Cardiology

Acute Coronary Syndrome / Coronary Artery Disease:
Article Name: Aspirin, Heparin, or Both to Treat Acute Unstable Angina 
URL: http://www.nejm.org/doi/full/10.1056/NEJM198810273191701 
Journal and year of publication: NEJM, 1988
Trial Design: Double-blind, randomized, placebo-controlled trial 
Population: 479 patients with ACS
Key inclusion criteria: Patients with unstable angina based on symptoms and ECG changes
Key exclusion criteria: Unclear from manuscript
Intervention Studied: Aspirin (325 mg twice daily), heparin (1000 units per hour by intravenous infusion), and a combination of the two 
Control: Placebo
Outcomes:
– Incidence of myocardial infarction was significantly reduced in the groups receiving aspirin (3 percent; P = 0.01), heparin (0.8 percent; P<0.001), and aspirin plus heparin (1.6 percent, P = 0.003).

The authors concluded that “In the acute phase of unstable angina, either aspirin or heparin treatment is associated with a reduced incidence of myocardial infarction.”
Citation: Aspirin, Heparin, or Both to Treat Unstable Angina. (1989). New England Journal of Medicine, 320(15), 1014–1015. https://doi.org/10.1056/nejm198904133201515
Article Name:  Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation
URL: http://www.nejm.org/doi/full/10.1056/NEJMoa010746
Journal and year of publication: NEJM, 2001
Trial Design: Double-blind, randomized, placebo-controlled trial 
Population: 12,562 patients with NSTEMI
Key inclusion criteria:
– Patients hospitalized within 24 hours after the onset of symptoms and did not have ST-segment elevation
Key exclusion criteria:
– Patients with contraindications to antithrombotic or antiplatelet therapy
– Patients who were at high risk for bleeding or severe heart failure
– Patients who were taking oral anticoagulants
– Patients who had undergone coronary revascularization in the previous three months
– Patients who had received intravenous glycoprotein IIb/IIIa receptor inhibitors in the previous three days
Intervention Studied: Clopidogrel (300 mg immediately, followed by 75 mg once daily) + Aspirin for 3 to 12 months 
Control: Placebo + Aspirin for 3 to 12 months
Outcomes:
– First primary outcome: a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stroke. Relative risk with clopidogrel as compared with placebo, 0.80; 95 percent confidence interval, 0.72 to 0.90; P<0.001
– The percentages of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures were also significantly lower with clopidogrel.
– Major bleeding: Relative risk with clopidogrel as compared with placebo,1.38; P=0.001). No significantly more patients with episodes of life-threatening bleeding (2.1 percent vs. 1.8 percent, P=0.13) or hemorrhagic strokes between groups

The authors concluded that “Clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation. However, the risk of major bleeding is increased among patients treated with clopidogrel.”
Citation: Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 Aug 16;345(7):494-502. doi: 10.1056/NEJMoa010746. Erratum in: N Engl J Med 2001 Dec 6;345(23):1716. Erratum in: N Engl J Med 2001 Nov 15;345(20):1506. PMID: 11519503.
Article Name:  Addition of Clopidogrel to Aspirin and Fibrinolytic Therapy for Myocardial Infarction with ST-Segment Elevation
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa050522
Journal and year of publication: NEJM, 2005
Trial Design: Double-blind, randomized, placebo-controlled trial 
Population: 3,491 patients with STEMI
Key inclusion criteria:
– Patients between 18 to 75 years of age with ischemic symptoms and ST-segment elevation of at least 0.1 mV in at least two contiguous limb leads, ST-segment elevation of at least 0.2 mV in at least two contiguous precordial leads, or left bundle-branch block that was not known to be old
– And who were scheduled to receive a fibrinolytic agent, an anticoagulant (if a fibrin-specific lytic agent was prescribed), and aspirin
Key exclusion criteria:
– Treatment with clopidogrel within 7 days before enrollment or planned treatment with clopidogrel or a glycoprotein IIb/IIIa inhibitor before angiography
– Contraindications to fibrinolytic therapy (including documented stroke, intracranial hemorrhage, and intracranial neoplasm)
– A plan to perform angiography within 48 hours in the absence of a new clinical indication
– Cardiogenic shock
– Prior coronary artery bypass grafting
Intervention Studied: Clopidogrel (300-mg loading dose, followed by 75 mg once daily) + Aspirin, fibrinolytic, and heparin when appropriate
Control: Placebo  + Aspirin, fibrinolytic, and heparin when appropriate
Outcomes:
– The primary outcome was a composite of an occluded infarct-related artery on angiography or death or recurrent myocardial infarction before angiography
– Absolute reduction of 6.7% in the rate and a 36% reduction in the odds of the endpoint with clopidogrel therapy (95% CI, 24-47%; P<0.001)
– Rates of major bleeding and intracranial hemorrhage were similar in the two groups

The authors concluded that “In patients 75 years of age or younger who have myocardial infarction with ST-segment elevation and who receive aspirin and a standard fibrinolytic regimen, the addition of clopidogrel improves the patency rate of the infarct-related artery and reduces ischemic complications.”
Citation: Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E; CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005 Mar 24;352(12):1179-89. doi: 10.1056/NEJMoa050522. Epub 2005 Mar 9. PMID: 15758000.
Article Name: An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction
URL: https://www.nejm.org/doi/full/10.1056/NEJM199309023291001
Journal and year of publication: NEJM, 1993
Trial Design: Randomized controlled trial 
Population: 41,021 patients with STEMI
Key inclusion criteria:
– Presenting to a participating hospital less than 6 hours after the onset of symptoms.
– Chest pain lasting at least 20 minutes
– ECG signs of ≥ 0.1 mV of ST-segment elevation in two or more limb leads or ≥ 0.2 mV in two or more contiguous precordial leads
Key exclusion criteria:
– Previous stroke.
– Active bleeding.
– Previous treatment with streptokinase or anistreplase.
– Recent trauma or major surgery.
– Relative contraindication to enrollment: Patients with severe, uncontrolled hypertension (systolic blood pressure ≥ 180 mm Hg, unresponsive to therapy).
Intervention Studied:
1) Streptokinase and subcutaneous heparin
2) Streptokinase and intravenous heparin
3) Accelerated tissue plasminogen activator (t-PA) and intravenous heparin*
4) Combination of streptokinase plus t-PA with intravenous heparin
Control: See above
Outcomes:
Mortality rates in the four treatment groups were as follows:
– – Streptokinase and subcutaneous heparin: 7.2%.
– – Streptokinase and intravenous heparin:  7.4%.
– – Accelerated t-PA and intravenous heparin: 6.3%.
– – Combination of both thrombolytic agents with intravenous heparin: 7.0%. 
*14% reduction (95% CI, 5.9 to 21.3%) in mortality for accelerated t-PA as compared with the two streptokinase-only strategies (P= 0.001).

A combined end point of death or disabling stroke:
– – Significantly lower in the accelerated-t-PA group than in the streptokinase-only groups (6.9 percent vs. 7.8 percent, P = 0.006)

The authors concluded that “Accelerated t-PA given with intravenous heparin provides a survival benefit over previous standard thrombolytic regimens.”
Citation: GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993 Sep 2;329(10):673-82. doi: 10.1056/NEJM199309023291001. PMID: 8204123.
Article Name:  Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes 
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0706482
Journal and year of publication: NEJM, 2007
Trial Design: Double-blind, randomized trial 
Population: 13,608 patients with acute coronary syndromes with scheduled PCI
Key inclusion criteria:
– For patients with NSTEMI: either ST-segment deviation of 1 mm or more or elevated cardiac biomarkers of necrosis and TIMI risk score of 3 or more,
– For patients with STEMI: within 12 hours after the onset of symptoms if primary PCI was planned, or  within 14 days after receiving medical treatment for ST-elevation myocardial infarction
Key exclusion criteria:
– Cardiogenic shock
– Fibrinolytic therapy within 24 hours
– Intracranial neoplasm or history of hemorrhagic stroke
– Clinical findings, in the judgment of the investigator, associated
with an increased risk of bleeding
Intervention Studied: Prasugrel (60 mg loading dose, 10 mg daily dose) for 6 to 15 months
Control:  Clopidogrel (300 mg loading dose, 75 mg daily dose) for 6 to 15 months
Outcomes:
– The primary efficacy endpoint: (rate of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke): occurred in 9.9% of patients receiving prasugrel and 12.1% of patients receiving clopidogrel – HR for prasugrel vs. clopidogrel, 0.81; 95% CI 0.73 – 0.90; P<0.001)
– Others: Lower rates of myocardial infarction, urgent target-vessel revascularization, and stent thrombosis in the prasugrel group
– Major bleeding: higher in the prasugrel group including life-threatening as well as fatal bleeding

The authors concluded that “In patients with ACS with scheduled PCI, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups.”
Citation: Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. doi: 10.1056/NEJMoa0706482. Epub 2007 Nov 4. PMID: 17982182
Article Name: Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0904327
Journal and year of publication: NEJM, 2009
Trial Design: Double-blind, randomized trial 
Population: 18,624 patients with ACS
Key inclusion criteria:
– Patients hospitalized for an acute coronary syndrome, with or without ST-segment elevation, with an onset of symptoms during the previous 24 hours
Key exclusion criteria:
– Contraindication to the use of clopidogrel or fibrinolytic therapy within 24 hours before randomization
– A need for oral anticoagulation therapy
– Increased risk of bradycardia
– Concomitant therapy with a strong CYP-450 3A inhibitor or inducer
Intervention Studied: Ticagrelor (180-mg loading dose, 90 mg twice daily thereafter)
Control:  Clopidogrel (300 to 600 mg loading dose, 75 mg daily thereafter)
Outcomes:
– At 12 months, the primary endpoint (a composite of death from vascular causes, myocardial infarction, or stroke):  lower in the ticagrelor group (HR 0.84; 95% CI 0.77 – 0.92; P<0.001)
– Bleeding: No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups, but ticagrelor was associated with a higher rate of major bleeding not related to CABG

The authors concluded that “In patients who have an ACS with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non–procedure-related bleeding”
Citation: Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. doi: 10.1056/NEJMoa0904327. Epub 2009 Aug 30. PMID: 19717846
Article Name: A Comparison of Coronary Angioplasty with Fibrinolytic Therapy in Acute Myocardial Infarction
URL:  https://www.nejm.org/doi/full/10.1056/NEJMoa025142
Journal and year of publication: NEJM, 2003
Trial Design: Randomized clinical trial 
Population: 1572 patients with acute MI 
Key inclusion criteria:
– The presence of symptoms for at least 30 minutes but less than 12 hours
– Cumulative ST-segment elevation of at least 4 mm in at least two contiguous leads
Key exclusion criteria:
– Contraindication to fibrinolysis
– LBBB
– Acute myocardial infarction and fibrinolytic treatment within the past 30 days
– Prior CABG
– Creatinine > 2.83 mg/dL
– Diabetics treated with metformin
Intervention Studied: Treatment with angioplasty (including those needing transfer)
Control:  Accelerated treatment with intravenous alteplase
Outcomes:
– Primary study endpoint: a composite of death, clinical evidence of reinfarction, or disabling stroke at 30 days
– At invasive treatment centers:  6.7 percent of the patients in the angioplasty group reached the primary endpoint, as compared with 12.3 percent in the fibrinolysis group (P=0.05)
– From referral hospitals: the primary endpoint was reached in 8.5 percent of the patients in the angioplasty group, as compared with 14.2 percent of those in the fibrinolysis group (P=0.002)
– Lower rates of re-infarction in the angioplasty group, but no differences in the rates of death or strokes between the two groups

The authors concluded that “A strategy for reperfusion involving the transfer of patients to an invasive-treatment center for primary angioplasty is superior to on-site fibrinolysis, provided that the transfer takes two hours or less”
Citation: Andersen HR, Nielsen TT, Rasmussen K, Thuesen L, Kelbaek H, Thayssen P, Abildgaard U, Pedersen F, Madsen JK, Grande P, Villadsen AB, Krusell LR, Haghfelt T, Lomholt P, Husted SE, Vigholt E, Kjaergard HK, Mortensen LS; DANAMI-2 Investigators. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med. 2003 Aug 21;349(8):733-42. doi: 10.1056/NEJMoa025142. PMID: 12930925
Article Name: Early intravenous then oral metoprolol in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial
URL: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67661-1/fulltext
Journal and year of publication: The Lancet, 2005
Trial Design: Randomized, placebo-controlled clinical trial 
Population: 45,852 patients with acute MI 
Key inclusion criteria:
– Patients who presented with ST-elevation, left-bundle branch block, or ST depression within 24 h of the onset of the symptoms
Key exclusion criteria:
– Bradycardia (HR < 50 bpm)
– Hypotension (SBP < 100 mmHg)
– Patients with planned PCI
– Heart block
– Cardiogenic shock
Intervention Studied: Metoprolol (up to 15 mg intravenous then 200 mg oral daily)
Control:  Matching placebo
Outcomes:
– Primary study endpoint (Death, reinfarction, or cardiac arrest): 9·4% of patients allocated to metoprolol had at least one such event compared with 9·9% allocated to placebo (OR 0·96, 95% CI 0·90–1·01; p=0·1)
– Reinfarction: 2.0% in the metoprolol group vs 2.5% in the placebo group (OR 0·82, 0·72–0·92; p=0·001)
– Ventricular fibrillation: 2.5% in the metoprolol group vs 3.0% in the placebo group (OR 0·83, 0·75–0·93; p=0·001)
– Cardiogenic shock: 5.0% in the metoprolol group vs 3.9% in the placebo group (OR 1·30, 1·19–1·41; p<0·00001)

The authors concluded that “The use of early β-blocker therapy in acute MI reduces the risks of reinfarction and ventricular fibrillation, but increases the risk of cardiogenic shock, especially during the first day or so after admission. Consequently, it might generally be prudent to consider starting β-blocker therapy in hospital only when the haemodynamic condition after MI has stabilised”
Citation: Chen ZM, Pan HC, Chen YP, Peto R, Collins R, Jiang LX, Xie JX, Liu LS; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005 Nov 5;366(9497):1622-32. doi: 10.1016/S0140-6736(05)67661-1. PMID: 16271643
Article Name: Drug-Eluting versus Bare-Metal Stents in Large Coronary Arteries 
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1009406
Journal and year of publication: NEJM, 2010
Trial Design: Randomized clinical trial 
Population:  2314 patients undergoing stenting 
Key inclusion criteria:
– Those who presented with chronic or acute coronary disease
– Undergoing angioplasty with stenting and who required only stents that were 3.0 mm or more in diameter
Key exclusion criteria:
– In-stent restenosis or thrombosis of stents placed before the study
– Unprotected left main coronary artery (i.e., with no functioning bypass graft) or substantial stenosis in a bypass graft
– Patients on oral anticoagulation
– Plans for any surgery within 12 months
Intervention Studied: Sirolimus-eluting, everolimus-eluting stents
Control:  Bare-metal stents
Outcomes:
– Primary endpoint (death from cardiac causes or nonfatal MI at 2 years): 2.6% in the sirolimus-eluting stents group, 3.2% in the everolimus-eluting stents group, and 4.8% in the bare-metal stents (no significant differences between groups)
– Rates of target-vessel revascularization for reasons unrelated to myocardial infarction: 3.7% in the sirolimus-eluting stents, 3.1% in the everolimus-eluting stents, and 8.9% in the bare-metal stents (p <0.001)

The authors concluded that “In patients requiring stenting of large coronary arteries, no significant differences were found among sirolimus-eluting, everolimus-eluting, and bare-metal stents with respect to the rate of death or myocardial infarction. With the two drug-eluting stents, similar reductions in rates of target-vessel revascularization were seen”
Citation: Kaiser C, Galatius S, Erne P, Eberli F, Alber H, Rickli H, Pedrazzini G, Hornig B, Bertel O, Bonetti P, De Servi S, Brunner-La Rocca HP, Ricard I, Pfisterer M; BASKET–PROVE Study Group. Drug-eluting versus bare-metal stents in large coronary arteries. N Engl J Med. 2010 Dec 9;363(24):2310-9. doi: 10.1056/NEJMoa1009406. Epub 2010 Nov 16. PMID: 21080780
Article Name: The TIMI Risk Score for Unstable Angina/Non–ST Elevation MI
A Method for Prognostication and Therapeutic Decision Making (TIMI) 
URL: https://jamanetwork.com/journals/jama/fullarticle/192996
Journal and year of publication: JAMA, 2000
Trial Design: Validation of scoring system in patients from 2 RCTs (TIMI & ESSENCE)
Population:   
Key inclusion criteria:
– All patients (n = 3910 in TIMI 11B and n = 3171 in ESSENCE) presented within 24 hours of an episode of UA/NSTEMI at rest. 
– At least 1 of the following: ST-segment deviation on the qualifying ECG, documented history of coronary artery disease, or elevated serum cardiac markers. 
Key exclusion criteria:
– Planned revascularization in 24 hours or less
– A correctable cause of angina
Intervention Studied: To develop a simple risk score that has broad applicability, is easily calculated at patient presentation, does not require a computer, and identifies patients with different responses to treatments for UA/NSTEMI
Control:  N/A
Outcomes:
– Event rates increased significantly as the TIMI risk score increased in the test cohort in TIMI 11B (P<.001 by χ2 for trend): 
— 4.7% for a score of 0/1
— 8.3% for 2
— 13.2% for 3
— 19.9% for 4
— 26.2% for 5
— 40.9% for 6/7 
– Significant interaction between TIMI risk score and treatment (P = .02)

The authors concluded that “In patients with UA/NSTEMI, the TIMI risk score is a simple prognostication scheme that categorizes a patient’s risk of death and ischemic events and provides a basis for therapeutic decision making.”
Citation: Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis G, Mautner B, Corbalan R, Radley D, Braunwald E. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. 2000 Aug 16;284(7):835-42. doi: 10.1001/jama.284.7.835. PMID: 10938172
Article Name: Early versus Delayed Invasive Intervention in Acute Coronary Syndromes 
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0807986
Journal and year of publication: NEJM, 2009
Trial Design: Randomized clinical trial
Population: 3031 patients with ACS   
Key inclusion criteria:
– Patients presenting with unstable angina or NSTEMI within 24 hours of symptoms onset
Key exclusion criteria:
– Patients not suitable candidates for revascularization
– Severe renal insufficiency (creatinine >3 g/dL)
– Hemorrhagic stroke within the past 12 months
Intervention Studied:  Routine early intervention (coronary angiography ≤24 hours after randomization)
Control:  Delayed intervention (coronary angiography ≥36 hours after randomization)
Outcomes:
– Primary outcome (a composite of death,  MI, or stroke at 6 months): 9.6% of patients in the early-intervention group, as compared with 11.3% in the delayed-intervention group (HR in the early-intervention group, 0.85; 95% CI 0.68 – 1.06; P=0.15)
– Early intervention improved the primary outcome in the third of patients who were at the highest risk (hazard ratio, 0.65; 95% CI, 0.48 to 0.89)
– Secondary outcome ( death, MI, or refractory ischemia at 6 months): 9.5 % in the early-intervention group as compared to 12.9% in the delayed-intervention group (HR 0.72; 95% CI 0.58 – 0.89; P=0.003)

The authors concluded that “Early intervention did not differ greatly from delayed intervention in preventing the primary outcome, but it did reduce the rate of the composite secondary outcome of death, myocardial infarction, or refractory ischemia and was superior to delayed intervention in high-risk patients.”
Citation: Mehta SR, Granger CB, Boden WE, Steg PG, Bassand JP, Faxon DP, Afzal R, Chrolavicius S, Jolly SS, Widimsky P, Avezum A, Rupprecht HJ, Zhu J, Col J, Natarajan MK, Horsman C, Fox KA, Yusuf S; TIMACS Investigators. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med. 2009 May 21;360(21):2165-75. doi: 10.1056/NEJMoa0807986. PMID: 19458363

Article Name: Optimal Medical Therapy with or without PCI for Stable Coronary Disease 
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa070829
Journal and year of publication: NEJM, 2007
Trial Design: Randomized controlled clinical trial
Population: 2,287 patients with stable CAD   
Key inclusion criteria:
– Stenosis of at least 70% in at least one proximal epicardial coronary artery  AND objective evidence of myocardial ischemia
Key exclusion criteria:
– Unstable angina and symptoms refractory to maximal oral and intravenous medical therapy
– Coronary angiographic exclusions such as patients with no prior CABG and left main coronary disease >50%, patients with nonsignificant CAD in whom PCI would not be considered appropriate or indicated, and patients with restenosis of a lesion previously treated with PCI and no other target lesion
– EF <30% (<35% if patient has 3-vessel disease including >70% LAD proximal stenosis)
– CABG or PCI within the last 6 months
– Concomitant valvular heart disease likely to require surgery or affect prognosis during follow-up
Intervention Studied:  PCI with optimal medical therapy
Control:  Optimal medical therapy alone
Outcomes:
– Primary outcome (death from any cause and nonfatal myocardial infarction during a follow-up period): were 19.0% in the PCI group and 18.5% in the medical therapy group (HR for the PCI group, 1.05. 95% CI 0.87-1.27; P=0.62)
– No significant differences in hospitalization either

The authors concluded that “As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy.”
Citation: Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503-16. doi: 10.1056/NEJMoa070829. Epub 2007 Mar 26. PMID: 17387127.

Article Name: Percutaneous Coronary Intervention versus Coronary-Artery Bypass Grafting for Severe Coronary Artery Disease 
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0804626
Journal and year of publication: NEJM, 2009
Trial Design: Randomized controlled clinical trial
Population: 1,800 patients with 3-vessel and/or left main CAD   
Key inclusion criteria:
– ≥50% stenosis in at least 3 coronary arteries and/or left main CAD

Key exclusion criteria:
– Previous PCI or CABG
– Acute MI
– Need for concomitant cardiac surgery
Intervention Studied:  Percutaneous coronary intervention (PCI)
Control:  Coronary-artery bypass grafting (CABG)
Outcomes:
– Primary outcome: rates of major adverse cardiac or cerebrovascular events at 12 months: Significantly higher in the PCI group (17.8%, vs. 12.4% for CABG; P=0.002), in large part because of an increased rate of repeat revascularization
– Rates of death were similar between the two groups
– Stroke was significantly more likely to occur with CABG (2.2%, vs. 0.6% with PCI; P=0.003)

The authors concluded that “CABG remains the standard of care for patients with three-vessel or left main coronary artery disease, since the use of CABG, as compared with PCI, resulted in lower rates of the combined end point of major adverse cardiac or cerebrovascular events at 1 year.“
Citation: Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, Ståhle E, Feldman TE, van den Brand M, Bass EJ, Van Dyck N, Leadley K, Dawkins KD, Mohr FW; SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009 Mar 5;360(10):961-72. doi: 10.1056/NEJMoa0804626. Epub 2009 Feb 18. Erratum in: N Engl J Med. 2013 Feb 7;368(6):584. PMID: 19228612.

Article Name: Strategies for Multivessel Revascularization in Patients with Diabetes 
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1211585
Journal and year of publication: NEJM, 2012
Trial Design: Randomized controlled clinical trial
Population: 1,900 patients with DM and CAD   
Key inclusion criteria:
– DM type 1 or 2
– Angiographically confirmed multivessel CAD (critical [≥70%] lesions in ≥2 major epicardial vessels) amenable to either PCI or CABG
– Indications for revascularization present
Key exclusion criteria:
– Previous CABG or cardiac valve surgery
– Left main CAD stenosis (>50%)
– Acute ST-elevation
– Planned simultaneous cardiac surgery
Intervention Studied:  Percutaneous coronary intervention (PCI) with DES
Control:  Coronary-artery bypass grafting (CABG)
Outcomes:
– Primary outcome (composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke): 5-year rates of 26.6% in the PCI group and 18.7% in the CABG group (P=0.005)
– Stroke: 5-year rates of 2.4% in the PCI group and 5.2% in the CABG group (P=0.03)

The authors concluded that “For patients with diabetes and advanced coronary artery disease, CABG was superior to PCI in that it significantly reduced rates of death and myocardial infarction, with a higher rate of stroke”
Citation: Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, Yang M, Cohen DJ, Rosenberg Y, Solomon SD, Desai AS, Gersh BJ, Magnuson EA, Lansky A, Boineau R, Weinberger J, Ramanathan K, Sousa JE, Rankin J, Bhargava B, Buse J, Hueb W, Smith CR, Muratov V, Bansilal S, King S 3rd, Bertrand M, Fuster V; FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012 Dec 20;367(25):2375-84. doi: 10.1056/NEJMoa1211585. Epub 2012 Nov 4. PMID: 23121323.

Article Name: Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes 
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa040583#t=abstract
Journal and year of publication: NEJM, 2004
Trial Design: Randomized, double-blinded controlled clinical trial
Population: 4,162 patients with ACS   
Key inclusion criteria:
– Hospitalized for an acute coronary syndrome
– Have a total cholesterol level of 240 mg/dL (6.21 mmol/L) or less
Key exclusion criteria:
– On any statin at a dose of 80 mg per day at the time of the index event or lipid-lowering therapy with fibric acid derivatives or niacin that could not be discontinued before randomization
– Had obstructive hepatobiliary disease or other serious hepatic diseases
– Had an unexplained elevation in the creatine kinase level that was more than three times the upper limit of normal
Intervention Studied:  80 mg of atorvastatin daily (intensive therapy)
Control:  40 mg of pravastatin daily (standard therapy)
Outcomes:
– Primary end point at two years (a composite of death from any cause, MI, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke): 26.3% in the pravastatin group vs 22.4% in the atorvastatin group, resulting in a 16% reduction in the HR in favor of atorvastatin (P=0.005; 95% CI 5-26%)
– Median LDL levels achieved during treatment: 95 mg per deciliter with pravastatin, 62 mg per deciliter with atorvastatin (P<0.001)

The authors concluded that “Intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular, in patients who have recently had an acute coronary syndrome, compared to a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels.“
Citation: Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004 Apr 8;350(15):1495-504. doi: 10.1056/NEJMoa040583. Epub 2004 Mar 8. Erratum in: N Engl J Med. 2006 Feb 16;354(7):778. PMID: 15007110.

Article Name: Effects of an Angiotensin-Converting–Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients 
URL: https://www.nejm.org/doi/full/10.1056/NEJM200001203420301#t=abstract
Journal and year of publication: NEJM, 2000
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population: 9,297 high CV risk patients   
Key inclusion criteria:
– At least 55 years old 
– History of CAD, stroke, peripheral vascular disease, OR diabetes plus at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL cholesterol levels, cigarette smoking, or documented microalbuminuria)
Key exclusion criteria:
– Heart failure known to have a low ejection fraction (<40%).
– Had uncontrolled hypertension or overt nephropathy.
– Had an MI or stroke within four weeks before the study began
Intervention Studied:  Ramipril (10 mg once per day orally) for a mean of five years
Control:  A matching placebo for a mean of five years
Outcomes:
– Primary endpoint (composite of myocardial infarction, stroke, or death from cardiovascular causes): 14% in the ramipril group vs 17.8% in the placebo group (relative risk, 0.78; 95% CI 0.70-0.86; P<0.001)
– Treatment with ramipril also reduced rates of death from any cause, revascularization procedures, cardiac arrest, heart failure, and diabetes complications

The authors concluded that “Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.“
Citation: Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000 Jan 20;342(3):145-53. doi: 10.1056/NEJM200001203420301. Erratum in: 2000 May 4;342(18):1376. Erratum in: N Engl J Med 2000 Mar 9;342(10):748. PMID: 10639539.

Article Name: Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI 
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1611594
Journal and year of publication: NEJM, 2016
Trial Design: Randomized controlled clinical trial
Population: 2,124 patients with nonvalvular Afib + PCI    
Key inclusion criteria:
– Undergone a PCI (with stent placement) for primary atherosclerotic disease
– Have documented medical history of non-valvular atrial fibrillation
Key exclusion criteria:
– Contraindication to anticoagulation
– Calculated CrCl <30 mL/min at screening or pre-randomization 
– Known significant liver disease
– Planned CABG
Intervention Studied:  
Group 1: low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months 
Group 2: Very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months
Control:  Group 3: standard therapy with a dose-adjusted vitamin K antagonist (once daily) plus DAPT for 1, 6, or 12 month
Outcomes:
– Primary endpoint (rates of clinically significant bleeding) was lower in the two groups receiving rivaroxaban: Group 1 was 16.8%, Group 2 was 18.0%, and  Group 3 was 26.7% (HR for group 1 vs. group 3 was 0.59; 95% CI 0.47-0.76; 
P<0.001; and HR for group 2 vs. group 3 was 0.63; 95% CI 0.50-0.80; P<0.001)
– The rates of death from cardiovascular causes, myocardial infarction, or stroke were similar in the three groups

The authors concluded that “In participants with atrial fibrillation undergoing PCI with placement of stents, the administration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a vitamin K antagonist plus DAPT for 1, 6, or 12 months. The three groups had similar efficacy rates, although the observed broad confidence intervals diminish the surety of any conclusions regarding efficacy.”
Citation: Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, Birmingham M, Ianus J, Burton P, van Eickels M, Korjian S, Daaboul Y, Lip GY, Cohen M, Husted S, Peterson ED, Fox KA. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016 Dec 22;375(25):2423-2434. doi: 10.1056/NEJMoa1611594. Epub 2016 Nov 14. PMID: 27959713.

Article Name: Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation 
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1817083
Journal and year of publication: NEJM, 2019
Trial Design: Randomized controlled clinical trial
Population: 4,614 patients with nonvalvular Afib + ACS/PCI    
Key inclusion criteria:
– History of atrial fibrillation and planned long-term use of an oral anticoagulant.
– Recent acute coronary syndrome or PCI.
– Planned use of a P2Y12 inhibitor for at least 6 months
Key exclusion criteria:
– Patients who were using anticoagulation for other conditions (e.g., prosthetic valves, venous thromboembolism, and mitral stenosis).
– Severe renal insufficiency.
– History of intracranial hemorrhage.
– Recent or planned coronary-artery bypass graft surgery.
Intervention Studied:  
Intervention 1: Apixaban (5 mg twice daily or to take 2.5 mg twice daily if they met reduced dose criteria)
Intervention 2: Aspirin (81 mg daily)
Control:
Control 1: Vitamin K antagonist to target INR of 2.0 – 3.0 
Control 2: Matching placebo 
Outcomes:
– Primary endpoint (major or clinically relevant nonmajor bleeding):
10.5% in the apixaban group vs 14.7% in the vitamin K antagonist group (HR 0.69; 95% CI 0.58-0.81; P<0.001 for both noninferiority and superiority) and 16.1% of the patients receiving aspirin vs  9.0% of those receiving placebo (HR 1.89; 95% CI 1.59-2.24, P<0.001)
– Patients in the apixaban group lower incidence of death or hospitalization than the VKA group, and both had similar incidences of ischemic events

The authors concluded that “In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both”
Citation: Lopes RD, Heizer G, Aronson R, Vora AN, Massaro T, Mehran R, Goodman SG, Windecker S, Darius H, Li J, Averkov O, Bahit MC, Berwanger O, Budaj A, Hijazi Z, Parkhomenko A, Sinnaeve P, Storey RF, Thiele H, Vinereanu D, Granger CB, Alexander JH; AUGUSTUS Investigators. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-1524. doi: 10.1056/NEJMoa1817083. Epub 2019 Mar 17. PMID: 30883055.

Article Name: Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy
URL: https://www.nejm.org/doi/full/10.1056/nejmoa1107579
Journal and year of publication: NEJM, 2011
Trial Design: Randomized controlled clinical trial
Population: 3,414 patients     
Key inclusion criteria:
– Low baseline levels of HDL cholesterol (<40 mg/dL for men; <50 mg/dL for women)
– 45 years and older with established vascular disease and atherogenic dyslipidemia
– Discontinued lipid-modifying drugs, except for statins or ezetimibe
Key exclusion criteria:
– Had a stroke within the preceding 8 weeks
– Fasting glucose >180 mg/dL or HbA1C >9.0% 
– Patients with left main coronary disease ≥50% and no prior CABG
Intervention Studied:  
Extended-release niacin 1500 to 2000 mg/day (+/- Simvastatin 40 to 80 mg/day, ezetimibe 10 mg/day, to maintain an LDL cholesterol level of 40 to 80 mg/dL)
Control:
Placebo (+/- Simvastatin 40 to 80 mg/day, ezetimibe 10 mg/day, to maintain an LDL cholesterol level of 40 to 80 mg/dL)
Outcomes:
At 2 years, Niacin group had the following changes in their lipid panel results:
– Median HDL cholesterol level: Increased from 35 to 42 mg/dL (P<0.001)
– Triglyceride level: Lowered from 164 to 122 mg/dL
– LDL cholesterol level: Lowered from 74 to 62 mg/dL 
Primary end point occurrence (first event of the composite of death from coronary heart disease, nonfatal MI, ischemic stroke, hospitalization for an ACS, or symptom-driven coronary or cerebral revascularization): 
– Niacin group: 282 patients (16.4%) vs Placebo group: 274 patients (16.2%);
HR:1.02 (95% CI: 0.87 to 1.21) (P=0.79)

The authors concluded that “Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter (1.81 mmol per liter), there was no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels.”
Citation: AIM-HIGH Investigators, Boden, W. E., Probstfield, J. L., Anderson, T., Chaitman, B. R., Desvignes-Nickens, P., Koprowicz, K., McBride, R., Teo, K., & Weintraub, W. (2011). Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. The New England journal of medicine, 365(24), 2255–2267. https://doi.org/10.1056/NEJMoa1107579

Hypertension:

Article Name: Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet
URL: https://www.nejm.org/doi/full/10.1056/NEJM200101043440101
Journal and year of publication: NEJM, 2001
Trial Design: Randomized controlled clinical trial
Population: 412 patients with HTN    
Key inclusion criteria:
– At least 22 years old.
– With an average systolic blood pressure  of 120-159 / 80-95 mm Hg
Key exclusion criteria:
– Heart disease
– Renal insufficiency
– Poorly controlled hyperlipidemia
– Poorly controlled diabetes mellitus, or diabetes requiring insulin
– Special dietary requirements
– Intake of more than 14 alcoholic drinks per week.
Intervention Studied:  DASH diet
Control: Diet typical of intake in the United States 
Outcomes:
– The DASH diet, as compared with the control diet, resulted in a significantly lower SBP at every level of sodium intake
– As compared with the control diet with a high sodium level, the DASH diet with a low sodium level led to a mean SBP that was: 7.1 mm Hg lower in participants without hypertension and 11.5 mm Hg lower in participants with hypertension.

The authors concluded that “The reduction of sodium intake to levels below the current recommendation of 100 mmol per day and the DASH diet both lower blood pressure substantially, with greater effects in combination than singly”
Citation: Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER 3rd, Simons-Morton DG, Karanja N, Lin PH; DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med. 2001 Jan 4;344(1):3-10. doi: 10.1056/NEJM200101043440101. PMID: 11136953.
Article Name: Effect of Treating Isolated Systolic Hypertension on the Risk of Developing Various Types and Subtypes of Stroke
URL: https://jamanetwork.com/journals/jama/fullarticle/192921
Journal and year of publication: JAMA, 2000
Trial Design: Randomized controlled clinical trial
Population: 4,736 patients    
Key inclusion criteria:
– Aged 60 years or older 
– Isolated systolic hypertension: SBP 160 – 219 mmHg and DBP <90mmHg
Key exclusion criteria:
– Atrial fibrillation or flutter, A-V block, multifocal VPB, HR<50 bpm, or permanent pacemaker
– Recent MI, recent stroke with residua, CABG in the past 6 months, insulin dependent DM, dementia, history of renal insufficiency, dementia, or alcohol abuse
Intervention Studied:  
Step 1: Chlorthalidone (12.5 mg/d) 
Step 2 (can be added): Atenolol (25 mg/d) OR Reserpine (0.05 mg/d)
Goal SBP was a decrease in baseline SBP of ≥20 mm Hg to an SBP of <160 mm Hg
Control: Placebo 
Outcomes:
– Ischemic strokes: Adjusted relative risk: 0.63 (95% CI: 0.48-0.82) in favor of treatment
– Hemorrhagic strokes: Adjusted relative risk: 0.46 (95% CI: 0.21-1.02) in favor of treatment

The authors concluded that “In this study, antihypertensive drug treatment reduced the incidence of both hemorrhagic and ischemic (including lacunar) strokes. Reduction in stroke incidence occurred when specific systolic blood pressure goals were attained”
Citation: Perry HM Jr, Davis BR, Price TR, Applegate WB, Fields WS, Guralnik JM, Kuller L, Pressel S, Stamler J, Probstfield JL. Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 2000 Jul 26;284(4):465-71. doi: 10.1001/jama.284.4.465. PMID: 10904510.
Article Name: Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
URL: https://jamanetwork.com/journals/jama/fullarticle/195626
Journal and year of publication: JAMA, 2002
Trial Design: Randomized, double-blinded controlled clinical trial
Population: 33,357 patients with HTN    
Key inclusion criteria:
– At least 55 years old.
– Hypertension + at least 1 other CAD risk factor
Key exclusion criteria:
– Individuals with a history of hospitalized or treated symptomatic heart failure
– Known left ventricular ejection fraction of less than 35%
Intervention Studied:  Amlodipine (2.5 to 10 mg daily) or lisinopril (10 to 40 mg daily)
Control: Chlorthalidone (12.5 to 25 mg/d) 
Outcomes:
– Primary outcome (combined fatal CAD or nonfatal myocardial infarction): no difference between treatment groups
– All-cause mortality: No difference between treatment groups
– Secondary outcomes such stroke and CAD tended to be lower in the thiazides group

The authors concluded that “Neither amlodipine (representing CCBs, particularly dihydropyridine [DHP]–CCBs) nor lisinopril (representing ACE inhibitors) was superior to chlorthalidone (representing thiazide-type diuretics) in preventing major coronary events or in increasing survival.”
Citation: ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97. doi: 10.1001/jama.288.23.2981. Erratum in: JAMA 2003 Jan 8;289(2):178. Erratum in: JAMA. 2004 May 12;291(18):2196. PMID: 12479763.
Article Name: Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients
URL: https://www.nejm.org/doi/full/10.1056/nejmoa0806182
Journal and year of publication: NEJM, 2008
Trial Design: Randomized controlled clinical trial
Population: 11,506 patients with HTN    
Key inclusion criteria:
– SBP 160 mmHg OR currently on antihypertensive therapy
– Aged 60 years of age or older with at least ONE additional risk factor OR Aged 55 -59 years  with at least TWO risk factors
Key exclusion criteria:
– History of symptomatic HF or evidence of LVEF <40%
– Current angina (Symptoms in the last 3 months)
– ACS or coronary revascularizations within 1 month
Intervention Studied:  
Group 1: Benazepril plus amlodipine 
Group 2: Benazepril plus hydrochlorothiazide
Control: See above
Outcomes:
– Primary outcome: (composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization):
– Benazepril–amlodipine group: 9.6% of patients
– Benazepril–hydrochlorothiazide group: 11.8% of patients
– Relative risk reduction: 19.6%, HR: 0.80 (95% CI: 0.72 to 0.90), P<0.001

– Death from cardiovascular causes, nonfatal MI, and nonfatal stroke: HR: 0.79 (95% CI: 0.67 to 0.92), P=0.002

The authors concluded that “The benazepril–amlodipine combination was superior to the benazepril–hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events.”
Citation: Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velazquez EJ; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008 Dec 4;359(23):2417-28. doi: 10.1056/NEJMoa0806182. PMID: 19052124.
Article Name: Treatment of Hypertension in Patients 80 Years of Age or Older
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0801369
Journal and year of publication: NEJM, 2008
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population: 3,845 patients >80 with HTN    
Key inclusion criteria:
– 80 years of age or older
– Sustained systolic blood pressure of 160 mm Hg or more
Key exclusion criteria:
– Secondary hypertension.
– Hemorrhagic stroke in the previous 6 months.
– Heart failure requiring treatment with antihypertensive medication.
– Serum creatinine level greater than 150 μmol/L (1.7 mg per deciliter).
– Serum potassium below 3.5 mmol/L or above 5.5 mmol/L.
– Diagnosis of clinical dementia, and a requirement of nursing care
Intervention Studied:  Indapamide (sustained release, 1.5 mg) +/- perindopril (2 or 4 mg) to achieve the target blood pressure of 150/80 mm Hg
Control: Matching placebo
Outcomes:
– Primary outcome (fatal or nonfatal stroke): 30% reduction in the active-treatment group (95% CI −1 to 51; P=0.06)
– Mean sitting blood pressure after 2 years: 15.0/6.1 mm Hg lower in the active-treatment group vs placebo
– There was also a 21% reduction in the rate of death from any cause (95% CI, 4 to 35; P=0.02), a 23% reduction in the rate of death from cardiovascular causes (95% CI, −1 to 40; P=0.06), and a 64% reduction in the rate of heart failure (95% CI, 42 to 78; P<0.001), and fewer adverse events in the treatment group

The authors concluded that “The results provide evidence that antihypertensive treatment with indapamide (sustained release), with or without perindopril, in persons 80 years of age or older is beneficial.”
Citation: Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F, Rajkumar C, Thijs L, Banya W, Bulpitt CJ; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008 May 1;358(18):1887-98. doi: 10.1056/NEJMoa0801369. Epub 2008 Mar 31. PMID: 18378519.
Article Name: A Randomized Trial of Intensive versus Standard Blood-Pressure Control
URL: https://www.nejm.org/doi/full/10.1056/nejmoa1511939
Journal and year of publication: NEJM, 2008
Trial Design: Randomized controlled clinical trial
Population:  9,361 patients with HTN    
Key inclusion criteria:
– Age of at least 50 years.
– Systolic blood pressure of 130 to 180 mm Hg
– An increased risk of cardiovascular events
Key exclusion criteria:
– Diabetes mellitus
– Prior stroke
– Symptomatic heart failure within the past 6 months or left ventricular ejection fraction < 35%
Intervention Studied:  Intensive Treatment (Systolic blood-pressure target of less than 120 mm Hg)
Control: Standard Treatment (systolic blood-pressure target of of less than 140 mm Hg)
Outcomes:
– Mean systolic blood pressure after 1 year: 121.4 mm Hg in the intensive-treatment group; 136.2 mm Hg in the standard-treatment group.
– Primary composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes: 1.65% per year with intensive treatment vs. 2.19% with standard treatment (HR 0.75, 95% CI 0.64-0.89, P<0.001)
– All-cause mortality: Significantly lower in the intensive-treatment group
(HR 0.73; 95% CI 0.60-0.90, P=0.003)
– Rates of serious adverse events were higher in the intensive-treatment

The authors concluded that “Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group.”
Citation: SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov 26;373(22):2103-16. doi: 10.1056/NEJMoa1511939. Epub 2015 Nov 9. Erratum in: N Engl J Med. 2017 Dec 21;377(25):2506. PMID: 26551272; PMCID: PMC4689591.
Article Name: The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels. Results of the Trials of Hypertension Prevention, Phase I
URL: https://jamanetwork.com/journals/jama/article-abstract/395495
Journal and year of publication: JAMA, 1992
Trial Design: Randomized clinical trial
Population:  2,182 patients with HTN    
Key inclusion criteria:
– Aged 30 through 54 years
– Diastolic blood pressure from 80 through 89 mm Hg 
– Not taking antihypertensive drugs for the prior 2 months
Key exclusion criteria:
– Hypertensive: DBP readings averaging 90 mm Hg or greater.
– Current use (within the previous 2 months) of antihypertensive medications.
– Gross obesity
– History of cardiovascular disease: including myocardial infarction, angina, intermittent claudication, congestive heart failure, and stroke.
– History of diabetes mellitus.
– History of chronic renal failure and/or kidney stones
Intervention Studied:
1) Three lifestyle change groups (weight reduction, sodium reduction, and stress management). 
2) Four nutritional supplement groups (calcium, magnesium, potassium, and fish oil)  
Control:
1) Unmasked nonintervention controls.
2) Placebo controls
Outcomes:
– Weight reduction intervention:
— Produced weight loss of 3.9 kg (P<.01)
— Diastolic blood pressure change of -2.3 mm Hg (P<.01)
— Systolic blood pressure change of -2.9 mm Hg (P<.01)
– Sodium reduction interventions:
— Diastolic blood pressure by 0.9 mm Hg (P<.05).
— Systolic blood pressure by 1.7mm Hg (P<.01).
– Stress management and nutritional supplements:
— No significant change in Blood pressure despite good compliance (P>.05).

The authors concluded that “Weight reduction is the most effective of the strategies tested for reducing blood pressure in normotensive persons. Sodium reduction is also effective. The long-term effects of weight reduction and sodium reduction, alone and in combination, require further evaluation.”
Citation: The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels. Results of the Trials of Hypertension Prevention, Phase I. JAMA. 1992 Mar 4;267(9):1213-20. doi: 10.1001/jama.1992.03480090061028. Erratum in: JAMA 1992 May 6;267(17):2330. PMID: 1586398.
Article Name: Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa011303
Journal and year of publication: NEJM, 2001
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population:  1,715 patients with T2DM + nephropathy
Key inclusion criteria:
– Age of 30 and 70 years
– Diagnosis of T2DM
– Hypertension (a sitting BP >135/85 mm Hg) or on antihypertensive agents
– Proteinuria (urinary protein excretion of at least 900 mg/ 24 hours)
– Serum creatinine between:
— 1.0 and 3.0 mg/dL (88 and 265 μmol/L) in women
— 1.2 and 3.0 mg/dL (106 and 265 μmol/L) in men
Key exclusion criteria:
– Unclear from manuscript
Intervention Studied:
1) Irbesartan (300 mg daily)
2) Amlodipine (10 mg daily)
Control:
1) Placebo controls
Outcomes:
– Primary endpoint (doubling of the baseline serum creatinine concentration, the development of end-stage renal disease, or death from any cause): lower risk in the irbesartan – 20% lower than that in the placebo group (P=0.02), and 23% lower than that in the amlodipine group (P=0.006)

The authors concluded that “The angiotensin-II–receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.”
Citation: Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):851-60. doi: 10.1056/NEJMoa011303. PMID: 11565517.

Heart Failure

Article Name: Effects of Enalapril on Mortality in Severe Congestive Heart Failure
URL: https://www.nejm.org/doi/full/10.1056/NEJM198706043162301
Journal and year of publication: NEJM, 1987
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population: 253 patients with CHF   
Key inclusion criteria:
– NYHA class IV HFrEF
Key exclusion criteria:
– Acute pulmonary edema
– Significant aortic or mitral valve stenosis
– MI within the previous two months
– Serum creatinine 3.39mg/dl or greater
Intervention Studied:
Enalapril (2.5 to 40 mg per day)
Control:
Matching placebo
Outcomes:
– Primary endpoint (the crude mortality at the end of six months): 26% in the enalapril group and 44% in the placebo group, reduction of 40% (P = 0.002)
– Mortality at one year: reduced by 31% with enalapril (P = 0.001)
– Also resulted in significant improvement in NYHA classification and reduction in need for other medications for CHF

The authors concluded that “The addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms. The beneficial effect on mortality is due to a reduction in death from the progression of heart failure.“
Citation: CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987 Jun 4;316(23):1429-35. doi: 10.1056/NEJM198706043162301. PMID: 2883575.
Article Name: Effects of Controlled-Release Metoprolol on Total Mortality, Hospitalizations, and Well-being in Patients With Heart Failure –
The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure
URL: https://jamanetwork.com/journals/jama/fullarticle/192477
Journal and year of publication: JAMA, 2000
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population:  3,991 patients with CHF   
Key inclusion criteria:
– Aged 40 to 80 years
– Symptomatic heart failure for at least 3 months (NYHA class II to IV)
– Left ventricular ejection fraction of 40% or less
– Resting heart rate had to be 68/min or more.
– Patients had to be receiving optimal treatment (any combination of diuretics and an ACE inhibitor) for at least 2 weeks prior to randomization.
Key exclusion criteria:
– Severe decompensated heart failure (eg, pulmonary edema, hypoperfusion).
– Supine systolic blood pressure of less than 100 mm Hg
Intervention Studied:
Metoprolol CR/XL, 25 mg once per day (NYHA class II), or 12.5 mg once per day (NYHA class III or IV), titrated for 6 to 8 weeks up to a target dosage of 200 mg once per day
Control:
Matching placebo
Outcomes:
– Compared to placebo, the Metoprolol group had a lower incidence of all predefined endpoints:
– Total mortality or all-cause hospitalizations: risk reduction of 19%; 95% CI, 10%-27%,  P<.001
– NYHA functional class, assessed by physicians improved in the Metoprolol CR/XL group vs the placebo group, P = .003

The authors concluded that “In this study of patients with symptomatic heart failure, metoprolol CR/XL improved survival, reduced the need for hospitalizations due to worsening heart failure, improved NYHA functional class, and had beneficial effects on patient well-being.”
Citation: Hjalmarson Å, Goldstein S, Fagerberg B, et al. Effects of Controlled-Release Metoprolol on Total Mortality, Hospitalizations, and Well-being in Patients With Heart Failure: The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA. 2000;283(10):1295–1302. doi:10.1001/jama.283.10.1295.
Article Name: Effect of Carvedilol on the Morbidity of Patients With Severe Chronic Heart Failure
URL: https://www.ahajournals.org/doi/full/10.1161/01.cir.0000035653.72855.bf
Journal and year of publication: Circulation, 2002
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population: 2,289 patients with CHF   
Key inclusion criteria:
– Dyspnea or fatigue at rest or on minimal exertion for ≥2 months 
– Left ventricular ejection fraction <25% 
– On a diuretic and an ACEi or ARB unless contraindicated
Key exclusion criteria:
– Patients who required intensive care, had marked fluid retention, or were receiving intravenous vasodilators or positive inotropic drugs.
– Heart failure that was caused by uncorrected primary valvular disease or a reversible form of cardiomyopathy.
– Had severe primary pulmonary, renal, or hepatic disease
Intervention Studied:
Carvedilol 3.125 mg twice daily, which was then increased (if tolerated) at 2-week intervals to 6.25 mg, 12.5 mg, and finally to a target dose of 25 mg twice daily
Control:
Matching placebo
Outcomes:
– Carvedilol reduced: Combined risk of death or hospitalization by a cardiovascular reason by 27% (P=0.00002), and the combined risk of death or hospitalization by heart failure by 31% (P=0.000004)
– Also reduced hospitalization days and symptoms

The authors concluded that “In euvolemic patients with symptoms at rest or on minimal exertion, the addition of carvedilol to conventional therapy ameliorates the severity of heart failure and reduces the risk of clinical deterioration, hospitalization, and other serious adverse clinical events.”
Citation: Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Staiger C,  Holcslaw TL, Amann-Zalan I, DeMets DL; Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002 Oct 22;106(17):2194-9. doi: 10.1161/01.cir.0000035653.72855.bf. PMID: 12390947.
Article Name: A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa010713
Journal and year of publication: NEJM, 2001
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population: 5,010 patients with CHF   
Key inclusion criteria:
– Heart failure for at least three months of NYHA II,III,IV
– Clinically stable
– Left Ventricular Ejection fraction of less than 40%
Key exclusion criteria:
– Right heart failure caused by pulmonary disease
– Hypertrophic cardiomyopathy
– Hemodynamically significant valve disease
– Clinically important renal (serum creatinine level > 2.5 mg/dL) or hepatic disorders
Intervention Studied:
Valsartan 160 mg twice daily
Control:
Matching placebo
Outcomes:
– The primary outcomes (mortality and the combined endpoint of mortality and morbidity – incidence of cardiac arrest with resuscitation, hospitalization for heart failure, or receipt of intravenous inotropic or vasodilator therapy for at least four hours): 13.2% lower incidence of the combined endpoint with valsartan than with placebo, relative risk, 0.87; 97.5% CI 0.77 – 0.97; P=0.009). Overall mortality was similar in the two groups
– There were fewer hospitalizations for HF and improved NYHA symptoms and EF in the valsartan group as well.

The authors concluded that “Valsartan significantly reduces the combined end point of mortality and morbidity and improves clinical signs and symptoms in patients with heart failure, when added to prescribed therapy. However, the post hoc observation of an adverse effect on mortality and morbidity in the subgroup receiving valsartan, an ACE inhibitor, and a beta-blocker raises concern about the potential safety of this specific combination.”
Citation: Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001 Dec 6;345(23):1667-75. doi: 10.1056/NEJMoa010713. PMID: 11759645.
Article Name: Effect of Captopril on Mortality and Morbidity in Patients with Left Ventricular Dysfunction after Myocardial Infarction — Results of the Survival and Ventricular Enlargement Trial
URL: https://www.nejm.org/doi/full/10.1056/NEJM199209033271001
Journal and year of publication: NEJM, 1992
Trial Design: Randomized placebo-controlled clinical trial
Population: 2,231 patients   
Key inclusion criteria:
– Survived the first three days after a myocardial infarction
– Left ventricular ejection fraction of 40 percent or less
Key exclusion criteria:
– Patients with overt heart failure
Intervention Studied: Captopril
Control: Placebo
Outcomes:
Compared to the placebo group, captopril group had significantly reduced:
– Mortality from all causes: 20% vs 25% in the placebo group; reduction in risk: 19% (P = 0.019). 
– Death from cardiovascular causes: Reduction in risk: 21% (95% CI, 5 to 35 percent; P = 0.014)
– Development of severe heart failure: Reduction in risk: 37% (95% CI, 20 to 50 percent; P<0.001)
– Recurrent Myocardial infarction: Reduction in risk: 25% (95% CI, 5 to 40 percent; P = 0.015)

The authors concluded that “In patients with asymptomatic left ventricular dysfunction after myocardial infarction, long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events.”
Citation: Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992 Sep 3;327(10):669-77. doi: 10.1056/NEJM199209033271001. PMID: 1386652.
Article Name: The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure
URL: https://www.nejm.org/doi/full/10.1056/NEJM199909023411001
Journal and year of publication: NEJM, 1999
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population: 1,663 patients with CHF   
Key inclusion criteria:
– Had had NYHA class IV heart failure within the 6 months before enrollment and were in NYHA class III or IV at the time of enrollment
– Diagnosed with heart failure at least 6 weeks before enrollment
– With left ventricular ejection fraction <35% within the last 6 months
– Were on an ACE inhibitor (if tolerated) and a loop diuretic
– Not on potassium-sparing diuretics
Key exclusion criteria:
– Primary operable valvular heart disease (other than mitral or tricuspid regurgitation with clinical symptoms due to left ventricular systolic heart failure)
– Congenital heart disease
– Unstable angina
Intervention Studied:
Spironolactone 25 mg daily
Control:
Matching placebo
Outcomes:
– The primary outcomes (death from any cause): 35% in the spironolactone group vs 46% in the placebo group (relative risk of death, 0.70; 95% CI, 0.60 – 0.82; P<0.001).
– There were fewer hospitalizations for HF and improved NYHA symptoms in the spironolactone group as well, but with increased gynecomastia

The authors concluded that “Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure”
Citation: Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999 Sep 2;341(10):709-17. doi: 10.1056/NEJM199909023411001. PMID: 10471456.
Article Name: Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1009492
Journal and year of publication: NEJM, 2001
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population: 2,737 patients with CHF   
Key inclusion criteria:
– Age of at least 55 years
– NYHA functional class II symptoms
– Ejection fraction of no more than 30%
– On an ACE inhibitor, an ARB, or both and a beta-blocker (unless contraindicated) at the recommended dose or maximally tolerated dose
Key exclusion criteria:
– Acute myocardial infarction
– NYHA class III or IV heart failure
– Estimated GFR of less than 30 ml per minute
Intervention Studied:
Eplerenone (up to 50 mg daily)
Control:
Matching placebo
Outcomes:
– Primary outcome occurrence (composite of death from cardiovascular causes or hospitalization for heart failure): 18.3% of patients on eplerenone vs 25.9% of patients on placebo (HR 0.63; 95% CI 0.54 – 0.74; P<0.001)
– Death: 12.5% of patients on eplerenone vs 15.5% of those on placebo (HR 0.76; 95% CI, 0.62 – 0.93; P=0.008)


The authors concluded that “Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms.“
Citation: Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011 Jan 6;364(1):11-21. doi: 10.1056/NEJMoa1009492. Epub 2010 Nov 14. PMID: 21073363.
Article Name: Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa042934
Journal and year of publication: NEJM, 2004
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population: 1,050 patients with CHF   
Key inclusion criteria:
– Patients self-identified as black (defined as of African descent)
– NYHA class III or IV heart failure for at least three months
– On standard therapy for heart failure
Key exclusion criteria:
– The presence of clinically significant valvular heart disease, hypertrophic or restrictive cardiomyopathy, active myocarditis, or uncontrolled hypertension; 
– History of cardiac arrest or life-threatening arrhythmias within the preceding 3 months
– Symptomatic hypotension
Intervention Studied:
37.5 mg of hydralazine hydrochloride and 20 mg of isosorbide dinitrate three times daily, the dose was increased for a total daily dose of 225 mg of hydralazine hydrochloride and 120 mg of isosorbide dinitrate. 
Control:
Matching placebo
Outcomes:
– Primary outcome occurrence (composite score made up of weighted values for death from any cause, a first hospitalization for heart failure, and change in the quality of life): significantly better in the group given isosorbide dinitrate plus hydralazine than in the placebo group (–0.1±1.9 vs. –0.5±2.0, P=0.01)
– 43% reduction in the rate of death from any cause [HR 0.57; P=0.01], 33 percent relative reduction in the rate of the first hospitalization for heart failure [16.4 percent vs. 22.4 percent, P=0.001], and an improvement in the quality of life 
– The study was terminated early owing to a significantly higher mortality rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine (10.2 percent vs. 6.2 percent, P=0.02).

The authors concluded that “The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure.“
Citation: Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN; African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004 Nov 11;351(20):2049-57. doi: 10.1056/NEJMoa042934. Epub 2004 Nov 8. Erratum in: N Engl J Med. 2005 Mar 24;352(12):1276. PMID: 15533851.
Article Name: Diuretic Strategies in Patients with Acute Decompensated Heart Failure
URL: https://www.nejm.org/doi/10.1056/NEJMoa1005419?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov
Journal and year of publication: NEJM, 2004
Trial Design: Randomized, double-blinded clinical trial
Population: 308 patients with acute decompensated HF   
Key inclusion criteria:
– Presented with acute Decompensated heart failure within the previous 24 hrs
– History of chronic heart failure
– Taking oral loop diuretic for at least 1 month before hospitalization
Key exclusion criteria:
– Systolic blood pressure < 90 mm Hg
– Serum creatinine > 3.0 mg/dL (265.2 μmo/L)
– Requiring intravenous vasodilators or inotropic agents (other than digoxin)
Intervention Studied:
1) Furosemide IV  bolus every 12 hours
2) Furosemide continuous infusion: 
A) Low dose (equal to the patient’s previous oral dose)
B) High dose (2.5 times the previous oral dose)
 
Control:
Matching placebo
Outcomes:
– Bolus vs continuous infusion: no significant difference in patients’ global assessment of symptoms (P=0.47) and no significant difference in mean change in the creatinine level (P=0.45)
– High-dose vs low-dose strategy: nonsignificant trend toward greater improvement in patients’ global assessment of symptoms in the high-dose group (P=0.06), no significant difference in mean change in the creatinine level
P=0.21

The authors concluded that “Among patients with acute decompensated heart failure, there were no significant differences in patients’ global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose.”
Citation: Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O’Connor CM; NHLBI Heart Failure Clinical Research Network. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011 Mar 3;364(9):797-805. doi: 10.1056/NEJMoa1005419. PMID: 21366472; PMCID: PMC3412356.
Article Name: Prophylactic Implantation of a Defibrillator in Patients with Myocardial Infarction and Reduced Ejection Fraction
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa013474
Journal and year of publication: NEJM, 2002
Trial Design: Randomized clinical trial
Population: 1,232 patients with HF   
Key inclusion criteria:
– Myocardial infarction one month or more before entry.
– LVEF of 30% or less within three months before entry
Key exclusion criteria:
– If there is an indication approved by the Food and Drug Administration (FDA) for an implantable defibrillator
– NYHA functional class IV at enrollment
– Advanced cerebrovascular disease
Intervention Studied:
Implantable defibrillator + medical therapy
Control:
Medical therapy
Outcomes:
– Mortality Rate: 14.2% in the defibrillator group and 19.8% in the conventional-therapy group (HR 0.69, 95% Cl 0.51 – 0.93; P=0.016)

The authors concluded that “In patients with a prior myocardial infarction and advanced left ventricular dysfunction, prophylactic implantation of a defibrillator improves survival and should be considered as a recommended therapy.”
Citation: Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML; Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002 Mar 21;346(12):877-83. doi: 10.1056/NEJMoa013474. Epub 2002 Mar 19. PMID: 11907286.
Article Name: Cardiac-Resynchronization Therapy for the Prevention of Heart-Failure Events
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0906431
Journal and year of publication: NEJM, 2009
Trial Design: Randomized controlled clinical trial
Population: 1,820 patients with HF   
Key inclusion criteria:
– Ischemic cardiomyopathy (NYHA class I or II) or nonischemic cardiomyopathy (NYHA class II only)
– Sinus rhythm with a prolonged intraventricular conduction (QRS duration of 130 msec or more)
– Ejection fraction of 30% or less
Key exclusion criteria:
– NYHA class III or IV symptoms
– Atrial fibrillation within 1 month before enrollment
Intervention Studied: CRT + ICD
Control: ICD alone
Outcomes:
– Primary endpoint (death from any cause or a nonfatal heart-failure event): 17.2% of patients in the CRT–ICD group vs 25.3% of patients in the ICD-only group (HR 0.66; 95% CI 0.52 – 0.84; P=0.001).
– The benefit did not differ significantly between patients with ischemic cardiomyopathy and those with nonischemic cardiomyopathy.

The authors concluded that “CRT combined with ICD decreased the risk of heart-failure events in relatively asymptomatic patients with a low ejection fraction and wide QRS complex.“
Citation: Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA 3rd, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W; MADIT-CRT Trial Investigators. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009 Oct 1;361(14):1329-38. doi: 10.1056/NEJMoa0906431. Epub 2009 Sep 1. PMID: 19723701.
Article Name: Advanced Heart Failure Treated with Continuous-Flow Left Ventricular Assist Device
URL: https://www.nejm.org/doi/full/10.1056/nejmoa0909938
Journal and year of publication: NEJM, 2009
Trial Design: Randomized controlled clinical trial
Population: 200 patients with HF   
Key inclusion criteria:
– Advanced heart failure symptoms (Class IIIB or IV) and one of the following:
– On optimal maintenance therapy, including dietary salt restriction, diuretics, digitalis, beta-blockers, spironolactone and ACE inhibitors
– In Class III or Class IV heart failure for at least 14 days, and dependent on intra aortic balloon pump (IABP) for 7 days and/or inotropes for at least 14 days
– Ineligible for cardiac transplant
– LVEF is < 25%.
Key exclusion criteria:
– Presence of mechanical aortic valve that will not be converted to a bioprosthesis at time of LVAD implant.
– History of severe COPD or severe restrictive lung disease
– Patient is receiving a calcium channel blocker (except amlodipine), or a Type I or Type III antiarrhythmic (except amiodarone) within 28 days prior to enrollment
Intervention Studied: Implantation of a continuous-flow device
Control: Pulsatile-flow device
Outcomes:
– Primary composite endpoint (at 2 years, survival free from disabling stroke and reoperation to repair or replace the device): 46% with continuous-flow devices vs 11% pulsatile-flow devices (HR 0.38; 95% CI 0.27-0.54; P<0.001)
– Had higher 2-year survival in the continuous flow device group (58% vs. 24%, P=0.008)

The authors concluded that ” Treatment with a continuous-flow left ventricular assist device in patients with advanced heart failure significantly improved the probability of survival free from stroke and device failure at 2 years as compared with a pulsatile device. Both devices significantly improved the quality of life and functional capacity.“
Citation: Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D, Sun B, Tatooles AJ, Delgado RM 3rd, Long JW, Wozniak TC, Ghumman W, Farrar DJ, Frazier OH; HeartMate II Investigators. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med. 2009 Dec 3;361(23):2241-51. doi: 10.1056/NEJMoa0909938. Epub 2009 Nov 17. Erratum in: N Engl J Med. 2018 Aug 16;379(7):697. PMID: 19920051.
Article Name: Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1409077
Journal and year of publication: NEJM, 2014
Trial Design: Randomized controlled clinical trial
Population: 8,442 patients with HF   
Key inclusion criteria:
– NYHA class II, III, or IV symptoms
– Ejection fraction of 40% or less 
Key exclusion criteria:
– Symptomatic hypotension
– Systolic blood pressure of less than 100 mm Hg at screening
– eGFR below 30 ml per minute 
Intervention Studied: Sacubitril-valsartan (LCZ696) 200 mg twice daily
Control: Enalapril 10 mg twice daily
Outcomes:
– Primary outcome (a composite of death from cardiovascular causes or hospitalization for heart failure): 21.8% in the sacubitril-valsartan group and 26.5% in the enalapril group (HR 0.80; 95% CI 0.73 – 0.87; P<0.001).
– Sacubitril-valsartan also lowered risk of hospitalization for heart failure and symptoms of heart failure

The authors concluded that ” LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure.”
Citation: McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30. PMID: 25176015.
Article Name: Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa2022190
Journal and year of publication: NEJM, 2020
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population: 3,730 patients with HF   
Key inclusion criteria:
– Chronic heart failure (functional class II, III, or IV)
– Left ventricular ejection fraction of 40% 
Key exclusion criteria:
– Cardiomyopathy based on infiltrative diseases
– Any severe (obstructive or regurgitant) valvular heart disease expected to require surgery
Intervention Studied: Empagliflozin (10 mg once daily)
Control: Placebo
Outcomes:
– Primary outcome (a composite of cardiovascular death or hospitalization for worsening heart failure): 19.4% in the empagliflozin group and 24.7% in the placebo group (HR 0.75; 95% CI 0.65 – 0.86; P<0.001)
– The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes
– There were lower numbers of heart failure hospitalizations and better renal outcomes in the empagliflozin group

The authors concluded that ” Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes.”
Citation: Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct 8;383(15):1413-1424. doi: 10.1056/NEJMoa2022190. Epub 2020 Aug 28. PMID: 32865377.
Article Name: Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1911303
Journal and year of publication: NEJM, 2019
Trial Design: Randomized controlled clinical trial
Population: 4,744 patients with HF   
Key inclusion criteria:
– EF of 40% or less and NYHA class II, III, or IV symptoms
Key exclusion criteria:
– Recent treatment with or unacceptable side effects associated with an SGLT2 inhibitor
– Type 1 diabetes mellitus
– Symptoms of hypotension or SBP less than 95 mmHg
Intervention Studied: Dapagliflozin (10 mg daily)
Control: Placebo
Outcomes:
– Primary outcome occurrence (Worsening heart failure or cardiovascular death):
Dapagliflozin group: 386 of 2373 patients (16.3%) vs Placebo group: 502 of 2371 patients (21.2%); HR : 0.74 (95% CI: 0.65 to 0.85), P<0.001
– Findings were similar in patients with diabetes and those without diabetes

The authors concluded that ” Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.”
Citation: McMurray, J., Solomon, S. D., Inzucchi, S. E., Køber, L., Kosiborod, M. N., Martinez, F. A., Ponikowski, P., Sabatine, M. S., Anand, I. S., Bělohlávek, J., Böhm, M., Chiang, C. E., Chopra, V. K., de Boer, R. A., Desai, A. S., Diez, M., Drozdz, J., Dukát, A., Ge, J., Howlett, J. G., … DAPA-HF Trial Committees and Investigators (2019). Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. The New England journal of medicine, 381(21), 1995–2008. https://doi.org/10.1056/NEJMoa1911303

Arrhythmias

Article Name: A Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa021328
Journal and year of publication: NEJM, 2002
Trial Design: Randomized clinical trial
Population: 4,060 patients with Afib   
Key inclusion criteria:
– Atrial fibrillation was likely to be recurrent
– Atrial fibrillation was likely to cause illness or death
– Long-term treatment for atrial fibrillation was warranted 
Key exclusion criteria:
– Cardiomyopathy based on infiltrative diseases
– Any severe (obstructive or regurgitant) valvular heart disease expected to require surgery
Intervention Studied: Cardioversion and treatment with antiarrhythmic drugs
Control: Use of rate-controlling drugs
Outcomes:
– Primary outcome (overall mortality): 23.8% among rhythm-control therapy group vs 21.3% among rate-control therapy group (HR 1.15 95% CI, 0.99 – 1.34] 
P=0.08)
– More hospitalization adn adverse events in the rhythm control group

The authors concluded that “Management of atrial fibrillation with the rhythm-control strategy offers no survival advantage over the rate-control strategy, and there are potential advantages, such as a lower risk of adverse drug effects, with the rate-control strategy. Anticoagulation should be continued in this group of high-risk patients.“
Citation: Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002 Dec 5;347(23):1825-33. doi: 10.1056/NEJMoa021328. PMID: 12466506.
Article Name: Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial
URL: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(96)03487-3/fulltext
Journal and year of publication: The Lancet, 1996
Trial Design: Randomized clinical trial
Population: 1,044 patients with Afib   
Key inclusion criteria:
– Adults with Afib 
Key exclusion criteria:
– Prosthetic heart valves, mitral stenosis, or other conditions such as recent pulmonary embolism that needed anticoagulation therapy
– NYHA Class IV
– Successful electrical or chemical cardioversion with no recurrence
Intervention Studied: Adjusted-dose warfarin (INR 2·0–3·0)
Control: Combination of low-intensity, fixed-dose warfarin (INR: 1·2–1·5 for initial dose adjustment) + aspirin (325 mg/day)
Outcomes:
– Primary endpoint (rate of ischemic stroke and systemic embolism): significantly higher in those on combination therapy (7.9%) per year vs those given adjusted-dose warfarin (1.9% per year) (p<0.0001).
– The rates of major bleeding were similar in both treatment groups

The authors concluded that “Low-intensity, fixed-dose warfarin plus aspirin in this regimen is insufficient for stroke prevention in patients with non-valvular AF at high-risk for thromboembolism; adjusted-dose warfarin (target INR 2.0-3.0) importantly reduces stroke for high-risk patients.“
Citation: Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet. 1996 Sep 7;348(9028):633-8. PMID: 8782752.
Article Name: Apixaban versus Warfarin in Patients with Atrial Fibrillation
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1107039
Journal and year of publication: NEJM, 2011
Trial Design: Randomized, double-blinded clinical trial
Population: 18,201 patients with Afib   
Key inclusion criteria:
– Adults with Afib and risk factors for stroke
Key exclusion criteria:
– Atrial fibrillation due to a reversible cause
– Moderate or severe mitral stenosis.
– Conditions other than atrial fibrillation that required anticoagulation
Intervention Studied: Apixaban (at a dose of 5 mg twice daily)
Control: Warfarin (target INR: 2.0 to 3.0)
Outcomes:
– Rate of primary outcome (ischemic or hemorrhagic stroke or systemic embolism): 1.27% per year in apixaban group vs 1.60% per year in warfarin group
(HR 0.79; 95% CI, 0.66 to 0.95, P<0.001 for noninferiority, P=0.01 for superiority)
– Rate of major bleeding: 2.13% per year in apixaban group vs 3.09% per year in warfarin group (HR 0.69; 95% CI, 0.60 to 0.80, P<0.001)
– Rate of death from any cause: 3.52% in apixaban group and 3.94% in warfarin group (HR 0.89; 95% CI, 0.80 to 0.99, P=0.047)
– Rate of hemorrhagic stroke: 0.24% per year in apixaban group vs 0.47% per year in warfarin group (HR 0.51; 95% CI, 0.35 to 0.75, P<0.001)

The authors concluded that “In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.“
Citation: Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92. doi: 10.1056/NEJMoa1107039. Epub 2011 Aug 27. PMID: 21870978.
Article Name: Use of Transesophageal Echocardiography to Guide Cardioversion in Patients with Atrial Fibrillation
URL: https://www.nejm.org/doi/full/10.1056/nejm200105103441901
Journal and year of publication: NEJM, 2001
Trial Design: Randomized clinical trial
Population: 1,222 patients with Afib
Key inclusion criteria:
– Candidates for electrical cardioversion
– Atrial fibrillation of more than two days’ duration
Key exclusion criteria:
– Patients with atrial flutter and no history of atrial fibrillation
– Hemodynamic instability.
– Long-term warfarin therapy (>7days)
Intervention Studied:  Treatment guided by the findings on transesophageal echocardiography
Control: Conventional treatment
Outcomes:
– Rate of embolic events: No significant difference between the two treatment groups (0.8% in TEE with guided treatment vs. 0.5% in conventional treatment group, P=0.50)
– Rate of hemorrhagic events: Significantly lower in the TEE group at 2.9% 
Vs. 5.5% in the conventional treatment group, P=0.03
– Time to Conversion: Shorter time in the TEE group (mean [±SD], 3.0±5.6 vs. 30.6±10.6 days, P<0.001
– Rate of successful restoration of sinus rhythm: Greater rate with TEE (71.1% vs. 65.2% in the conventional treatment group, P=0.03)

The authors concluded that “The use of transesophageal echocardiography to guide the management of atrial fibrillation may be considered a clinically effective alternative strategy to conventional therapy for patients in whom elective cardioversion is planned.“
Citation: Klein AL, Grimm RA, Murray RD, Apperson-Hansen C, Asinger RW, Black IW, Davidoff R, Erbel R, Halperin JL, Orsinelli DA, Porter TR, Stoddard MF; Assessment of Cardioversion Using Transesophageal Echocardiography Investigators. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med. 2001 May 10;344(19):1411-20. doi: 10.1056/NEJM200105103441901. PMID: 11346805.
Article Name: Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1501035
Journal and year of publication: NEJM, 2015
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population: 1,884 patients with Afib   
Key inclusion criteria:
– Chronic (permanent or paroxysmal) atrial fibrillation or flutter
– Receiving warfarin therapy (for at least 3 months) (INR target 2 – 3)
– Requires interruption for procedure/surgery
– At least one of the CHADS2 stroke risk factors.
Key exclusion criteria:
– Mechanical heart valve.
– Creatinine clearance <30 ml/min
– Platelet count of less than 100×103/cubic millimeter
– Planned cardiac, intracranial, or intraspinal surgery
Intervention Studied:  Bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin/kg)
Control: Matching placebo administered subcutaneously
Outcomes:
– Incidence of arterial thromboembolism: 0.4% in the no-bridging group and 0.3% in the bridging group (P=0.01 for noninferiority)
– Incidence of major bleeding: 1.3% in the no-bridging group and 3.2% in the bridging group (P=0.005)

The authors concluded that “In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding.“
Citation: Douketis JD, Spyropoulos AC, Kaatz S, Becker RC, Caprini JA, Dunn AS, Garcia DA, Jacobson A, Jaffer AK, Kong DF, Schulman S, Turpie AG, Hasselblad V, Ortel TL; BRIDGE Investigators. Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. N Engl J Med. 2015 Aug 27;373(9):823-33. doi: 10.1056/NEJMoa1501035. Epub 2015 Jun 22. PMID: 26095867; PMCID: PMC4931686.
Article Name: Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1611594
Journal and year of publication: NEJM, 2016
Trial Design: Randomized clinical trial
Population: 2,124 patients with Afib undergoing PCI   
Key inclusion criteria:
– Undergone PCI with stent placement
– Documented atrial fibrillation 1 year before screening OR
– Atrial fibrillation that occurred more than 1 year before screening and had been receiving oral anticoagulation for atrial fibrillation for the 3 months immediately preceding the index PCI
Key exclusion criteria:
– History of stroke or transient ischemic attack
– Creatinine clearance of less than 30 ml/L
– Anemia of an unknown cause with a hemoglobin concentration< 10 g/dL
– Any other condition known to increase the risk of bleeding
Intervention Studied:  
Group 1: low-dose rivaroxaban (15 mg/day) +  P2Y12 inhibitor for 12 months
Group 2: very-low-dose rivaroxaban (2.5 mg twice daily) + DAPT for 1, 6, or 12 months
Control:
Group 3: Dose-adjusted vitamin K antagonist (once daily) + DAPT for 1, 6, or 12 months
Outcomes:
– Rates of clinically significant bleeding: lower in the two groups receiving rivaroxaban than in the group receiving standard therapy (16.8% in group 1, 18.0% in group 2, and 26.7% in group 3, P<0.001)
– Rates of death from cardiovascular causes, myocardial infarction, or stroke: similar in the three groups

The authors concluded that “In participants with atrial fibrillation undergoing PCI with placement of stents, the administration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a vitamin K antagonist plus DAPT for 1, 6, or 12 months. The three groups had similar efficacy rates, although the observed broad confidence intervals diminish the surety of any conclusions regarding efficacy.”
Citation: Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, Birmingham M, Ianus J, Burton P, van Eickels M, Korjian S, Daaboul Y, Lip GY, Cohen M, Husted S, Peterson ED, Fox KA. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016 Dec 22;375(25):2423-2434. doi: 10.1056/NEJMoa1611594. Epub 2016 Nov 14. PMID: 27959713.
Article Name: Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1817083
Journal and year of publication: NEJM, 2019
Trial Design: Randomized, double-blinded, placebo-controlled clinical trial
Population: 2,124 patients with Afib undergoing PCI   
Key inclusion criteria:
– Previous, persistent, permanent, or paroxysmal atrial fibrillation and planned long-term use of an oral anticoagulant
– Recent acute coronary syndrome or PCI and planned use of a P2Y12 inhibitor for at least 6 months. 
Key exclusion criteria:
– Use of Anticoagulation for other conditions.
– Severe renal insufficiency
Intervention Studied:  
Group 1: Apixaban + ASA +  P2Y12 inhibitor
Group 2: Apixaban + placebo +  P2Y12 inhibitor
Group 3: VKA + ASA +  P2Y12 inhibitor
Group 4: VKA + placebo +  P2Y12 inhibitor
Control:
See above
Outcomes:
– Primary outcome (major or clinically relevant nonmajor bleeding): 10.5% of the patients on apixaban, vs 14.7% with vitamin K antagonist (P<0.001); 16.1% of the patients receiving aspirin vs 9.0% of those on placebo
– Incidence of death or hospitalization: 23.5% in the apixaban group (23.5%) compared to 27.4% vitamin K antagonist (P=0.002)

The authors concluded that “In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both.”
Citation: Lopes RD, Heizer G, Aronson R, Vora AN, Massaro T, Mehran R, Goodman SG, Windecker S, Darius H, Li J, Averkov O, Bahit MC, Berwanger O, Budaj A, Hijazi Z, Parkhomenko A, Sinnaeve P, Storey RF, Thiele H, Vinereanu D, Granger CB, Alexander JH; AUGUSTUS Investigators. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-1524. doi: 10.1056/NEJMoa1817083. Epub 2019 Mar 17. PMID: 30883055.
Article Name: Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease
URL: https://www.nejm.org/doi/full/10.1056/nejmoa1904143
Journal and year of publication: NEJM, 2019
Trial Design: Randomized placebo-controlled clinical trial
Population: 2,236 patients with Afib and CAD   
Key inclusion criteria:
– Diagnosed with atrial fibrillation and stable coronary artery disease
– CHADS2 scale score of at least 1
Plus, at least one of the following: 
– PCI, with or without stenting, at least 1 year before enrollment
– Angiographically confirmed CAD (with stenosis of ≥50%) not requiring revascularization
– CABG at least 1 year before enrollment. 
Key exclusion criteria:
– History of stent thrombosis
– Coexisting active tumor
Intervention Studied:  
Rivaroxaban monotherapy
Control:
Rivaroxaban + a single antiplatelet agent
Outcomes:
– Trial was stopped early due to increased mortality in combination-therapy group. 
– Primary efficacy end point (composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause): Rivaroxaban monotherapy: 4.14% per patient-year vs Combination therapy: 5.75% per patient-year. Rivaroxaban monotherapy was noninferior to combination therapy; HR: 0.72 (95%CI: 0.55 to 0.95) (P<0.001 for noninferiority)
– Primary safety end point (major bleeding): Rivaroxaban monotherapy: 1.62% per patient-year vs Combination therapy: 2.76% per patient-year. Rivaroxaban monotherapy was superior to combination therapy. HR 0.59 (95%CI: 0.39 to 0.89) ( P=0.01 for superiority).

The authors concluded that “As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease.”
Citation: Lopes RD, Heizer G, Aronson R, Vora AN, Massaro T, Mehran R, Goodman SG, Windecker S, Darius H, Li J, Averkov O, Bahit MC, Berwanger O, Budaj A, Hijazi Z, Parkhomenko A, Sinnaeve P, Storey RF, Thiele H, Vinereanu D, Granger CB, Alexander JH; AUGUSTUS Investigators. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-1524. doi: 10.1056/NEJMoa1817083. Epub 2019 Mar 17. PMID: 30883055.

Valvular diseases

Article Name: Transcatheter versus Surgical Aortic-Valve Replacement in High-Risk Patients
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1103510
Journal and year of publication: NEJM, 2011
Trial Design: Randomized clinical trial
Population: 699 patients with severe AS   
Key inclusion criteria:
– Severe aortic stenosis
– NYHA class II or worse due to AS
– Co-morbidities such that the surgeon and cardiologist co-PIs concurred that the predicted risk of operative mortality was ≥ 15%
Key exclusion criteria:
– Coronary artery disease requiring revascularization
– Left ventricular ejection fraction of less than 20%
– Aortic annulus diameter <18 mm or > 25 mm,
– Severe (4+) mitral or aortic regurgitation (>3+)
– Prosthetic heart valve in any position, prosthetic ring
Intervention Studied:  
Transcatheter aortic-valve replacement with a balloon-expandable bovine pericardial valve (either a transfemoral or a transapical approach)
Control:
Surgical aortic valve replacement
Outcomes:
– Rates of death from any cause:
— At 30 days: 3.4% in the transcatheter group and 6.5% in the surgical group  (P=0.07)
–At 1 year (primary endpoint): 24.2% in the transcatheter group and 26.8% in the surgical group  (P=0.44)
– Rates of major stroke:
— At 1 year: 5.1% in the transcatheter group and 2.4% in the surgical group
(P=0.07)

The authors concluded that “In high-risk patients with severe aortic stenosis, transcatheter and surgical procedures for aortic-valve replacement were associated with similar rates of survival at 1 year, although there were important differences in periprocedural risks.”
Citation: Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Williams M, Dewey T, Kapadia S, Babaliaros V, Thourani VH, Corso P, Pichard AD, Bavaria JE, Herrmann HC, Akin JJ, Anderson WN, Wang D, Pocock SJ; PARTNER Trial Investigators. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011 Jun 9;364(23):2187-98. doi: 10.1056/NEJMoa1103510. Epub 2011 Jun 5. PMID: 21639811.
Article Name: Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1814052
Journal and year of publication: NEJM, 2019
Trial Design: Randomized clinical trial
Population: 1000 patients with severe AS   
Key inclusion criteria:
– Severe calcific aortic stenosis AND:
– NYHA ≥ 2 OR 
– Exercise tolerance test that demonstrates a limited exercise capacity, abnormal BP response, or arrhythmia OR
– Asymptomatic with LVEF <50%
– Considered to be at low surgical risk according to the results of clinical and anatomical assessment
Key exclusion criteria:
– Severe aortic regurgitation (>3+)
– Severe mitral regurgitation (>3+) or ≥ moderate stenosis 
– Pre-existing mechanical or bioprosthetic valve in any position
– Ventricular dysfunction with LVEF < 30%
Intervention Studied:  
Transcatheter aortic-valve replacement with a balloon-expandable valve
Control:
Surgical aortic valve replacement
Outcomes:
– Rate of primary composite endpoint (composite of death, stroke, or rehospitalization at 1 year): 8.5% in TAVR group vs. 15.1% in the surgery group (P<0.001) for noninferiority
– At 30 days, compared to surgery, TAVR resulted in: lower rates of stroke, death, Afib

The authors concluded that “Among patients with severe aortic stenosis who were at low surgical risk, the rate of the composite of death, stroke, or rehospitalization at 1 year was significantly lower with TAVR than with surgery.”
Citation: Mack MJ, Leon MB, Thourani VH, Makkar R, Kodali SK, Russo M, Kapadia SR, Malaisrie SC, Cohen DJ, Pibarot P, Leipsic J, Hahn RT, Blanke P, Williams MR, McCabe JM, Brown DL, Babaliaros V, Goldman S, Szeto WY, Genereux P, Pershad A, Pocock SJ, Alu MC, Webb JG, Smith CR; PARTNER 3 Investigators. Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients. N Engl J Med. 2019 May 2;380(18):1695-1705. doi: 10.1056/NEJMoa1814052. Epub 2019 Mar 16. PMID: 30883058.
Article Name: Transcatheter Mitral-Valve Repair in Patients with Heart Failure
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1806640
Journal and year of publication: NEJM, 2018
Trial Design: Randomized clinical trial
Population: 614 patients with MR and CHF   
Key inclusion criteria:
– Cardiomyopathy with a LVEF of 20 to 50%
– Moderate-to-severe (grade 3+) or severe (grade 4+) secondary mitral regurgitation
– Remained symptomatic (NYHA II, III, or IVa ) despite the use of stable maximal doses of GDMT
Key exclusion criteria:
– CABG, PCI or TAVR within the prior 30 days
– Aortic or tricuspid valve disease requiring surgery or transcatheter intervention
– Physical evidence of right-sided congestive heart failure
Intervention Studied:  
Transcatheter mitral-valve repair plus medical therapy (device group)
Control:
Medical therapy alone
Outcomes:
– Primary outcome (rate of all hospitalizations for heart failure within 24 months):
35.8% per patient-year in the device group vs 67.9% per patient-year in the control group (P<0.001)
– Death from any cause within 24 months: 29.1% of the patients in the device group vs 46.1% in the control group (P<0.001)

The authors concluded that “Among patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy, transcatheter mitral-valve repair resulted in a lower rate of hospitalization for heart failure and lower all-cause mortality within 24 months of follow-up than medical therapy alone. The rate of freedom from device-related complications exceeded a prespecified safety threshold.”
Citation: Stone GW, Lindenfeld J, Abraham WT, Kar S, Lim DS, Mishell JM, Whisenant B, Grayburn PA, Rinaldi M, Kapadia SR, Rajagopal V, Sarembock IJ, Brieke A, Marx SO, Cohen DJ, Weissman NJ, Mack MJ; COAPT Investigators. Transcatheter Mitral-Valve Repair in Patients with Heart Failure. N Engl J Med. 2018 Dec 13;379(24):2307-2318. doi: 10.1056/NEJMoa1806640. Epub 2018 Sep 23. PMID: 30280640.
Article Name: Early Surgery versus Conventional Treatment for Infective Endocarditis
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1112843
Journal and year of publication: NEJM, 2012
Trial Design: Randomized clinical trial
Population: 76 patients with infective endocarditis   
Key inclusion criteria:
– Diagnosis of Infective endocarditis according to the modified Duke criteria
– Severe mitral valve or aortic valve disease and vegetation with a diameter greater than 10 mm
Key exclusion criteria:
– Moderate-to-severe congestive heart failure
– Infective endocarditis complicated by heart block
– Annular or aortic abscess
– Destructive penetrating lesions requiring urgent surgery
– Fungal endocarditis
– Infective endocarditis involving a prosthetic valve
– Right-sided vegetations
Intervention Studied:  
Early surgery
Control:
Medical therapy
Outcomes:
– Primary endpoint occurrence (in-hospital death and embolic events that occurred within 6 weeks after randomization): 3% in the early-surgery group vs  23% in the conventional-treatment group (P=0.03)
– The rate of the composite endpoint of death from any cause, embolic events, or recurrence of infective endocarditis at 6 months: 3% in the early-surgery group vs 28% in the conventional-treatment group (P=0.02)

The authors concluded that “As compared with conventional treatment, early surgery in patients with infective endocarditis and large vegetations significantly reduced the composite end point of death from any cause and embolic events by effectively decreasing the risk of systemic embolism.”
Citation: Kang DH, Kim YJ, Kim SH, Sun BJ, Kim DH, Yun SC, Song JM, Choo SJ, Chung CH, Song JK, Lee JW, Sohn DW. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med. 2012 Jun 28;366(26):2466-73. doi: 10.1056/NEJMoa1112843. PMID: 22738096.

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