonfatal myocardial infarction. The study was stopped early when the median follow-up time was 5 years and monitors determined that prolonging the study could not find aspirin beneficial. There was no significant difference in the primary endpoint (5-year event rate, 2.77% for aspirin vs. 2.96% for no aspirin; hazard ratio, 0.94; P = 0.54). Aspirin did significantly reduce the risk for nonfatal myocardial infarction (5-year event rate, 0.3% vs. 0.6%; hazard ratio, 0.53; P = 0.02) or transient ischemic event (5-year event rate, 0.26% vs. 0.49%; hazard ratio, 0.57; P = 0.04), but aspirin also significantly increased the risk for extracranial hemorrhage necessitating transfusion or hospitalization (5-year event rate, 0.86% vs. 0.51%; hazard ratio, 1.85; P = 0.004). Cautions: This study examined only patients at low risk for cardiovascular events. The Japanese patients in this
Ann Intern Med. 2015;162:W86-W90. doi:10.7326/M15-0272 For author affiliations, see end of text. This article was published online first at www.annals.org on 30 April 2015.
Annals of Internal Medicine
Coronary Artery Disease Dual Antiplatelet Therapy Protects Against Ischemic Events Beyond 1 Year Mauri L, Kereiakes DJ, Yeh RW, et al; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371:2155-66. [PMID: 25399658] doi:10.1056/NEJMoa1409312
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Update in Cardiology
study had different characteristics from those of primary care patients in many other countries. Implications: Aspirin is unlikely to benefit people without known cardiovascular disease who are at low risk for cardiovascular death.
Pericarditis Colchicine Reduces the Recurrence of Pericarditis Imazio M, Belli R, Brucato A, et al. Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial. Lancet. 2014;383:2232-7. [PMID: 24694983] doi:10.1016/S0140-6736(13)62709-9
Background: Pericarditis recurs in as many as 30% of patients after acute pericarditis. Colchicine effectively treats acute pericarditis and prevents first recurrences of pericarditis, and nonrandomized trials suggest that colchicine may prevent multiple recurrences of pericarditis. Findings: In this double-blind trial conducted at 4 general hospitals in northern Italy, 240 patients with 2 or more recurrences of pericarditis received conventional therapy—nonsteroidal anti-inflammatory drugs or corticosteroids with a proton-pump inhibitor—and were randomly assigned to 6 months of placebo or colchicine (0.5 mg daily for patients weighing ≤70 kg and 0.5 mg twice daily for patients weighing >70 kg). Compared with patients receiving placebo, fewer patients receiving colchicine had recurrent pericarditis during a mean follow-up of 20 months (21.6% vs. 42.5%). This difference persisted when colchicine was compared with placebo, irrespective of the type of concurrent nonsteroidal anti-inflammatory drugs (aspirin, ibuprofen, or indomethacin), but statistical significance was lost when colchicine was compared with placebo for patients taking corticosteroids (36.8% vs. 52.2%). Colchicine was effective in patients with idiopathic pericarditis but not in patients with nonidiopathic pericarditis, such as the post– cardiac injury syndrome and pericarditis related to connective tissue disease. The frequency of adverse events was similar in the different groups. Cautions: The utility of adjunctive treatment with nonsteroidal anti-inflammatory drugs and corticosteroids remains unclear. Implications: Colchicine appears to be safe and effective for preventing recurrent pericarditis.
Atrial Fibrillation Guidelines for Atrial Fibrillation Management Change January CT, Wann LS, Alpert JS, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the man-
agement of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:e1-76. [PMID: 24685669] doi:10.1016/j.jacc.2014.03.022
Background: The previous American Heart Association, American College of Cardiology, and Heart Rhythm Society guidelines for atrial fibrillation were published in 2006 and updated in 2011. Findings: Major changes to the guidelines include replacing the CHADS2 score (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack) with the CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, sex category) for deciding which patients with nonvalvular atrial fibrillation should receive anticoagulation to prevent stroke. In addition, the guidelines now provide a stronger recommendation (class I) that anticoagulation should be based on the patient's risk for thromboembolism without consideration of the pattern or duration of atrial fibrillation. Patients with a CHA2DS2-VASc score of 2 or greater should receive anticoagulation with warfarin, dabigatran, rivaroxaban, or apixaban, although aspirin can still be considered for those with a CHA2DS2-VASc score of 1. Only warfarin should be used in patients with a mechanical valve; no specific guidance is given for a patient with a bioprosthetic valve. Catheter ablation is recommended for patients with symptomatic paroxysmal atrial fibrillation in whom antiarrhythmic medications have failed or who cannot tolerate these medications. Catheter ablation should be considered as initial rhythm-control therapy only for those who have had a full assessment of the risks and benefits of treatment options. Cautions: To address the needs of individual patients, physicians must modify these recommendations for patient type. Implications: The new guidelines recommend change in some established ways of managing patients with atrial fibrillation.
Heart Failure Angiotensin–Neprilysin Inhibition Improves Outcomes in Heart Failure McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:9931004. [PMID: 25176015] doi:10.1056/NEJMoa1409077
Background: Neprilysin is a neutral endopeptidase that degrades several endogenous vasoactive peptides, including the natriuretic peptides. Inhibition of neprilysin helps offset the neurohormonal dysregulation that occurs in heart failure. Prior trials of a neprilysin inhibitor combined with an angiotensin-converting enzyme in-
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hibitor for the treatment of heart failure found an association with angioedema and failed to show benefit. Findings: The PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) study was an industry-supported, randomized, double-blind trial that compared enalapril, which is known to benefit patients with heart failure, against a combination of sacubitril (a neprilysin inhibitor) with valsartan (an angiotensin-receptor blocker). The trial enrolled 8442 patients with symptomatic heart failure and an ejection fraction of 40% or greater and excluded those with severe renal insufficiency and hyperkalemia. The trial was stopped early at a median follow-up of 27 months because the results met prespecified rules for determining that the combination drug was superior to enalapril for preventing a composite outcome of death from cardiovascular causes or first hospitalization for heart failure (21.8% vs. 26.5%; P < 0.001). The combination drug was also better for preventing cardiovascular death (13.3% vs. 16.5%), death from any cause (17% vs. 19.8%), and progression of heart failure symptoms. Use of the combination drug was discontinued less frequently for an adverse event than was use of enalapril (10.7% vs. 12.3%), and the combination drug was associated with lower rates of hyperkalemia, cough, and worsening of renal insufficiency. The frequency of angioedema was similar between groups, and no airway compromise occurred in either group. Cautions: The combination drug was associated with a higher rate of symptomatic hypotension. Implications: For patients with heart failure and a reduced ejection fraction, the combination of a neprilysin inhibitor with an angiotensin-receptor blocker reduced rates of total mortality, cardiovascular death, and heart failure hospitalization compared with standard therapy.
vated natriuretic peptide level in the preceding 60 days were randomly assigned to spironolactone or placebo. Patients were excluded if they had baseline hyperkalemia (potassium level ≥5.0 mmol/L) or renal insufficiency (estimated glomerular filtration rate 2.5 mg/dL [>221 μmol/L]). The median ejection fraction was 56%, and most patients had New York Heart Association class II or III symptoms. When compared with the placebo group, the spironolactone group experienced a statistically nonsignificant reduction in the primary composite endpoint of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization (18.6% vs. 20.4%; hazard ratio, 0.89; P = 0.14), but the reduction was statistically significant for the subgroup of spironolactone recipients with elevated natriuretic peptide levels (hazard ratio, 0.65; P = 0.003). Cautions: Patients enrolled in the United States, Canada, Brazil, and Argentina had a significant reduction in the primary outcome (27.3% vs. 31.8%), but those enrolled in Russia and Georgia did not (9.3% vs. 8.4%), possibly because of an unexpectedly low event rate in the placebo group. Implications: This study failed to find a benefit for spironolactone in patients with heart failure and preserved ejection fraction, but regional differences complicate how the results should be interpreted.
Spironolactone Has Uncertain Benefit in Heart Failure With Preserved Ejection Fraction
Koren MJ, Lundqvist P, Bolognese M, et al; MENDEL-2 Investigators. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2531-40. [PMID: 24691094] doi:10.1016/j.jacc.2014.03.018
Pitt B, Pfeffer MA, Assmann SF, et al; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383-92. [PMID: 24716680] doi: 10.1056/NEJMoa1313731
Background: Despite improvement in the treatment of patients with heart failure and a reduced ejection fraction, therapy for heart failure with preserved ejection fraction remains largely empiric. Mineralocorticoidreceptor antagonists reduce overall mortality and heart failure hospitalizations for patients with heart failure and a reduced ejection fraction (relative risk reduction, 25% to 30%), and they improve echocardiographic measures of diastolic function. Findings: In the international TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial, 3445 patients age 50 years or older with an ejection fraction of 45% or greater, hospitalization for heart failure in the past year, or an ele-
Hyperlipidemia Antibodies Against PCSK9 Decrease Low-Density Lipoprotein Cholesterol Levels Blom DJ, Hala T, Bolognese M, et al; DESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809-19. [PMID: 24678979] doi:10.1056/NEJMoa1316222
Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63: 2541-8. [PMID: 24694531 doi: 10.1016/j.jacc.2014.03.019
Background: The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the hepatic low-density lipoprotein (LDL) receptor. Evolocumab is a human monoclonal antibody that inhibits PCSK9. The GAUSS-2 (Goal Achievement after Utilizing an AntiPCSK9 Antibody in Statin Intolerant Subjects-2), MENDEL-2 (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2), and DESCARTES (Durable Effect of PCSK9 Antibody Compared with Placebo Study) trials studied whether evo-
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locumab could reduce LDL cholesterol levels in patients with hyperlipidemia. Findings: GAUSS-2 and MENDEL-2 were 12-week, double-blind trials that randomly assigned patients to evolocumab or placebo with or without ezetimibe. GAUSS-2 studied 307 patients previously intolerant of statins, and MENDEL-2 studied 614 patients previously or currently treated with statins. In both trials, evolocumab reduced LDL cholesterol by 53% to 57% compared with placebo and 37% to 40% compared with ezetimibe. In GAUSS-2, fewer evolocumab recipients had muscle-related adverse effects than ezetimibe recipients (12% vs. 23%). DESCARTES was a 52-week, double-blind trial of evolocumab versus placebo. After 4 to 12 weeks of traditional treatment to decrease lipids (various combinations of diet, atorvastatin, and ezetimibe), 901 patients with LDL cholesterol levels greater than 75 mg/dL (>1.94 mmol/L) were randomly assigned to evolocumab or placebo and followed for 52 weeks. The overall reduction in LDL cholesterol was 57% for evolocumab compared with placebo. Slightly more adverse events (nasopharyngitis, upper respiratory tract infection, back pain) occurred in the evolocumab group. Cautions: These trials did not study long-term results or clinical outcomes. The U.S. Food and Drug Administration (FDA) has expressed concern about possible neurocognitive adverse effects from aggressive lowering of LDL cholesterol. Implications: Therapy with human monoclonal antibody directed against PCSK9 decreases LDL cholesterol levels in patients not taking statins, those intolerant of statins, and those receiving appropriate traditional therapy. Whether these effects lead to more favorable clinical outcomes remains uncertain.
Structural Heart Disease Transcatheter Aortic Valve Replacement Improves Survival Compared With Surgery in Patients With Severe Aortic Stenosis and High Surgical Risk Adams DH, Popma JJ, Reardon MJ, et al; U.S. CoreValve Clinical Investigators. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med. 2014;370:1790-8. [PMID: 24678937] doi:10.1056/NEJMoa1400590 Popma JJ, Adams DH, Reardon MJ, et al; CoreValve United States Clinical Investigators. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol. 2014;63:1972-81. [PMID: 24657695] doi: 10.1016/j.jacc.2014.02.556
Background: Transcatheter aortic valve replacement with the Sapien balloon-expandable system (Edwards, Irvine, California) was approved in the United States in 2011 for patients whose condition is inoperable or who have a greater than 8% risk for 30-day mortality after surgery to replace the aortic valve. Approval was based
on a randomized trial that demonstrated noninferiority of the system compared with surgery. Patients with the system had more major vascular complications, but surgical patients had more major bleeding and atrial fibrillation. The FDA has also approved a different system that uses the CoreValve self-expanding transcatheter aortic valve, on the basis of a prospective nonrandomized study. Findings: The U.S. CoreValve High Risk Study randomly assigned 795 patients with an estimated postsurgery mortality greater than 15% to receive a self-expanding transcatheter aortic valve or to undergo open aortic valve surgery. Compared with the open surgery group, fewer patients in the group that received a transcatheter aortic valve experienced the primary endpoint of death from any cause at 1 year (14.2% vs. 19.1%; P = 0.04 for superiority). Both groups experienced similar improvements in symptoms. The transcatheter aortic valve group had a higher rate of major vascular complications and permanent pacemaker placement and a nonsignificantly lower incidence of stroke. Cautions: The patients in this trial were not as high risk as those in the randomized trial of the balloonexpandable system. Implications: Transcatheter aortic valve replacement with the self-expanding system appears to be superior to open surgery in patients with a high risk for death after surgery.
Percutaneous Left Atrial Appendage Closure May Be Similar to Warfarin for Preventing Thromboembolism in Atrial Fibrillation Holmes DR Jr, Kar S, Price MJ, et al. Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol. 2014;64:112. [PMID: 24998121] doi:10.1016/j.jacc.2014.04.029 Reddy VY, Sievert H, Halperin J, et al; PROTECT AF Steering Committee and Investigators. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA. 2014;312:1988-98. [PMID: 25399274] doi:10.1001/jama.2014.15192
Background: The Watchman device (Boston Scientific, Marlborough, Massachusetts) is a percutaneous left atrial appendage closure device currently under evaluation by the FDA for prevention of thromboembolism in patients with nonvalvular atrial fibrillation. Findings: PROTECT AF (WATCHMAN Left Atrial Appendage Closure Device for Embolic PROTECTion in Patients with Atrial Fibrillation) was an unblinded clinical trial that randomly assigned 707 patients (CHADS2 score of at least 1 and no contraindication for long-term warfarin therapy) to warfarin alone or to left atrial appendage closure with aspirin and warfarin; in the latter group, warfarin was administered until transesophageal echocardiography confirmed minimal peridevice flow and no thrombus, after which aspirin alone was continued. Most patients stopped warfarin at 45 days (348 of 401 patients). At a mean follow-up of 3.8 years, fewer patients in the device group than in the warfarin group experienced the primary endpoint, which was a
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Update in Cardiology
continue to occur as more long-term information accumulates. Implications: The FDA is evaluating the role of the percutaneous left atrial appendage closure device to prevent thromboembolism in patients with nonvalvular atrial fibrillation. From Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. Disclosures: Disclosures can be viewed at www.acponline
.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15 -0272. Requests for Single Reprints: Peter Zimetbaum, MD, Beth Israel Deaconess Medical Center, 185 Pilgrim Road, Baker 4, Boston, MA 02215; e-mail, [email protected]. Current Author Addresses: Drs. Steinhaus and Zimetbaum:
Beth Israel Deaconess Medical Center, 185 Pilgrim Road, Baker 4, Boston, MA 02215. Author Contributions: Conception and design: D.A. Steinhaus, P.J. Zimetbaum. Analysis and interpretation of the data: D.A. Steinhaus. Drafting of the article: D.A. Steinhaus, P.J. Zimetbaum. Critical revision of the article for important intellectual content: D.A. Steinhaus, P.J. Zimetbaum. Final approval of the article: D.A. Steinhaus, P.J. Zimetbaum. Collection and assembly of data: D.A. Steinhaus.
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