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REWIND Trial: Dulaglutide and cardiovascular outcomes in type 2 diabetes

The REWIND trial aimed to assess the cardiovascular (CV) safety of dulaglutide, a glucagon-like peptide-1 (GLP-1) agonist, in patients with type 2 diabetes mellitus at higher risk for CV events. The trial involved 9,901 patients and randomized them to dulaglutide and compared outcomes with placebo. The results of the REWIND trial indicated that once-weekly dulaglutide administered via subcutaneous injection is superior to placebo in improving glycemic control and reducing CV events in patients with type 2 diabetes and higher CV risk. There was also a significant reduction in nonfatal strokes and improvement in the composite renal outcomes. Source: Lancet

MET-REMODEL Trial: Metformin on LVH in patients with CAD without diabetes

MET REMODEL Trial

2019, MET-REMODEL Trial: Metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes, Source: EHJ

VADT Trial: Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes

VADT Trial:

2009, VADT Trial: Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes, Source

CAPRICORN Trial: Effect of carvedilol on outcome after MI in patients with LV dysfunction

CAPRICORN Trial

2001, Effect of carvedilol on outcome after MI in patients with LV dysfunction. Source

ALIVE Trial: Amiodarone as Compared with Lidocaine for Shock-Resistant Ventricular Fibrillation

ALIVE trial

2002, ALIVE Trial Visual Summary: Amiodarone as Compared with Lidocaine for Shock-Resistant Ventricular Fibrillation. NEJM

ARREST Trial: Amiodarone for Resuscitation after Out-of-Hospital Cardiac Arrest Due to Ventricular Fibrillation

ARREST Trial: 1999, Amiodarone for Resuscitation after Out-of-Hospital Cardiac Arrest Due to Ventricular Fibrillation. NEJM

RE-SPECT ESUS Trial: Dabigatran for Prevention of Recurrent Stroke after Cryptogenic Stroke

2019, RE-SPECT ESUS Trial Summary: Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source | Source: NEJM

OCTAVE Trial: Omapatrilat and enalapril in patients with hypertension

OCTAVE Trial summary

Source: American journal of hypertension

ALCOHOL-AF Trial: Impact of Alcohol Abstinence in Moderate Drinkers With Atrial Fibrillation

The goal of ALCOHOL-AF trial was to assess effect of alcohol abstinence on recurrence of AF and AF burden in patients with paroxysmal or persistent AF. The trial showed results significantly in favor of alcohol abstinence. Take a look at the visual abstract.

Source: ACC

PARTNER 3 Trial (2019): Transcatheter Aortic-Valve Replacement With a Balloon-Expandable Valve in Low-Risk Patients

PARTNER 3 Trial Summary: Mack MJ et al. randomized 1000 patients (mean age, 73 years), male population (69.3%), with lower STS-PROM scores (mean 1.9%) and fewer comorbidities (low-risk surgical candidates) to either TAVR with balloon-expanded valve or surgery. The primary objective was to compare outcomes with TAVR vs. surgical AV replacement in patients with severe AS and low surgical risk. Based on the results the composite of death from any cause, stroke, or rehospitalization was significantly lower in patients undergoing TAVR as compared with surgery. (P<0.001 for noninferiority, P=0.001 for superiority). The authors of PARTNER 3 trial concluded that among patients with severe AS 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.

Source: NEJM

CARRESS-HF Trial (2012): Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome

CARRESS HF Trial Summary: Bart et al. randomized 188 patients with decompensated acute heart failure and worsening renal function (Increase in serum creatinine ≥0.3 mg/dL) – [cardiorenal syndrome] to ultrafiltration (fluid removal of 200 mL/hr, n=94) or medical therapy (Protocol driven IV diuresis, n=94). The primary objective was to assess if ultrafiltration improves volume removal, renal function, and reduce HF complications when compared to medical therapy in acutely decompensated heart failure and cardiorenal syndrome. The results showed worsening of change in serum creatinine level and change in weight at day 4 in the ultrafiltration group (P=0.003). The authors of CARRESS HF trial concluded that in patients with acute decompensated HF and cardiorenal syndrome, ultrafiltration is associated with more adverse events, worsening renal function, and no change in weight when compared to medical therapy.

Source: NEJM

BRIDGE Trial (2015): Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation

BRIDGE Trial visual abstract

BRIDGE Trial Summary: Douketis JD et al. randomized 1,884 patients on warfarin (INR 2-3 for ≥3m) with AF or A-flutter and CHADS2 Score ≥1 to LMWH: dalteparin (100 IU/kg BID) or placebo. The objective was to assess if bridging anticoagulation reduce rates of arterial thromboembolism compared to no bridging in patients with atrial fibrillation undergoing an invasive procedure. The results showed noninferiority (P=0.01) of the primary outcome (TIA or stroke or arterial embolism) in patients with no bridging as compared with bridging. The authors of the BRIDGE trial concluded that among patients with low- and intermediate-risk atrial fibrillation receiving anticoagulation and undergoing an invasive procedure, periprocedural bridging anticoagulation with LMWH did not reduce the incidence of arterial thromboembolism when compared to no bridging, but did increase the risk of major bleeding.

Source: NEJM

VALIANT Trial (2003): Valsartan, Captopril, or Both in Myocardial Infarction

VALIANT Trial Summary visual abstract

VALIANT Trial Summary: Pfeffer et al. randomized 14,703 patients with acute MI within prior 10 days complicated by HF and/or LVEF ≤35% to either valsartan or captopril or combination of both. The objective was to assess the efficacy of ARBs compared with ACE-I in patients in the post-MI period complicated by HF and/or LV systolic dysfunction. The results of the trial showed similar mortality rates among both ACE and ARB groups along with similar rates in combination of both.  The authors of the VALIANT trial concluded that Valsartan was as effective as captopril in improving survival among patients with HF and/or LV dysfunction in the post-MI period.

Source: NEJM

COMMANDER HF Trial (2018): Rivaroxaban in Patients with Heart Failure, Sinus Rhythm, and Coronary Disease

COMMANDER HF trial

COMMANDER HF Trial Summary: Zannand F et al. randomized 5,022 patients with coronary artery disease and heart failure to undergo treatment with either rivaroxaban or a placebo. The primary objective of the study was to assess if rivaroxaban could reduce thrombin production and improve outcomes in patients with CAD and HF. The results showed that rivaroxaban did not affect the composite

Source: NEJM

TRED-HF Trial (2019): Withdrawal of treatment for HF in patients with recovered DCM

TRED-HF visual abstract

TRED-HF Trial Summary: Halliday et al. randomized 51 patients with dilated cardiomyopathy (LVEF<40%) who recovered with the improvement of symptoms to either continual treatment with HF medications or withdrawal of HF therapy. The objective was to assess the safety of withdrawing treatment in patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered. The results showed significant replase of HF in patients who were taken of HF management. (P <0.0001) The authors of TRED-HF trial concluded that withdrawal of HF medications among patients with DCM who had recovered their LV function results in relapse of HF, and should probably be avoided indefinitely unless necessary.

Source: Lancet

DECLARE TIMI 58 Trial (2019): Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

DECLARE TIMI 58 Trial Summary: Wiviott et al. randomized 17,160 patients with DMII (HbA1c 6.5-12%) who had multiple risk factors for or had established atherosclerotic CV disease to either dapagliflozin or a placebo. Their objective was to assess the cardiovascular safety profile of dapagliflozin, a selective inhibitor of SGLT2 in patients with type 2 diabetes. The results were promising and showed a significant decrease in CV death and HF hospitalizations (P=0.005). No difference was noted in the major adverse CV events. The authors of DECLARE TIMI 58 trial concluded that in patients with type 2 DM who had or were at risk for atherosclerotic CV disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE but did result in a lower rate of CV death or hospitalization for heart failure.

Source: NEJM

MOMENTUM 3 Trial (2018): Magnetically Levitated Cardiac Pump in Heart Failure

MOMENTUM 3 trial visual abstract

MOMENTUM 3 Trial Summary: Mehra et al. randomized 366 patients with advanced HF (NYHA class III-IV, LVEF ≤ 25%), inotrope dependant, cardiac index < 2.2 without inotropes to either HeartMate III (centrifugal-flow LVAD) or HeartMate II (axial-flow LVAD). Their objective was to assess if is a magnetically levitated centrifugal-flow LVAD is superior to an axial-flow LVAD with regards to reoperation for device malfunction or disabling stroke in patients with advanced HF. The results showed the superiority of HeartMate III in terms of freedom from device failure. No differences in stroke were noticed. The authors of MOMENTUM 3 trial concluded that implantation of a fully magnetically levitated centrifugal-flow pump was associated with better outcomes at 6 months than was implantation of an axial-flow pump, primarily because of the lower rate of reoperation for pump malfunction.

Source: NEJM

TNT Trial (2005): Intensive lipid lowering with atorvastatin in patients with Stable CAD

TNT Trial visual abstract

TNT Trial Summary: LaRosa et al. randomized 10,001 patients with CAD defined by prior MI, prior or current anginal symptoms with evidence of CAD, prior revascularization to either high dose 80 mg atorvastatin or low dose 10 mg atorvastatin. Their objective was to assess if atorvastatin 80 mg PO daily have a greater reduction in CV events when compared to 10 mg atorvastatin in patients with stable CAD and hyperlipidemia. The results showed a significant decrease in major CV events. (P<0.001; NNT 45) These events were composite of CAD mortality, MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke. The authors of the TNT trial concluded that intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit when compared to low-dose daily 10 mg atorvastatin.

Source: NEJM

RE-DUAL PCI Trial (2017): Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation

RE-DUAL PCI Trial Summary

RE-DUAL PCI trial was a multi-center, randomized trial that compared the outcomes of triple and dual therapy as well as warfarin and dabigatran. Patients with AF who have undergone PCI (N=2,725) were randomly assigned to either triple therapy (aspirin, warfarin and a P2Y12 inhibitor) or dual therapy (dabigatran 150mg BD or 110mg BD and a P2Y12 inhibitor). In the triple therapy group, aspirin was discontinued 1 month in those who received a bare metal stent and after 3 months in those who received a drug eluting stent. In the warfarin group, the dose of warfarin was adjusted to maintain the INR between 2 and 3. It is important to note that elderly patients outside of the US were assigned to either the 110mg BD group or warfarin group (not dabigatran 150mg BD).

The primary end-point of the study was the first ISTH major bleed or clinically relevant non-major bleed. The trial also tested for noninferiority in the efficacy of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin and the occurrence of a composite of MI, stroke, systemic embolization, death, or unplanned revascularization. The mean duration of treatment with the anticoagulants was 12.3 months, and the mean follow up was 14.0 months. Of the patients enrolled, 50.5% received a PCI for ACS. Most patients received clopidogrel, and only 12.0% received ticagrelor. In the triple therapy group, the mean percentage of time within the therapeutic INR range was 64%

Compared with the warfarin group, the primary safety endpoint occurred in a smaller proportion of the dual therapy group with 110mg BD of dabigatran (15.4%, HR 0.52, 95% CI 0.42-0.63, P<0.001), followed by the 150mg BD group (20.2%, HR 0.72, 95% CI 0.58-0.88, P<0.001). The incidence of the primary endpoint in the warfarin group was 26.9% in all patients and 25.7% when excluding elderly patients outside the US. The incidence of the composite efficacy endpoint in the combined dabigatran group and triple therapy groups were 13.7% and 13.4% respectively (HR 1.04, 95% CI 0.84-1.29, P=0.005 for noninferiority).

Summarized by Dr. Tarek Nafee

WOEST Trial (2013): Clopidogrel with or without aspirin in patients taking OAC and undergoing PCI

WOEST Trial visual abstract

WOEST Trial Summary

WOEST trial was an open-label randomized controlled trial in patients who were on oral anticoagulants and underwent PCI with coronary stenting. Patients who were on oral anticoagulants and underwent PCI with coronary artery stenting (N=573) were randomly assigned to 2 groups: Dual therapy (Clopidogrel and OAC) or triple therapy (Aspirin, clopidogrel, and OAC).

The primary outcome observed was any bleeding episode that occurred within 1 year of PCI. The secondary end point was a composite of death, myocardial infarction, stroke, target-vessel revascularization and stent thrombosis. The allocated antiplatelet treatment was continued for at least one month and up to 1 year for those patients who received a bare metal stent. For those who received a drug-eluting stent or had ACS clopidogrel was given for at least a year. The occurrence of any bleeding (primary endpoint) in the double therapy group was 19.4% as compared to triple therapy group which was 44.4%, with a HR of 0.36 (p <0.0001, 95% CI 0.26-0.50).

TIMI major and minor bleeding events occurred in 14% and 31.3% of the double and triple therapy groups respectively with a HR of 0.40 (p <0.0001, 95% CI 0.27-0.58). The composite secondary endpoint was observed in 11.1% and 17.6% of patients in the double and triple therapy groups respectively (HR 0.60, p =0.025, 95% CI 0.38-0.94). The WOEST trial investigators showed that the use of dual therapy reduced the risk of bleeding by the end of 1 year in patients who underwent PCI. An interesting finding in the study also showed that rates of thrombotic and thromboembolic events did not differ between the patients who did and did not receive aspirin.

Summary by:
Dr Tarek Nafee, MD
BIDMC, Mass

AF-CHF Trial (2008): Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure

 

AF-CHF Trial Summary: Roy D et al. randomized 1,376 patients with nonvalvular atrial fibrillation and HFrEF (LVEF ≤35% and NYHA II-IV symptoms) were randomized to rhythm control (pharmacologic or electrical approach) or rate control (target <80 bpm at rest). The objective was to assess if rhythm-control reduce CV mortality in patients with AF and HFrEF as compared to rate control. The results showed no difference in terms of CV mortality in both groups. (P=0.59) The authors of the AF CHF trial concluded that among patients with AF and HFrEF, rhythm-control did not reduce cardiovascular mortality but did reduce AF related hospitalizations, as compared to rate control.

Source: NEJM

SPRINT MIND Trial (2019): Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia

SPRINT MIND Trial visual abstract

SPRINT-MIND Trial Summary: Authors of this trial randomized 9,361 adults aged 50 years or older with hypertension but without diabetes or history of stroke to either intensive control (SBP < 120 mmHg) or standard control (SBP < 140 mmHg). The objective was to assess if intensive blood pressure control reduces the occurrence of dementia as compared moderate control. The results showed no difference in terms of adjudicated probable dementia (P=0.10). However, it did show a significant decrease in mild cognitive impairment in patients whose BP was intensively controlled. (P=0.007) The authors of SPRINT-MIND trial concluded that in ambulatory adults with hypertension, intensive BP control (SBP < 120 mmHg) did not reduce the risk of probable dementia but significantly reduced mild cognitive impairment.

Source: JAMA

FAME 2 Trial (2012): FFR-Guided PCI vs Medical Therapy in Stable CAD

Source: NEJM

FAME Trial (2009): FFR vs Angiography for Guiding PCI

FAME Trial summary visual abstract

Source: NEJM

MADIT-II (2002): Prophylactic ICD in Patients with Myocardial Infarction and Reduced Ejection Fraction

Source: NEJM

IMPROVE IT (2015): Ezetimibe + statin in acute coronary syndrome (ACS)

Source: NEJM

PROVE IT Trial (2004): Intensive vs Moderate Lipid Lowering with Statins after ACS

PROVE IT trial summary

PROVE IT Trial Summary

In 2004, Dr. Cannon et al. randomly assigned over 4,162 patients with acute coronary syndrome within past 10 days to either high dose atorvastatin 80 mg or moderate dose 40 mg pravastatin. Their goal was to assess all cause mortality and major cardiovascular events in these patients. Patients who received high dose atorvastatin showed almost 16% absolute reduction in terms of primary outcome (P=0.005) as compared with pravastatin group. These results were similar to the previously performed MIRACL trial that reported similar 16% absolute reduction when atorvastatin was compared with placebo.

The authors concluded that among patients with recent acute coronary syndrome, an intensive lipid-lowering statin therapy provides greater protection against death or major cardiovascular events than does a standard regimen.

The current ESC, as well as ACC/AHA guidelines recommend starting all patients with ACS on high dose statin therapy. 

Grade IA. Source

NEJM

SMART-DATE Trial (2018): 6 vs 12 months of DAPT after PCI with DES in ACS

SMART-DATE trial summary

The SMART-DATE trial tested the hypothesis as to whether 6 months of dual antiplatelet therapy (DAPT) is non-inferior to 12 months of DAPT in patients who underwent percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and require DAPT. Source

SMART-DATE Trial Key Points:

6 months DAPT was found to be noninferior in terms of major cardiovascular events (MACCE). However, myocardial infarction was found to be more recurrent in patients undergoing a shorter duration of DAPT compared to complete 12 months.

The SMART-DATE trial tested the shorter duration and is comparable to DAPT trial which tested 18 months duration of DAPT versus 12 months standard management.

Guidelines based on SMART-DATE trial

The last ACC/AHA guidelines were before this trial and recommends:

Complete 12 months of DAPT in patients who underwent PCI with either DES or BMS. (recommendation: 1a, LOE: A)

For patients who have complications such as bleeding, guidelines recommend that DAPT can be discontinued after 6 months.
(recommendation: IIa)

For patients at low risk of bleeding, DAPT can be continued beyond 12 months. (recommendation: IIa)

http://www.onlinejacc.org/content/68/10/1082

MIRACL Trial (2001): Atorvastatin use for early recurrent ischemic events in ACS

MIRACL Trial - atorvastatin in acute coronary syndrome

2001, Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA

MIRACL Trial Key Points:

  1. In addition to lowering the cholesterol and LDL levels, statins have been coined to lower the platelet aggregability, thrombus deposition and vascular inflammation as well.
  2. This observation led to the hypothesis that statins might be useful in lowering the recurrence of ischemic events after UA or NSTEMI.
  3. The MIRACL trial tested this hypothesis and showed 2.6% absolute reduction in recurrent ischemic events after early initiation of atorvastatin in patients who presented with UA or NSTEMI.

Guidelines changes

The 2014 ACC/AHA guidelines on NSTEMI recommends:

Initiate or continue high-intensity statin therapy in patients with no contraindications (Grade I, LOE: A)

Obtain a fasting lipid profile, preferably within 24 h (Grade IIa, LOE: C)

http://www.ncbi.nlm.nih.gov/pubmed/25260718

VANISH Trial (2016): VT Ablation vs Escalation of Antiarrhytmic drugs

VANISH Trial on VT ablation vs medical therapy

2016, VANISH Trial – Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs, NEJM

VANISH Trial Key Points:

  1. Patients with ischemic cardiomyopathy and LVEF < 35% are candidated for ICD implantation but high VT burden in these patients is associated with higher mortality despite ICD placement.
  2. Previously, antiarrhythmic therapy (AAT) specifically amiodarone has been used to suppress VT in these patients. However, newer data suggested VT ablation in addition to AAT lowers mortality further.
  3. The VANISH trial answered this particular question of using VT ablation rather than escalating AAT for patients with recurrence of VT despite being on AAT.
  4. The trial showed 10% absolute decrease in composite outcome of death, VT storm (3 more episodes of VT within 24 hours), and appropriate ICD shock after 2 years of follow up.

Guideline Changes based on VANISH trial:

The 2017 AHA/ACC/HRS guidelines recommend:

In patients with prior myocardial infarction and recurrent episodes of symptomatic sustained ventricular tachycardia (VT), or who present with VT or ventricular fibrillation storm and have failed or are intolerant of amiodarone (Level of Evidence B-R) or other antiarrhythmic medications (Level of Evidence B-NR), catheter ablation is recommended.

https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2017/10/29/08/56/2017-guideline-for-management-of-patients-with-ventricular-arrhythmias

CANTOS Trial (2017): Canakinumab for Atherosclerotic Disease

CANTOS trial explaining role of Canakinumab in coronary artery disease

2017, CANTOS Trial: Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease, NEJM

The CANTOS trial evaluated the inflammatory nature of coronary artery disease where hypothesis was that decreasing the inflammation marker such as interleukin 1B will result in lower incidence of cardiovascular events. For this purpose, canakinumab which is a monoclonal antibody against IL-1B was tested against a placebo. The only dose that achieved significance after multiplicity-adjusted threshold for statistical significance was the 150 mg group.

The patients that responded best were those who achieved on-treatment hsCRP concentrations less than 2 mg/L. The authors observed a 25% decrease in major cardiovascular events in these patients. This was in contrast to those who continued to elevated hsCRP levels despite treatment. Based on this observation, the CANTOS trial authors concluded, “the magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment.”

With CANTOS trial results, Dr. Paul Ridker et al. decided to take a step forward and tried to inhibit the chain of inflammatory markers including IL-1, IL6 and CRP. They utilized methotrexate for this purpose and described their results in the CIRT trial.

FOURIER Trial (2017): Evolocumab and Clinical Outcomes in Patients with CVD

evolocumab PCSK9 inhibitor role in atherosclerotic disease - FOURIER Trial

FOURIER Trial Key Points:

  1. FOURIER trial established the role of PCSK9 inihibitor therapy in reducing future cardiovascular events and mortality.
  2. Evolocumab showed benefit in terms of cardiovascular disease but didn’t show any mortality benefit.
  3. These agents were utilized in patients who were already on moderate to high intensity statin therapy.
  4. PCSK9 inhibition was well-tolerated without excess new-onset diabetes or neurocognitive effects despite dramatic LDL reduction.

Guidelines on PCSK9 inhibition – ACC 2017 Update for Non-Statin Therapy

  1. If patients with clinical ASCVD and comorbidities require >25% additional lowering of LDL-C, a PCSK9 inhibitor may be preferred as the initial non-statin agent.
  2. If patients with clinical ASCVD and baseline LDL-C ≥190 mg/dL require >25% additional lowering of LDL-C or have additional comorbidities as defined in the previous text, a PCSK9 inhibitor may be preferred as the initial non-statin agent.
  3. If high-risk patients with baseline LDL-C ≥190 mg/dL require additional LDL-C lowering (<50% reduction in LDL-C, may consider LDL-C ≥100 mg/dL or non–HDL-C ≥130 mg/dL) after the addition of a single non-statin agent (i.e., ezetimibe) to maximally tolerated statin therapy, it is reasonable to consider the addition of a second non-statin agent (i.e., ezetimibe plus PCSK9 inhibitor).
  4. Read full guidelines at ACC

Source: NEJM

FRISC II Trial (2006): Invasive vs non-invasive treatment in unstable CAD

FRISC trial on NSTEMI
FRISC II Trial Visual Summary

1999, Invasive compared with non-invasive treatment in unstable coronary-artery disease, The Lancet

The FRISC II trial established the role of early intervention in patients with UA/NSTEMI. The study compared maximal medical therapy or non invasive approach with intervention and showed significant decrease in the incidence of MI.

The combine MI and/or mortality was found to be significantly lower after 5 years in patients who underwent invasive approach compared with non invasive approach 19.9% vs. 24.5% (RR 0.81; 95% CI 0.69–0.95; P=0.009). The early vs late intervention question was later answered by the TIMACS trial.

TIMACS Trial (2009): Early versus Delayed Invasive Intervention in ACS

2009, TIMACS trial: Early vs delayed invasive intervention in acute coronary syndrome, NEJM

TIMACS trial addressed the question of when to intervene in patients who come to hospital with unstable angina and/or NSTEMI. Although the results showed no benefits of early intervention but in subgroup analysis, the results were significantly in favor of performing early intervention in high risk patients (GRACE score> 140). The GRACE ACS score prognosticates patients with ACS and is a useful predictor of 6 months mortality.

The ABOARD and OPTIMA trial were done during the same year but these were smaller trials with limited study population compared to TIMACS trial. The FRISC II trial (1999) also showed benefits of early intervention within 7 days in terms of 5 year recurrence of MIs but the comparison was with patients who were treated with maximal medical therapy before intervention.

The 2014 ACC/AHA guidelines on NSTE-ACS recommends early invasive strategy (within 24 hours of admission) over a delayed invasive strategy (within 25 to 72 hours) for initially stabilized high-risk patients with NSTE-ACS.

IABP-SHOCK II Trial (2012): Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock

balloon pump in cardiogenic shock - IABP SHOCK II trial results

2012, Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock, NEJM

RESPECT Trial (2013): Closure of PFO versus Medical Therapy after Cryptogenic Stroke

2013, Closure of Patent Foramen Ovale versus Medical Therapy after Cryptogenic Stroke, NEJM

RESPECT Trial Key Points:

  1. Patients with cryptogenic stroke have higher incidence of PFO compared to general population. This led to the concept that closing PFO might be beneficial in terms of preventing recurrence of stroke in this population.
  2. The initial CLOSURE I trial showed no benefits of closing PFO percutaneously. In contrast, RESPECT trail showed benefits of PFO closure with the Amplatzer device.
  3. Patients deriving the maximum benefit from PFO closure were those with high grade shunt with presence of left atrial aneurysm.
  4. CLOSE and REDUCE are two more recent trials that show similar benefits of PFO closure over medical management.

Guideline changes based on the RESPECT Trial:

The last AHA/ASA guidelines were from 2014 which were published based on results of CLOSURE I and RESPECT trial. They recommended:

For patients with an ischemic stroke or TIA and a PFO who are not on anticoagulation therapy, antiplatelet therapy is recommended. (Class I, LOE B)

For patients with an ischemic stroke or TIA and both a PFO and a venous source of embolism, anticoagulation is indicated, depending on stroke characteristics. (Class I, LOE A). When anticoagulation is contraindicated, an inferior vena cava filter is reasonable. (Class IIa, LOE C).

For patients with a cryptogenic ischemic stroke or TIA and a PFO without evidence for DVT, available data does not support a benefit for PFO closure. (Class III, LOE A)

In the setting of PFO and DVT, PFO closure by a transcatheter device might be considered, depending on the risk of recurrent DVT. (Class IIb, LOE C)

http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@smd/documents/downloadable/ucm_462196.pdf

SURVIVE Trial (2007): Levosimendan vs dobutamine for patients with acute decompensated heart failure

survive trial levosimendan visual abstract summary

2007, Levosimendan in acute decompensated heart failure, JAMA

ULTIMATE Trial: IVUS vs Angiography-Guided Implantation of DES

ULTIMATE Trial visual abstract summary
Visual abstract of the ULTIMATE trial

ULTIMATE Trial Key Points:

  1. At 12 months, patients undergoing IVUS guided PCI had lower rate of target vessel failure when compared to traditional andiography guided PCI.
  2. Enrolled patients had complex coronary disease including multi vessel disease as well as bifurcation blockages.
  3. The study re-emphasized the rationale for the more routine use of IVUS to guide PCI.

Current Guidelines on Use of IVUS for PCI

ESC guidelines:

  1. IVUS in selected patients for optimizing stent implantation. (Class IIa, LOE: B)
  2. IVUS to assess severity and guide management of unprotected left main stem disease. (Class IIa, LOE: C)

AHA/ACC Guidelines

  1. IVUS reasonable for assessment of angiographically indeterminate left main CAD. (Class IIa, LOE: B)

Source

2018, IVUS vs angiography guided implantation of DES, JACC

AVERT Trial: Apixaban to Prevent VTE in Patients with Cancer

AVERT trial Apixaban

2018, Apixaban to Prevent Venous Thromboembolism in Patients with Cancer, NEJM

The AVERT trial evaluated the use of apixaban for preventing venous thromboemboli such as deep venous thrombosis and pulmonary embolism in patients with cancer who were scheduled to start chemotherapy. These patients were at high risk of VTE based on the Khorana score.

The point that differentiated AVERT trial from other similar trials of using drugs for prevention of VTE in cancer patients was that it enrolled patients who did not have a history of VTE and the primary target was to lower the first incidence of VTE. In comparison, the CLOT and Hokusai VTE trials studied the use of LMWH for secondary prevention of VTE.

The study did show benefits of apixaban in preventing the first episode of VTE but this was countered by significant increase in bleeding risk. Currently based on guidelines, LMWH are preferred agents of choice for secondary prevention of VTE in patients with cancer. The 2012 CHEST guidelines on antithrombotic therapy recommend:

In patients with DVT of the leg and cancer, we suggest LMWH over VKA therapy (Grade 2B). In patients with DVT and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2B).

Source

BLOCK HF: Biventricular versus Right Ventricular Pacing in Heart Failure Patients with AV Block

 

2013, Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block, NEJM

BLOCK HF Trial Summary

The Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) trial is a prospective, multicentric, double-blinded, industry (Medtronic) sponsored, randomized controlled trial conducted to evaluate role of biventricular (BiV) pacing in patients with high-degree atrioventricular (AV) block (as a surrogate for obligatory RV pacing) and LV systolic dysfunction in comparison to standard right ventricular (RV) pacing.

691 patients were randomized 1:1 to BiV pacing (n=349) or RV pacing (n=342) in 58 centers in the United States and 2 centers in Canada between 2003 and 2011. Initially, patients enrolled in the study received pacemakers only. However, with evidence supporting the use of implantable cardioverter–defibrillator (ICD) therapy in patients with heart failure and left ventricular dysfunction for the primary prevention of sudden cardiac death, the protocol was revised in December 2005 to allow ICD implantation in such patients.

The study included patients with Class I or IIa indication for pacemaker implantation owing to high-degree AV block who also had NYHA class I-III heart failure with LVEF <= 50%. High-degree AV block was defined as documented complete AV block (including patients who had AV node ablation) or demonstration of second-degree AV block or PR interval >= 300 ms when paced at 100 beats/min. It excluded previous recipient of a cardiac implantable electrical device, patients with unstable angina or acute myocardial infarction, percutaneous or surgical coronary intervention within 30 days before enrollment, valvular disease with an indication for valvular repair or replacement and patients with an indication for a CRT device.

Baseline characteristics were similar in both groups. Mean LVEF was 40 +/- 8.3%. Most were NYHA II or III patients. Baseline mean heart rate was 68.8 bpm, QRS duration was 123 ms. 48.8% had third-degree AV block, 31.6% had second-degree and 19.3% had first-degree AV block. 29.8% had left bundle branch block and 21.6% had right bundle branch block. The mean ventricular pacing in both groups was more than 97%.

After mean follow-up of 37 months, there was a statistically significant difference in favor of BiV pacing (45.8%) over RV pacing (55.6%) in the primary outcome of time to death from any cause, an urgent care visit for heart failure (HF) that required IV therapy, or >= 15% increase in left ventricular end-systolic volume index (surrogate marker for LV remodeling) (HR 0.74; 95% credible interval, 0.60 to 0.90). When patients were stratified according to the type of device implanted- pacemaker or ICD, the results were similar (for BiV pacing: HR in pacemaker only cohort was 0.73; 95% credible interval, 0.58 to 0.9; and HR in ICD cohort was 0.75; 95% credible interval, 0.57 to 1.02).

Secondary outcome of – death or urgent care visit for HF, death or hospitalization for HF, and HF hospitalization alone were all in favor for BiV pacing. But death alone was similar for the two groups.

The study concluded that BiV pacing provided significant clinical benefit over RV pacing in patients with LV dysfunction and AV block who required ventricular pacing.

In patients with high-degree AV block and HF with LV systolic dysfunction, the BiV pacing is associated with a approximately 10% absolute risk reduction in death, urgent HF care and adverse LV remodeling compared with RV pacing, and this is primarily driven by reduced HF hospitalizations and reduced LV remodeling.

Authors:
Trial summarized by Mansour Almunajem, MD
Reviewed by Saurabh Joshi, MD
Affiliation: Department of Cardiovascular disease, University of Connecticut Health Center

EXCEL: Everolimus-Eluting Stents or Bypass Surgery for Left Main CAD

2016, Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Artery Disease, NEJM

EXCEL Trial Summary

Summarized by Lina Ya’qoub, MD – Cardiovascular disease fellow at Louisiana State University

Methods

The Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial is an international, open-label, non-inferiority, multicenter randomized trial that compared everolimus-eluting stents with CABG in patients with left main coronary artery disease. Inclusion criteria were stenosis of the left main coronary artery of 70% or more, as estimated visually, or stenosis of 50-69% if determined by means of noninvasive or invasive testing to be hemodynamically significant, and a consensus among the members of the heart team regarding eligibility for revascularization with either PCI or CABG. In addition, participants were required to have low-to-intermediate anatomical complexity of coronary artery disease, as defined by a site-determined SYNTAX score, with low score being <=22 and intermediate score being 23-32.

Randomization

Among the 1905 patients who underwent randomization, 948 were assigned to the PCI group and 957 to the CABG group. Baseline clinical and angiographic characteristics were well balanced between the groups. Among the 948 patients assigned to the PCI group, 942 underwent revascularization; PCI was the first procedure in 935 patients. A mean of 2.4 stents with a mean total stent length of 49.1 mm were implanted per patient; 99.2% of the stents implanted were everolimus-eluting stents. Among the 957 patients assigned to the CABG group, 940 underwent revascularization; CABG was the first procedure in 923 patients. A mean of 2.6 grafts per patient were placed; an internal thoracic artery graft was used in 98.8% of the patients.

Follow-up/end-point events

The median duration of follow-up was 3.0 years (interquartile range, 2.4 to 3.0) in both groups. The primary composite end-point event of death, stroke, or myocardial infarction at 3 years occurred in 15.4% of the patients in the PCI group and in 14.7% of the patients in the CABG group (difference, 0.7 percentage points; upper 97.5% confidence limit, 4.0 percentage points; P=0.02 for noninferiority; hazard ratio, 1.00; 95% confidence interval [CI], 0.79 to 1.26; P=0.98 for superiority).

At 30 days, the composite end-point event of death, stroke, or myocardial infarction had occurred in 4.9% of the patients in the PCI group and in 7.9% of the patients in the CABG group (difference, −3.1 percentage points; upper 95.0% confidence limit, −1.2 percentage points; P<0.001 for noninferiority).At 3 years, the composite end-point event of death, stroke, myocardial infarction, or ischemia-driven revascularization had occurred in 23.1% of the patients in the PCI group and in 19.1% of the patients in the CABG group (difference, 4.0 percentage points; upper 95% confidence limit, 7.2 percentage points; P=0.01 for noninferiority).

Author Comments

Several studies have shown that outcome and safety of left main disease percutaneous coronary intervention (PCI) is similar to caronary artery bypass graft (CABG) in selected patients. The EXCEL trial aim was to assess major adverse cardiac events (death, stroke, MI) for PCI versus CABG over 3 years in patients with low-intermediate syntax scores. This randomized controlled trial proved that PCI was non-inferior to CABG in this population.

LIPID: Pravastatin in patients with coronary heart disease

1998, Pravastatin in patients with coronary heart disease, NEJM

PIONEER-HF: Angiotensin-neprilysin inhibition in acute decompensated heart failure

2018, Angiotensin-neprilysin inhibition in acute decompensated heart failure, NEJM

Ancillary DIG: Digoxin in HFpEF

2006, Digoxin in Heart failure with preserved ejection fraction, Circulation

DIG: Digoxin in HFrEF

1997, Digoxin in Heart failure with reduced ejection fraction, NEJM

EMPA-REG OUTCOMES: Empagliflozin, CV, and Mortality in Type 2 Diabetes

2015, Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes, NEJM

REDUCE-IT: CV risk reduction with Icosapent ethyl for hypertriglyceridemia

2018, Cardiovascular risk reduction with Icosapent ethyl for hypertriglyceridemia, NEJM

DAPT: 12 or 30 months of DAPT after DES-PCI

2014, 12 or 30 months of dual antiplatelet therapy after drug-eluting stents PCI, NEJM

FREEDOM: PCI vs CABG in Patients with Diabetes and multivessel CAD

2012, Percutaneous Coronary Intervention (PCI) vs CABG in Patients with Diabetes and multivessel CAD

CASTLE-AF: Catheter Ablation for Atrial Fibrillation with Heart Failure

2018, Catheter Ablation for AF with Heart Failure, NEJM

ARISTOTLE: Apixaban vs. warfarin in atrial fibrillation

2011, Apixaban vs. warfarin in atrial fibrillation, NEJM

ROCKET-AF: Rivaroxaban vs. warfarin in atrial fibrillation

2011, Rivaroxaban vs. warfarin in atrial fibrillation, NEJM

PARTNER A: Transcatheter versus Surgical Aortic-Valve Replacement in High-Risk Patients

2011, TAVR vs SAVR in High-Risk Patients, NEJM

CULPRIT-SHOCK: Culprit lesion vs multivessel PCI in ACS with cardiogenic shock

2018, Culprit lesion vs multivessel PCI in ACS with cardiogenic shock, NEJM

ESSENCE: Enoxaparin vs Unfractionated Heparin for UA/NSTEMI

1997, Enoxaparin vs Unfractionated Heparin for UA/NSTEMI, NEJM

EPHESUS: Eplerenone in patients with LV dysfunction after MI

2003, Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction, NEJM

CURE: Effects of Clopidogrel plus Aspirin in Patients with NSTEMI

2001, Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation, NEJM 

CAST I: Use of Antiarrhythmics post-MI for Cardiac Arrhythmia Suppression

1991, Mortality and morbidity in patients receiving encainide, flecainide, or placebo, NEJM

CHARISMA: Aspirin/clopidogrel vs. aspirin for CV prevention

2006, Clopidogrel and aspirin versus aspirin alone for prevention of atherothrombosis, NEJM

CHAMPION PHOENIX: Cangrelor in PCI

2013, Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events, NEJM

ASCEND: Effects of n−3 Fatty Acid Supplements in Diabetes Mellitus

2018, N3 fatty acid supplements for primary prevention in DM2, NEJM

ASCEND: Aspirin for primary prevention in patients with Diabetes

2018, Aspirin for primary prevention in patients with Diabetes mellitus, NEJM

POISE: Metoprolol succinate in patients undergoing non-cardiac surgery

 

 

2008, Extended-release metoprolol succinate in patients undergoing non-cardiac surgery, The Lancet 

COMET: Comparison of Carvedilol and Metoprolol in Chronic Heart Failure

2003, Carvedilol vs Metoprolol in Heart Failure, The Lancet

The COMET trial randomized 3029 patients with NYHA Class II, III or IV heart failure and a reduced ejection fraction of 35% or less to receive either 25mg of carvedilol twice daily or 50mg of metoprolol twice daily on top of optimal therapy with diuretics and ACE inhibitors unless not tolerated. The co-primary endpoints were all-cause mortality and a composite of all-cause death or all-cause hospitalization.

Patients were followed for 5 years. Overall, 35% of patients assigned to the carvedilol group and 40% in the metoprolol group died (HR:0.83; 95%CI: 0.74 to 0.93; p=0.0017). This reduction in mortality was consistent across all pre-specified subgroups, including: sex, age, NYHA class, LVEF, heart rate, systolic blood pressure, or diabetic status. The co-primary composite endpoint occurred in 75% of patients in the carvedilol group and 74% of those in the metoprolol group (HR: 0.94; 95%CI: 0.86 to 1.02; p=0.122).

RACE II: Strict vs Lenient Control of Heart Rate in Atrial Fibrillation

 

2010, Heart Rate Control in patients with Atrial Fibrillation in Preventing CV events, NEJM

RACE II Visual Summary

RACE II was a randomized, prospective, open label, multicenter (33 centers in Netherlands), parallel-group,non-industry sponsored, controlled noninferiority trial investigatingthe role of lenient ratecontrol (HR<110 bpm) versus strict rate control (HR<80 bpm) in preventing cardiovascular events in patients with permanent atrial fibrillation (AF).

614 patients randomized [lenient rate control (n=311) vs. strict rate control (n=303)]. Enrollment was between 2005 & 2007 with follow up for 2-3 years.Patient <= 80 years, with permanent AF for up to 12 months, having mean resting HR > 80 bpm, and on oral anticoagulation therapy or aspirin (if no risk factors for thromboembolic complication present) were included. Those with paroxysmal AF, known contraindications to either strict or lenient rate control, NYHA class IV or HF admission <3 months, cardiac surgery <3 months, stroke, current or planned PPM, ICD or CRT, SSS or AV conduction disturbance, untreated hyperthyroidism, or inability to walk/bike were excluded.

AV nodal blocking agents (beta-blockers, non-dihydropyridine CCBs, or digoxin; alone or in combination) were administered and dose adjusted to achieve target heart rate. More patients in the lenient control arm achieved the target heart rate than in the strict control arm (97.7% vs 75.2%; P<0.001). The mean heart rate in the lenient and strict control arms were 93 & 76 bpm respectively at the end of dose adjustment phase and 85 & 76 bpm respectively at the end of the study follow up period. INR was similar in the two arms.

Primary outcome was the composite of cardiovascular death, HF hospitalization, stroke, systemic embolism, major bleeding and arrhythmic events (syncope, sustained VT, cardiac arrest, life-threatening adverse effect of rate control agents, and implantation of PPM or ICD). Primary outcome was met in 12.9% in the lenient control arm vs 14.9% in the strict control arm [absolute difference of 2% (90% CI -7.6 to 3.5%; P < 0.001); HR 0.84 (90% CI 0.58 to 1.21)].

Individual components of the primary outcome were similar in the two arms. All-cause death, symptoms from AF, number of patients in each NYHA class I to III, frequency of hospitalization and adverse events were similar in the two arms as well. Authors (Van Gelder IC et al) concluded that “in patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve”.

HOPE: ACE inhibitors, ramipril in high risk CV patients

2000, Effect of ACE inhibitors, ramipril on cardiovascular morbidity and mortality, NEJM

HOPE Trial Summary

HOPE – “Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients’ was a randomized, double-blinded, multi-national (267 centers), placebo-controlled, clinical trial (recruited patients between 1993 and 1995), which investigated the role of ACE inhibitor (ramipril 10mg oral daily) in patients >= 55 years of age with vascular disease (CAD, stroke, or PAD) or diabetes and one additional CV risk factor (HTN, elevated total cholesterol, low HDL, smoking, or microalbuminuria), but who did not have MI or stroke in the preceding 4 weeks, history of HF, LVEF <40%, uncontrolled HTN, overt nephropathy, and who were not already on ACE inhibitor.

After a run-in phase, 9541 patients were randomized. The study was terminated early because of the beneficial effect of ramipril. At 4 years, the primary outcome, which was the composite of MI, stroke and cardiovascular death, was significantly less with ramipril (14% vs 17.8%; RR: 0.78; 95% CI: 0.70-0.86; P<0.001). Of note, these beneficial effects became statistically significant at 2 years and continued to improve. Rates of individual components primary outcome were also statistically lower with ramipril.

Other outcomes- death from any cause, worsening angina and heart failure were less with ramipril as well. The benefit with ramipril, in terms of the primary outcome, was also observed in the predefined subgroups- above or below 65 years of age, male or female, with or without diabetes, with or without evidence of vascular disease, with or without history of HTN, with or with or without microalbuminuria.

Worth mentioning, the BP at baseline was similar in the two groups (139/79 mmHg) and very small reduction in systolic and diastolic BP (3 and 2 mmHg respectively) was noticed in the ramipril arm.

Authors of this trial (Yusuf S., et al) concluded: “treating 1000 patients with ramipril for four years prevents about 150 events in approximately 70 patients”.

CRYSTAL-AF: Cryptogenic Stroke and Underlying Atrial Fibrillation

2014, 30 Days AF monitoring in patients with Cryptogenic Stroke, NEJM

CRYSTAL AF Trial Summary

The Cryptogenic Stroke and Underlying Atrial Fibrillation (CRYSTAL AF) trial randomized 441 patients ,who were 40 years or older and with a diagnosis of cryptogenic stroke or transient ischemic attack within 90 days, in a 1:1 ratio to Insertable Cardiac Monitor (ICM) implantation or routine monitoring at the investigator’s discretion. Prior to randomization, all patients underwent at least 24 hours of ECG monitoring and had no evidence of atrial fibrillation at baseline. Patients were enrolled in 55 centers in Canada, Europe, and the United States. The primary endpoint was the time to first detection of atrial fibrillation, lasting >30 seconds, within 6 months. Approximately, 8.9% of patients in the ICM group were diagnosed with AF, compared with 1.4% in the control group (HR: 6.4; 95%CI: 1.9 to 21.7; p<0.001). Results were consistent through 12 months and 36 months.  Atrial fibrillation diagnosed in the ICM group was more frequently asymptomatic than in the control group. Prescription of oral anticoagulants was more than doubled in the ICM group, as compared with the control group, at both 6 and 12 months.

SYNTAX: PCI vs CABG in Severe CAD

 

2009, Percutaneous Coronary Intervention versus CABG for Severe Coronary Artery Disease, NEJM

SYNTAX Trial Summary

SYNTAX trial was a noninferiority, randomized, prospective, multicenter (85 sites in 17 countries), open label, industry sponsored, parallel-group trial to investigate the outcomes (at 12 monthsof follow up) with two different revascularization strategies- PCI (with Taxus Express paclitaxel-eluting stents) vs. CABG, in patients with known LMCAD (with or without additional epicardial CAD)or 3 vessel CAD. The lesions had to be >=50%, previously untreated, and in patients with angina or atypical chest pain or asymptomatic with evidence of myocardial ischemia. Patients were screened between March 2005 and April 2007, and 1800 patients were randomly assigned (1:1) to either of the groups. They were also stratified according to the presence or absence of LM CAD. Coronary angiograms were scored according to the SYNTAX score algorithm. The primary end point of major cardiac or cerebrovascular events (cumulative of death from any cause, stroke, MI, and repeat revascularization) at 12 months were significantly higher in the PCI group than CABG group (17.8% vs. 12.4%; P =0.002). At 12 months, individual components of primary end point- death from any cause and MI were similar in the two groups, but stroke rates were higher in the CABG group whereas repeat revascularizations were higher in the PCI group. The rates of major cardiac or cerebrovascular events were similar in the two groups (PCI & CABG) and higher in the PCI group in the pre-stratified subgroups of LM CAD and 3 vessel CADrespectively. Of importance, the rates of major cardiac or cerebrovascular events were similar in the two groups for the low SYNTAX score (<=22), non-statistically numerically higher in the PCI group for the intermediate SYNTAX score (23-32), and statistically higher in the PCI group for the high SYNTAX score (>=33).

Serruys, P.W. et al. NEJM. March 2009.

HACA: Hypothermia in Cardiac Arrest

2002, Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest, NEJM

COURAGE: PCI vs Medical Therapy in Stable CAD

2007, PCI + medical therapy vs medical therapy only in stable coronary artery disease, NEJM

Courage Trial Summary

COURAGE was a randomized, open label, multicenter (50 centers in US & Canada), co-industry sponsored, clinical trial which tested the hypothesis that PCI with optimal medical therapy (OMT) is superior to OMT alone in reducing primary outcome of all cause death and nonfatal MI in patients with stable CAD.

Patients with >=70% stenosis in at least one proximal epicardial coronary artery with objective evidence of ischemia (ST segment depression or TWI on resting ECG, or inducible ischemia with exercise or pharmacologic vasodilator stress) or at least one coronary stenosis of >= 80% with classic angina without provocative test were included. Those with >=50% LM CAD, class IV angina, markedly positive stress test (ST depression or hypotension in Bruce stage I), coronary anatomy not suitable for PCI, in-stent restenosis, LVEF <30%, refractory HF, or revascularization in last 6 months were excluded.

Enrolled between 1999 and 2004, 2287 patient were randomized and followed for median of 4.6 years, with 9% lost to follow up. 85% were male, 86 % were white, 58% had class II or III angina, 69% had multivessel CAD and 34% had proximal LAD CAD. In those who received stents, only 31 had DES.

OMT included antiplatelet therapy with aspirin, anti-ischemic therapy with long acting metoprolol, amlodipine, or isosorbide mononitrate (alone or in combination), along with lisinopril or losartan and aggressive lipid therapy. In PCI group, in addition to OMT, patients received second antiplatelet agent (clopidogrel), and the target vessel revascularization was always attempted with complete revascularization as clinically appropriate.

Primary outcome (composite of all-cause death and nonfatal MI) was similar in PCI group (PCI + OMT) and medical therapy group (OMT alone) (19% vs 18.5% respectively; HR 1.05, 95% CI 0.87-1.27; P=0.62), and so were its individual components and secondary outcome (composite of death, MI and stroke). No difference was seen in terms of hospitalization for ACS and even with ethe xclusion of periprocedural MI, the primary outcome did differ in the 2 groups. Primary outcome was similar even in the prespecified subgroups of multivessel CAD, prior MI and diabetes. Substantial reduction in angina was seen in both groups, more so in the PCI group.

Authors (Boden WE et al) concluded :“as an initial management strategy in patients with stable CAD, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to OMT”.

 

COAPT Trial: Mitral Valve Repair in Heart Failure Patients with Functional Mitral Regurgitation

2018, Transcatheter mitral valve repair in patients with Heart failure, NEJM, ACC

COAPT Trial Summary

COAPT trial was an open label, multicentered, parallel-group and industry-sponsored randomized controlled trial investigating the outcomes with ‘transcatheter mitral valve repair with MitraClip device’ vs. ‘guideline directed medical & device therapy only’ in heart failure patients with dilated cardiomyopathy (CM) (both ischemic and non-ischemic) who had moderate to severe and severe secondary (functional) mitral regurgtation. In addition, these patients were NYHA class II, III or IVa, had LVEF >=20% &<=50%, had LVEDD <=7mm, were on maximally tolerated GDMT and CRT (if indicated), were determined not to be apprpriate for mitral valve surgery, and did not have HCM, RCM, infiltrative CM or constritive pericarditis. Primary end point of all heart failure hospitalization within 24 months was significantly lower in the MitraClip device group (hazard ratio of 0.53; NNT 3.1). Primary safety end point of freedom from MitraClip device-related complications at 12 months was better (at 96.6%) than the set performance goal (of 88%). All 10 prespecified secondary end point were in favor of MitraClip device, including statistically significant lower all-cause mortality within 24 months (NNT of 5.9) and better quality of life.

COMMIT Trial: Metoprolol in Acute Myocardial Infarction

2005, Early intravenous then oral metoprolol after acute MI, The LANCET

ARRIVE Trial: Aspirin for Primary Prevention in Adults at Moderate Cardiovascular Risk

 

2018, Effect of Aspirin in elderly at moderate CVD risk | LANCET

ASPREE Trial: Aspirin for Primary Prevention in Healthy Adults

2018, Effect of Aspirin on CV Events and Bleeding in the Healthy Elderly | NEJM

SCOT-HEART Trial: Coronary CT Angiography and Risk of Myocardial Infarction

2018, CTA vs standard care in preventing MI, SCOT-HEART Visual Abstract | NEJM

CREST Trial: Stenting versus CEA for Treatment of Carotid-Artery Stenosis

2010, Carotid artery stenting vs carotid endarterectomy visual abstract, NEJM

AFFIRM Trial: Rate control vs Rhythm control in Atrial Fibrillation

2002, Rate-control and Rhythm-Control in Patients in patients with AF, NEJM

SADHART Trial: Sertraline Use in Depression after ACS

2002, Safety of Sertraline after ACS, JAMA

MANAGE Trial: Dabigatran in myocardial injury after non-cardiac surgery

2018, MANAGE Trial Visual Abstract: Dabigatran in myocardial injury surgery, Lancet

ATLAS ACS-2: Rivaroxaban after ACS

The ATLAS ACS-2 trial tested the use of rivaroxaban in addition to standard dual antiplatelet therapy in patients with acute coronary syndrome. The results showed a reduction in the composite of CV mortality, recurrent MI, and stroke, but increased the risk of nonfatal bleeding.

2012, ATLAS ACS-2 Trial Visual Abstract: Rivaroxaban after ACS, NEJM

PARAMEDIC2 Trial: Epinephrine in Out-of-Hospital Cardiac Arrest

The PARAMEDIC2 trial that was recently published in NEJM studied the use of epinephrine in the out-of-hospital cardiac arrest and compared the final outcome of survival with placebo. Patients who had a cardiac arrest out of hospital were treated with the standard resuscitation protocol. The patient population which was given epinephrine compared to placed were noted to have slightly better survival rates. Take a look at the visual abstract that is now published in ACC.

COMPASS Trial: Rivaroxaban plus aspirin in stable cardiovascular disease

compass trial visual abstract on rivaroxaban use with or without aspirin in CAD

Does adding rivaroxaban to aspirin therapy in patients with stable cardiovascular disease affect outcomes? This was the question answered by the large-sized multi-center COMPASS trial that evaluated the combination of rivaroxaban and aspirin and compared it with aspirin alone. The results showed moderate improvement in outcomes at the expense of increased bleeding risk.

Source: NEJM

ACT Trial: Acetylcysteine in patients undergoing Angiography

ACT trial on angiography visual abstract

ACT trial was the initial large sized randomized controlled trial that was initiated to test the role of acetylcysteine in protecting kidneys from contrast. More than 2000 patients were enrolled in this placebo-controlled trial. The results failed to establish any renal protective role of acetylcysteine in patients undergoing coronary or peripheral angiography.

Source

Basic Modes of Mechanical Ventilation Infographic

Mechanical ventilation is a complex topic to understand. With this infographic, I have tried to explain 4 most commonly used ventilator modes in intensive care units. The two broad categories are the volume limited and pressure limited ventilation while each of them have further sub-branches. In future posts, I’m going to create a basic flowchart of all ventilator modes with their benefits and disadvantages. Till then, use this infographic to understand the basic of mechanical ventilation and how pressure, flow and volumes are linked to each other.

TOPCAT trial: Spironolactone in HFpEF

Spironolactone is a well known survival improvement agent for heart failure with reduced ejection fraction. Its use in heart failure with preserved EF was however controversial. The TOPCAT trial established the failure of spironolactone to improve mortality in patients with HFpEF. The visual abstract illustrates the trial salient features.

Source

WARFASA Trial: Aspirin for preventing VTE Recurrence

warfasa trial on use of aspirin for preventing venous thromboembolism recurrence

Summarized by / Author: Usama bin Nasir, MD

Contribution To Literature:

WARFASA trial established role of aspirin for prevention of recurrent VTE in patients who have completed 6-18 months course of anticoagulation and were no longer on it.

Guidelines Adaptation

According to ACCP (CHEST) Antithrombotic Therapy for VTE Disease 2016 guidelines, in patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, aspirin over no aspirin to prevent recurrent VTE (Grade 2B) is recommended.

Study Design

It was a multicenter, randomized, double-blind, placebo-controlled that took place and involved enrollment from 2004 to 2010. 403 patients were enrolled and distributed among the study groups. Median follow up period was 2 years.

 

Inclusion criteria:

  • Age ≥18 years
  • Completed therapy with 6-18 months of vitamin K antagonist for first, symptomatic, unprovoked, objectively confirmed proximal DVT, PE, or both

Exclusion criteria:

Important exclusion criteria included

  • Cancer or major thrombophilia
  • Indication for long-term anticoagulation
  • Atherosclerotic disease requiring antiplatelet therapy
  • Active bleeding

Primary outcomes:

  • Recurrent VTE was significantly decreased in patients on aspirin compared to patients on placebo. (HR 0.58; 95% CI 0.36-0.93; P=0.02)

Secondary outcomes:

  • Bleeding (4 events in each group) and death rates (HR 1.04; 95% CI 0.32-3.42; P=0.95) were similar in both groups.

Interpretation:

The WARFASA trial successfully established role of aspirin in prevention of VTE recurrence. Another trial that was done during same time period was the ASPIRE trial. The ASPIRE trial results were non-significant but the important difference between the trials was that in WARFASA all patients completed minimum of 6 months oral anticoagulation. Recurrent rates of VTE after 3-6 months of OAC for unprovoked VTE can reach up to 11% (2) once the anticoagulation is stopped therefore starting aspirin is important and carries grade 2B recommendation per CHEST 2016 guidelines.

References:

  1. Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959-67. Source
  2. Prandoni P, et al. “The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients.”Haematologica 2007. 92(2):199-205.
  3. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-352.

AMPLIFY Trial: Oral apixaban for VTE

amplify trial visual abstract, oral apixaban use in venous thromboembolism
Use of novel oral anticoagulation agents for VTE was established after a series of non-inferior trials that compared NAOCs with conventional therapy of LMWH and warfarin. The AMPLIFY trial was a randomized non-inferior trial that studied the usefulness of apixaban in preventing the recurrence of VTE after initial episode compared to conventional therapy of warfarin. The trial not only successfully established the efficacy of apixaban but also indicated its safety profile in terms of bleeding risk. Based on this trial, the 2016 CHEST guidelines for long term anticoagulation for VTE recommended NOAC over vitamin K antagonist (VKA) therapy. (all Grade 2B)

PROTECT AF Trial: Closure of the LAA versus warfarin therapy in patients with Atrial Fibrillation

PROTECT AF Trial Visual abstract and quick summary poster

We currently lack significant data or clear cut guidelines for closing left atrial appendage in patients with LAA for prevention of stroke. The current ACC/AHA/HRS guidelines recommends anticoagulation in patients with atrial fibrillation and CHA2DS2-VASc >2 (Grade Ia) irrespective of presence or absence of LAA.

The PROTECT AF trial was a randomized non-inferior trial that studied the usefulness of WATCHMAN device in closing LAA and prevention of stroke. The trial did show non-inferiority of the device closure vs warfarin anticoagulation but it was associated with higher side effects which were mostly periprocedural.

Based on this trial, the 2012 Focus European Society of Cardiology Guidelines called for “LAA closure/occlusion/excision” using percutaneous device in patients who are at high stroke risk and have contraindications for long-term oral anticoagulation (Class IIb; Level of Evidence B). The current AHA/ACC/HRS, however, does not include recommendations of LAA closure devices due to lack of enough robust evidence. However, both ESC and AHA/ACC guidelines suggest that surgical excision of the LAA may be considered in patients undergoing cardiac surgery or thoracoscopic atrial fibrillation surgery (Grade IIB)

Sources: Lancet, 2015 ACC/HRS/SCAI LAA Occlusion Device Societal Overview

USPSTF/ACC/AHA guidelines for Statin Use for the Primary Prevention of Cardiovascular Disease in Adults

The USPSTF and ACC/AHA guidelines for statin use in adults aged 40-75 years are consistent over level of recommendation. Adults who have no history of cardiovascular disease but have 1 or more risk factors for developing CVD along with >10% ASCVD risk are recommended to be started on low- to moderate dose statin. (USPSTF = B). The ACC/AHA however recommends moderate to high dose statin for ASCVD risk of >7.5% for primary prevention (ACC/AHA Level I). The above visual abstract summarizes both the societies’ recommendations in to one easy to use graphic.

UPSTF Source, ACC/AHA source

Risks of concomitant aspirin therapy with oral anticoagulation in patients with atrial fibrillation

orbit AF substudy visual abstract on use of aspirin versus OAC in patients with atrial fibrillation

Summarized by: Usama bin Nasir, MD

Contribution To Literature:

Atrial fibrillation (AF) was noted to be a risk marker for stroke in the Framingham cohort in 1978. Since then anticoagulation is an important part of managing AF. Use of aspirin in patients with AF is a common practice based on this notion that it might add to prevention of MI or stroke in such patients. The ORBIT-AF study tackled this question by determining the risk factors associated with concomitant use of aspirin and oral anticoagulation (OAC) in patients with AF.

Study Design

The present study was a retrospective review of ORBIT-AF prospective registry that enrolled 7.347 patients with AF on OAC. The ORBIT-AF registry enrolled patients from 174 US sites. Follow up period of this review was of 6 months and the primary outcomes that were studied were: bleeding, hospitalization, CV events, and mortality.

Inclusion Criteria

  • Age ≥ 18 years
  • Atrial fibrillation on EKG

Exclusion Criteria

  • Anticipated life expectancy <6 months
  • Atrial flutter only
  • Patients not taking oral anticoagulant
  • Patients taking antiplatelet therapies other than ASA
  • Transient AF secondary to a reversible condition
  • Current enrollment in a randomized clinical trial of antithrombotic therapy for AF

AF Characterisitcs:

Among 7347 patients, 4804 were on OAC alone and 2543 patients were on both OAC plus aspirin.

Overall (n=7347) OAC Alone (n=4804) OAC+ASA (n=2543)
AF type, %
 New onset 4.0 3.8 4.6
 Paroxysmal 46 45 47
 Persistent 18 18 18
 Long-standing persistent 32 33 30

Primary Outcomes

  • After adjustment for baseline characteristics the primary outcomes for OAC vs OAC + ASA were as follows:
    Risk of major bleeding: HR 1.53 (1.20–1.96), p = 0.0006
    (note, the risk for bleed is almost 1.5 times for OAC + ASA compared to OAC alone)
    All-Cause Hospitalization: HR 1.08 (1.00–1.17), p = 0.06
    Mortality: HR 1.26 (0.98–1.63), p = 0.08

Interpretation:

The present study indicates worse outcomes in terms of major bleeding and also indicates towards higher mortality and hospitalizations but the latter results are not significant.  Based on the real-world National Cardiovascular Data Registry (NCDR) Practice Innovation and Clinical Excellence (PINNACLE) registry more than one-third of 210,380 patients who had CHA2DS2-VASc scores ≥2 were treated with aspirin alone, and not with oral anticoagulants as per ACC/AHA/HRS guidelines. (2) Using OAC is important for prevention of stroke in patients with AF and this has been presented in a number of studies. However, the use of aspirin in addition to OAC in AF has always been questioned. The current study tackled this very question. The results suggest that we should avoid combination therapy in patients who do not have history of CAD. While in patients with history of CAD, using combination therapy outweighs the risks. Note The 2011 ACC/AHA/HRS guidelines recommend using ASA + OAC in patients with history of MI. However, 2014 guidelines have not commented on combination therapy.

References

  1. Wolf PA, et al. “Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: The Framingham study.” Neurology.1978;28(10):973-977.
  2. Hsu J.C., Maddox T.M., Kennedy K., et al. (2016) Aspirin instead of oral anticoagulant prescription in atrial fibrillation patients at risk for stroke. J Am Coll Cardiol 67:2913–2923.

Source

Radial-Artery or Saphenous-Vein Grafts in CABG

Current ACC/AHA guidelines recommend (IIb) radial artery grafting for >70% LAD stenosis. Most surgeons, however, still prefer saphenous vein grafts in addition to LIMA for LAD stenosis. The following combines the population of 6 RCTs to perform a individual based analysis and showed that radial artery grafting has significant benefits over saphenous vein grafts in CABG.

Source: NEJM

CABANA Trial: Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation

Source: ACC

ANNEXA Trial: Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity

Source: NEJM

EAGLES Trial: Cardiovascular Safety of Varenicline, Bupropion, and Nicotine Patch in Smokers

Source: JAMA Internal Medicine

TTM Trial: Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest

Source: NEJM

Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality

Source: NEJM

Undetectable High-Sensitivity Cardiac Troponin T Level in the Emergency Department and Risk of Myocardial Infarction

Source: JACC

PEITHO Trial: Fibrinolysis for patients with intermediate-risk pulmonary embolism

peitho trial studied the use of fibrinolytics in intermediate risk pulmonary embolism

Source: NEJM

PRECISION Trial: Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis

This visual abstract represents the important findings of the PRECISION trial. The trial compares the COX-2 selective NSAID celecoxib with traditionally used NSAIDs such as naproxen and ibuprofen. It establishes non inferiority in terms of cardiovascular events and superiority in terms of GI and renal safety. As of March 2017, no guidelines have been published that reflect the results of this trial.

Source: NEJM

MASS trial: Screening men for abdominal aortic aneurysm: 10 year mortality and cost effectiveness

mass trial on abdominal aortic aneurysm screening

Source: BMJ

ICON-RELOADED Study: N-Terminal Pro–B-Type Natriuretic Peptide in the Emergency Department

Source: JACC

PROMISE Trial: Outcomes of Anatomical versus Functional Testing for Coronary Artery Disease

Source: NEJM

CANVAS Trial: Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

Source: NEJM

A Cluster-Randomized Trial of Blood-Pressure Reduction in Black Barbershops

barbership trial about blood pressure control

Source: NEJM

VEST Trial: Vest Prevention of Early Death Trial

Source: ACC 2018

ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes with Alirocumab after an ACS

2018, Alirocumab after Acute Coronary Syndrome, ACC

ODYSSEY Outcomes Trial Summary

ODYSSEY OUTCOMES trial was a randomized, multicenter (1315 sites; 57 countries), placebo control, industry sponsored clinical trial to investigate the efficacy and safety of alirocumab (a PCSK9 inhibitor) in patients with an ACS in the preceding 1-12 months, who had inadequate control of lipids (LDL-C >=70mg/dl, or Non-HDL-C >=100mg/dl, or Apolipoprotein B >=80 mg/dl) despite of intensive or maximally tolerated statin therapy. These patients were >40 years of age, and did not have uncontrolled HTN, NYHA class III or IV HF, history of hemorrhagic stroke, fasting TGL>400 mg/dl, AST or ALT>3 x of normal, CK >3 x normal, eGFR< 30ml/min/1.73m2and hepatitis B or C. 18,924 patients were randomized after a run-in period of 2-16 weeks on high intensity or maximally tolerated dose of statin if they met at least one lipid entry criteria. Patients received every other week subcutaneous alirocumab or placebo. Alirocumab dose was adjusted (75or 150 mg) to target LDL-C levels to 25-50 mg/dl (but levels as low as 15 mg/dl were acceptable). Mean age of patients was 58 years, 25% were female, 35% had STEMI, 49% had NSTEMI, 93% met LDL-C lipid entry criteria, and 89% were on high-intensity statin. With alirocumab, LDL-C levels reduced by >50% (which occurred early on and was sustained). At 4 years, primary efficacy outcome of MACE [composite of coronary heart disease (CHD) death, non-fatal MI, ischemic stroke, and unstable angina requiring hospitalization]was significantly lower with alirocumab [9.5 % vs 11.1% in (HR 0.85; P 0.0003)]. Other than CHD death, all other components of MACE were statistically lower as well. Also, all-cause death was lower with alirocumab (3.5% vs 4.1%; HR 0.85).In the prespecified subgroups, patients with LDL-C >=100 mg/dl derived the maximum benefit with alirocumab. No safety signals with alirocumab, specifically no increase in neurocognitive disorder or hemorrhagic stroke; except higher local injection site reaction.

 

Source: ACC2018

DOSE Trial: Diuretic Strategies in Patients with Acute Decompensated Heart Failure

Source: NEJM

JUPITER Trial: Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein

Source: NEJM

ALLHAT Trial: Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic

Source: JAMA

 

PARADIGM-HF Trial: Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure

2014, Sacubitril-valsartan vs Enalapril in HF, NEJM.

PARADIGM-HF Trial Summary

The PARADIGM HF trial randomized 8442 patients with NYHA Class II, III or IV heart failure and a reduced ejection fraction of 40% or less to receive either 200 mg of LCZ696 (which consists of sacubitril and valsartan) or enalapril in a 1:1 ratio, in addition to standard medical therapy.

The primary outcome was a composite of cardiovascular death or heart failure hospitalization but the trial was also powered to detect a difference in cardiovascular death. For at least 4 weeks before screening, patients were required to take a stable dose of a beta-blocker and an ACE inhibitor (or ARB) equivalent to at least 10 mg of enalapril daily. The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, for an overwhelming benefit with LCZ696.

The primary outcome occurred in 21.8% of patients in the LCZ696 group and 26.5% in the enalapril group (HR: 0.80; 95%CI: 0.73 to 0.87; p<0.001). A total of 17% of patients in the LCZ696 arm and 19.8% in the enalapril arm died. (HR:0.84; 95%CI: 0.76 to 0.93; p<0.001). As compared with enalapril, LCZ696 also reduced the risk of heart failure hospitlizations by 21% and decreased the symptoms of heart failure (P<0.001).

RENAAL Trial: Losartan in Patients with Type 2 Diabetes and Nephropathy

RENAAL Trial Visual Abstract

Source: NEJM

RENAAL Trial Key Points
1. Losartan was found to have significant reno-protective role in patients with type II diabetes and nephropathy.
2. Losartan did not affect mortality in this patient population.
3. Proteinuria significant improved in patients taking losartan compared to placebo.
4. The IDNT trial tested irbesartan and reported similar renoprotective role in diabetic nephropathy.

Guideline Recommendations based on RENAAL Trial:

The JNC8 guidelines recommend: In patients who are diabetic with high levels of albuminuria, the medication regimen should include an ACE inhibitor or an ARB alone or in combination with medication from another drug class for treatment of HTN.

The KDIGO guidelines recommend use of an ACE or an ARB and a BP goal <130/80 mmHg in all patients with CKD and albuminuria irrespective of diabetes status.

Source

SPRINT Trial: Intensive versus Standard Blood Pressure Control

sprint trial visual abstract on standard versus intensive blood pressure control

The SPRINT trial study was an important leap towards tighter blood pressure control in patients who had a history of cardiovascular disease and were at high risk of recurrent event but with no history of stroke or diabetes.

Guidelines update based on SPRINT trial

The 2017 ACC/AHA update on hypertension recommended:

For patients with Stable coronary artery disease – Treat to BP goal <130/80 mm Hg (COR I, LOE B-R for SBP and C-EO for DBP)

Use antihypertensive medications if prior clinical CVD or 10-year ASCVD risk score is ≥10% and BP is ≥130/≥80 mm Hg (COR I, LOE A for SBP and C-EO for DBP)

Source: NEJM,

ACC

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