Clinical Trials Flashcards
What is the ISCHEMIA Trial?
What were the major findings?
How many patients were enrolled?
Who is the first author?
What are the weaknesses of the trial?
The ISCHEMIA trial randomized 5179 patients with stable CAD and moderate or severe ischemia on stress testing to an initial invasive strategy or initial conservative strategy with invasive strategy if medical management failed.
Exclusion criteria were: patients with ACS, LM >50%, LVEF <35%, advanced CKD, recent PCI/CABG within the last year, NYHA 3-4 symptoms. In the invasive strategy 96% underwent angiography and in the conservative strategy 26% underwent angiography.
At a median follow-up of 3.2 years, there was no difference between groups in the primary outcome, a composite of death from CV causes, MI, hospitalization for UA, CHF or resuscitated cardiac arrest. There was no difference in a composite of death from CV causes, MI or angina QoL. There was no difference in all cause mortality. There were more procedural MIs of unclear significance but less non-procedural MIs with the invasive strategy.
The primary definition of MI is similar to the SCAI and a secondary definition of MI yielded higher rates of MI using the 3rd universal definition of MI. 1/3rd of patients did not report anginal symptoms prior to enrollment in this trial.
The first author is David Maron
The weaknesses of the trial include reduced power and lower event rates than expected and a limited median follow-up of only 3.2 years
The trial showed that for patients with moderate to severe ischemia and stable CAD and normal LVs, an initial invasive strategy vs initial conservative strategy showed no difference in mortality or a composite outcome at 3.2 years. The invasive strategy was associated with an initial higher rate of procedural MI but a lower rate of spontaneous MI. The initial higher rate of total MI reversed itself by 2 years. The invasive strategy did provide a modest benefit in terms of relieving symptoms of angina particularly in patients reporting daily/weekly anginal symptoms.
At 5 years:
Primary endpoint: composite of CV death, MI,
hospitalization for UA, CHF, or cardiac arrest
16.4% invasive, 18.2% conservative at five years (NSD)
No difference in secondary outcomes: death from any
cause, CV death or MI, MI alone
What is the SYNTAX Trial?
What was the SYNTAX(ES) Trial?
What were the major findings?
Who was the first author?
What are the common criticisms?
What are the inclusion and exclusion criteria?
What are the procedural indications?
What are technical considerations?
What are side effects/adverse effects
How did this trial impact current guidelines?
What was the primary outcome and the %s?
What were the key secondary outcomes and their %s?
What are the 1 year, 5 year, 10 year %s?
Non inferiority trial for PCI (1st gen DES) vs CABG for 3VD and/or LMS disease
All lesions deemed amenable to either therapy
1800 patients
First author is Patrick Serruys
Primary outcome: MACCE (death, MI, stroke, repeat revascularization)
MACE or stroke @ 12 months significantly higher for PCI (RR 1.44; p=0.002)
-Largely due to increased rate of repeat revascularization (RR 2.29; p<0.001)
Death from cardiac causes higher for PCI (RR 1.75; p=0.05)
Reduced rate of stroke for PCI (RR 0.25; p=0.003) (2.2% stroke rate in CABG, 0.6% for PCI at 1 year)
Similar rates of death and MI
At 5 years 37% for PCI, 27% for CABG
Each individual MACE component was analyzed, CABG superior for MI and repeat revascularization
Subgroup analysis based on SYNTAX scores
SYNTAX(ES) trial used same patient group with a primary outcome of all cause mortality at 10 years 28% PCI, 24% CABG (p=0.066)
All cause death at maximum follow-up was 35% PCI, 29% CABG (p=0.05), driven by higher mortality in PCI for 3VD
Criticisms include use of 1st gen DES instead of 2nd gen DES and lower rates of OMT in the CABG group
What is the STITCH Trial?
The STITCH Trial is an open label RCT that randomized 1212 patients with CAD amenable to CABG and an LVEF <35% to either medical therapy, medical therapy+CABG or medical therapy+CABG+SVR. Patients were categorized into one of 3 strata, those eligible for medical therapy + CABG only, those eligible for all three and those eligible for medical therapy+CABG or medical therapy+CABG+SVR. This was published in two studies, one which compared medical therapy to medical therapy+CABG and another one which compared medical therapy+CABG to medical therapy+CABG+SVR.
What were the findings of the STITCH CABG vs OMT study?
Median followup of 56 months
Ejection fraction of 35% or less & coronary disease:
- There was 17% crossover from medical therapy to CABG at a median of 142 days and there was a 9% crossover from CABG to medical therapy
CABG + medical therapy vs. medical therapy alone
- No significant difference to all-cause mortality (p=0.12, favouring CABG)
- Became significant when adjusting for baseline statistics (p=0.039)
- Significant difference in cardiovascular mortality (HR 0.81, p=0.05) and all cause death + hospitalization for heart failure (HR 0.84, p=0.03) all cause death + hospitalization for cardiovascular causes (HR 0.74, p=<0.001)
- Early risk of death as a result of the surgical intervention itself
- -Disappeared at 2 years
- Significant reduction in death from any cause or hospitalization for CV causes
N.B. An as-treated analysis showed significant mortality benefit (p<0.001)
What were the findings of the STITCH CABG vs CABG+SVR study?
Median followup of 48 months
Surgical ventricular reconstruction reduced the end-systolic volume index by 19%, as compared with a reduction of 6% with CABG alone.
Cardiac symptoms and exercise tolerance improved from baseline to a similar degree in the two study groups.
No significant difference was observed in the primary outcome (death or hospitalization for cardiac causes), which occurred in 292 patients (59%) who were assigned to undergo CABG alone and in 289 patients (58%) who were assigned to undergo CABG with surgical ventricular reconstruction (hazard ratio for the combined approach, 0.99; 95% confidence interval, 0.84 to 1.17; P=0.90).
Weaknesses of this study included the open label nature of the trial, a lower amount of reduction in SVI than in previous studies and the perceived conduct of the trial by surgeons who may not have been experienced in SVR.
What is the REDUCE-IT trial?
What is the EVAPORATE trial?
RCT of 8000 patients randomized to icosapent ethyl + statin vs statin + placebo
Inclusion and Exclusion Criteria:
Inclusion Criteria:
Age ≥45 years with established cardiovascular disease (CVD) or age ≥50 years with diabetes mellitus and at least one additional CV risk factor.
Fasting triglyceride levels between 135-499 mg/dL.
Low-density lipoprotein cholesterol (LDL-C) levels between 41-100 mg/dL.
Stable statin therapy for at least 4 weeks prior to enrollment.
Exclusion Criteria:
Severe heart failure (NYHA Class IV).
Active severe liver disease.
Hemoglobin A1c >10%.
Planned coronary intervention or surgery.
History of acute or chronic pancreatitis.
Known hypersensitivity to fish, shellfish, or ingredients of IPE or placebo.
Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² or need for renal replacement therapy.
70% were secondary prevention, 30% primary prevention
Median triglycerides, 2.44
HDL, 1.03
Primary endpoint: CV death, nonfatal MI, nonfatal stroke, coronary revasc, hospitalization for unstable angina
Key outcome: CV death
Primary Outcome and Percentages:
The primary composite endpoint (CV death, nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or unstable angina) occurred in:
IPE Group: 17.2%
Placebo Group: 22.0%
This represents a 25% relative risk reduction (hazard ratio [HR] 0.75; 95% confidence interval [CI], 0.68-0.83; p < 0.0001).
Key Secondary Outcomes and Percentages:
Key Secondary Composite Endpoint (CV death, nonfatal MI, nonfatal stroke):
IPE Group: 11.2%
Placebo Group: 14.8%
Relative Risk Reduction: 26% (HR 0.74; 95% CI, 0.65-0.83; p < 0.0001).
Total Mortality:
IPE Group: 6.7%
Placebo Group: 7.6%
HR: 0.87 (95% CI, 0.74-1.02; p = 0.09).
Outcomes: 1% increase in a-fib/flutter and non-significant increase in bleeding (primary GI, not cerebral)
About 12.5-15% of patients with CAD met the REDUCE-IT criteria
The EVAPORATE trial is a small RCT of 80 patients following REDUCE-IT that looked at those patients comparing icosapent ethyl and compared it to placebo and followed by CTA. There was reduction in plaque as well as high risk plaque (low attenuation) at 9 months with increased reduction at 18 months.
What is the FOURIER trial?
Randomized double blinded trial of 27,564 patients comparing Evolocumab (PCSK9 inhibitor) to placebo for atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy.
The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.
The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years.
Evolocumab reduced CV risk by 2% ARR in a secondary prevention population and lowered LDL cholesterol levels by 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001).
What is the TIME study and its major findings?
Trial of Invasive versus Medical Therapy in Elderly Patients with Chronic Symptomatic Coronary Artery Disease. In elderly patients, there was no difference in symptoms, quality of life, death or non-fatal MI in patients treated with an initial medical invasive strategy (20 vs 17%). Medically treated patients had a higher risk of major clinical events (64 vs 26%) and had a 50% crossover rate to revascularization.
What is the MASS-II Study and its major findings?
The Medicine, Angioplasty, or Surgery study (MASS-II) randomized patients with multivessel disease among medical therapy, PCI and CABG. 10 year survival rates were 74.9% with CABG, 75.1% with PCI and 69% with MT. Re-intervention at 1 year was highest in PCI at 86.7%, 93.7% in MT and 99.5% in CABG patients.
What is the COURAGE trial and its major findings? What was the main criticism of the trial?
The COURAGE trial randomized 2287 patients with stable angina and objective evidence of ischemia to OMT or PCI and OMT. The trial found no difference between PCI and OMT for death, MI or MACCE. The primary criticism of the study was low rate of DES (3%)
What is the SHOCK trial and what were the major findings?
The SHOCK trial randomized patients to emergency revascularization versus initial medical stabilization in patients presenting with STEMI and cardiogenic shock. It found similar survival between CABG and PCI despite a higher rate of T2DM and complex coronary anatomy in the CABG cohort.
What is the PARTNER 3 trial?
What are the inclusion and exclusion criteria?
What are the procedural indications?
What are technical considerations?
What are side effects/adverse effects
How did this trial impact current guidelines?
What was the primary outcome and the %s?
What were the key secondary outcomes and their %s?
What are the 1 year and 5 year %s?
The PARTNER 3 trial was a pivotal study evaluating the efficacy and safety of transcatheter aortic valve replacement (TAVR) compared to surgical aortic valve replacement (SAVR) in patients with severe, symptomatic aortic stenosis who were at low surgical risk. Conducted between 2016 and 2019, the trial aimed to determine whether TAVR could be a viable alternative to SAVR in this patient population.
Inclusion and Exclusion Criteria:
The trial enrolled 1,000 patients with the following inclusion criteria:
Inclusion Criteria:
65 years of age or older at time of consent.
Symptomatic, severe, calcific aortic stenosis with the following TTE criteria: Jet velocity ≥ 4.0 m/s or mean gradient ≥ 40 mmHg AND AVA ≤ 1.0 cm2 or AVA index ≤ 0.6 cm2/m2 Note: Qualifying echo must be within the 90 days prior to randomization.
Aortic valve annulus 273 mm2 – 683 mm2 measured by 3D imaging (CT, TEE or MRI)
Adequate iliofemoral access with minimum average vessel diameter of 5.5mm (20, 23, 26mm) and 6.0mm (29mm) and acceptable level of vessel calcification and tortuosity for safe device implant
NYHA Functional Class ≥ II
Heart team agrees the patient has a risk of operative mortality < 2% (e.g., STS <4). The heart team evaluation should include risk calculators such as the STS as well as overall clinical status and comorbidities not fully addressed by the STS risk score (verified during the case review process).
Exclusion Criteria:
- ≥ 1/4 frailty. (Only 0/4 frail patients may be enrolled in the trial).
- Evidence of an acute myocardial infarction ≤ 1 month (30 days) before randomization with evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Any one of the following criteria meets the diagnosis for MI: Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin (cTn)] with at least one value above the 99th percentile upper reference limit (URL) and with at least one of the following: - - - - Symptoms of ischemia New or presumed new significant ST-segment–T wave (ST–T) changes or new left bundle branch block (LBBB) Development of pathological Q waves in the ECG Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality Identification of an intracoronary thrombus by angiography
- Aortic valve is a congenital unicuspid or congenital bicuspid valve, or is non-calcified
- Severe aortic regurgitation (>3+)
- Severe mitral regurgitation (>3+)
- Pre-existing mechanical or bioprosthetic valve in any position. (Of note, mitral ring is not an exclusion).
- Any patient with a balloon valvuloplasty (BAV) within 30 days of the valve implant procedure (unless BAV is a bridge to procedure after a qualifying ECHO).
- Any therapeutic invasive cardiac procedure performed within 30 days of the valve implant procedure. Pre-planned PCI performed within 2 weeks prior to valve procedure or implantation of a permanent pacemaker or Implantable Cardioverter Defibrillator (ICD) is not considered exclusionary criteria.
- Complex coronary artery disease: Unprotected left main coronary artery Syntax score > 32 (in the absence of prior revascularization)
- Non-complex, flow limiting coronary artery disease requiring revascularization that cannot be treated at the time of or within 2 weeks prior to the valve procedure.
- Patients with a planned concomitant surgical or transcatheter ablation for atrial fibrillation
- Leukopenia (WBC < 3000 cell/mL), anemia (Hgb < 9 g/dL), Thrombocytopenia (Plt < 50,000 cell/mL)
- Hemodynamic or respiratory instability requiring inotropic support, mechanical ventilation or mechanical heart assistance within 30 days of the screening visit
- Emergency interventional/surgical procedures within 30 days of the valve implant procedure
- Any planned surgical or peripheral procedure to be performed within the 30 day follow-up from the valve implant procedure
- Hypertrophic cardiomyopathy with or without obstruction (HOCM)
- Ventricular dysfunction with LVEF < 45%
- Cardiac imaging (echo, CT, and/or MRI) evidence of intracardiac mass, thrombus or vegetation
- History of upper GI bleeding within 90 days of the valve implant procedure 20. Inability to tolerate anti-thrombotic/anticoagulation therapy during or after the valve implant procedure
- Stroke or transient ischemic attack (TIA) within 180 days of the valve implant procedure
- Renal insufficiency (eGFR < 40 ml/min per the Cockcroft-Gault formula) and/or renal replacement therapy at the time of screening
- Active bacterial endocarditis within 180 days of the valve implant procedure
- Severe lung disease (FEV1 < 50% predicted) or currently on home oxygen
- Chronic liver disease (MELD Score ≥ 10 or Child-Pugh Class B or C)
- Significant aortic disease, including marked tortuosity (hyperacute bend), aortic arch atheroma [especially if thick (>5mm), protruding or ulcerated] or narrowing (especially with calcification and surface irregularities) of the abdominal thoracic aorta, severe “unfolding” and tortuosity of the thoracic aorta.
- Porcelain aorta
- Complications with prior cardiac surgery (i.e., mediastinitis, prolonged intubation)
- Patient refuses blood products
- Severe chest deformity (i.e., pectus excavaatum, mastectomy, iatrogenic radiation exposure)
- BMI > 50 kg/m2
- Estimated life expectancy < 24 months
- Known blood dyscrasia
- Aortic coarctation
- Absolute contraindications or allergy to iodinated contrast that cannot be pre-medicated
- Immobility that would prevent completion of study procedures
- Patient refuses SAVR
Bicuspid aortic valve morphology.
Left ventricular ejection fraction <30%.
Recent myocardial infarction (within 30 days).
Stroke or transient ischemic attack within 90 days.
Severe aortic or mitral regurgitation.
Anatomical features increasing procedural risk.
Procedural Indications:
The primary indication for intervention was severe, symptomatic aortic stenosis in patients deemed to be at low surgical risk. The trial specifically assessed the outcomes of TAVR using the SAPIEN 3 valve system compared to traditional SAVR.
The trial was a non-inferiority and superiority trial.
Technical Considerations:
Key technical aspects of the trial included:
Access Route: All TAVR procedures were performed via the transfemoral approach.
Valve Type: Utilization of the balloon-expandable SAPIEN 3 valve.
Anesthesia: A significant proportion of TAVR procedures (65%) were conducted under conscious sedation.
Procedure Duration: TAVR procedures had a shorter duration compared to SAVR.
Side Effects/Adverse Effects:
The trial reported several adverse effects associated with both procedures:
TAVR:
Higher incidence of mild paravalvular aortic regurgitation at 1 year (29.4% vs. 2.1% in SAVR).
Numerically higher, but not statistically significant, need for permanent pacemaker implantation within 30 days (6.5% vs. 4.0% in SAVR).
SAVR:
Higher rates of new-onset atrial fibrillation at 30 days (39.5% vs. 5.0% in TAVR).
Longer hospital stays (median of 7 days vs. 3 days in TAVR).
Impact on Current Guidelines:
The positive outcomes from the PARTNER 3 trial have significantly influenced clinical guidelines, leading to the expansion of TAVR indications to include low-risk patients with severe, symptomatic aortic stenosis. This shift reflects the recognition of TAVR as a less invasive alternative with comparable, if not superior, outcomes to SAVR in selected patient populations.
Primary Outcome and Percentages:
The primary composite outcome measured at 1 year included all-cause mortality, stroke, or rehospitalization. Results demonstrated:
TAVR Group: 8.5%
SAVR Group: 15.1%
This indicates a statistically significant reduction in the primary outcome favoring TAVR.
Key Secondary Outcomes and Percentages:
Notable secondary outcomes at 1 year included:
Stroke:
TAVR: 0.6%
SAVR: 2.4%
New-Onset Atrial Fibrillation:
TAVR: 5.0%
SAVR: 39.5%
Death or Disabling Stroke:
TAVR: 1.0%
SAVR: 2.9%
One-Year and Five-Year Percentages:
At 1 year, the composite outcome of death, stroke, or rehospitalization was:
TAVR: 8.5%
SAVR: 15.1%
At 5 years
The first primary end point was
a composite of death, stroke, or rehospitalization related to the valve, the procedure, or heart failure.
22.8% in the TAVR group and
27.2% in the surgery group
The Kaplan–Meier estimates for the components of the first primary end point were as follows: death, 10.0% in the TAVR group and 8.2% in the surgery group; stroke, 5.8% and 6.4%, respectively; and rehospitalization, 13.7% and 17.4%.
The second primary end point was a hierarchical composite that included death, disabling stroke, nondisabling stroke, and the number of rehospitalization days, analyzed with the use of a win ratio analysis.
The win ratio for the second primary end point was 1.17 (95% CI, 0.90 to 1.51; P = 0.25)
The hemodynamic performance of the valve, assessed according to the mean (±SD) valve gradient, was 12.8±6.5 mm Hg in the TAVR group and 11.7±5.6 mm Hg in the surgery group. Bioprosthetic-valve failure occurred in 3.3% of the patients in the TAVR group and in 3.8% of those in the surgery group.
What is SYNTAX 2 (EHJ 2017)
What are the comparator groups?
What is the primary outcome and numbers?
Compares contemporary (2014-2015) PCI group to historical SYNTAX cohort
Bioreabsorbable DES (instead of 1st gen paclitaxel), IVUS, GDMT
Primary outcome was MACCE at 1 year (death, stroke, MI, repeat revasc)
PCI was superior 10.6% vs 17.4%
What is the FREEDOM trial? (NEJM 2012)
What were the comparator groups?
What was the primary and secondary outcomes?
How long was the follow-up?
1900 patients with MVD and T2DM randomized to CABG vs PCI
* Primary outcome was all cause mortality, MI, or stroke at 5 years follow up
* 27% PCI vs 19% CABG (p=0.005)
* Secondary outcomes included:
* All cause mortality 16% PCI, 11% CABG (p=0.049)
* MI 14% PCI, 6% CABG (p<0.001)
* Stroke 2.4% PCI, 5% CABG (p=0.03)
* CV death 11% PCI, 7% CABG (p=0.12)
What is the NOBLE trial? (Lancet 2020)
What were the Inclusion criteria?
What was the primary outcome and what were the %s?
1201 patients randomised to PCI (DES) vs CABG for treatment of LM CAD
Inclusion: stable angina, UA, or ACS with at least 50% LM stenosis
Primary outcome: MACCE (all cause mortality, non procedural MI, repeat
revascularization, stroke) at 5 years
28% PCI, 19% CABG (p=0.0002)
CABG was superior for individual components of non procedural MI and
repeat revascularization
What is the EXCEL trial? (NEJM 2019)
What were the inclusion criteria?
What was the primary endpoint and the %s?
What were key secondary endpoints and their %s?
1905 patients randomized to PCI or CABG for LM CAD
Inclusion: LM >70% visually or 50-70& by invasive testing, SYNTAX score <33
Primary endpoint composite of all cause mortality, stroke, or MI
22% PCI, 19% CABG
All cause mortality favours CABG (13% PCI, 9% CABG)
Ischemia driven revascularization favours CABG (17% PCI, 10% CABG)
CVA not significantly different (3% PCI, 4% CABG)
What is the Evolut low risk trial?
What are the inclusion and exclusion criteria?
What are the procedural indications?
What are technical considerations?
What are side effects/adverse effects
How did this trial impact current guidelines?
What was the primary outcome and the %s?
What were the key secondary outcomes and their %s?
What are the 1 year and 5 year %s?
What were key criticisms of the trial?
The Evolut Low Risk trial was a significant study evaluating the safety and efficacy of transcatheter aortic valve replacement (TAVR) using the self-expanding CoreValve Evolut system compared to surgical aortic valve replacement (SAVR) in patients with severe symptomatic aortic stenosis who were at low surgical risk. Conducted between 2016 and 2019, the trial aimed to determine if TAVR could be a viable alternative to SAVR in this patient population.
Inclusion and Exclusion Criteria:
Inclusion Criteria:
Severe symptomatic aortic stenosis.
Anatomy suitable for TAVR or SAVR.
Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) score ≤3%.
Exclusion Criteria:
Contraindication for placement of a bioprosthetic valve.
Bicuspid aortic valve morphology.
Known hypersensitivity or contraindication to all anticoagulation/antiplatelet regimens.
Procedural Indications:
The primary indication for intervention was severe symptomatic aortic stenosis in patients deemed to be at low surgical risk, with an STS PROM score of 3% or less. The trial assessed the outcomes of TAVR using the self-expanding CoreValve Evolut system compared to traditional SAVR.
Technical Considerations:
Valve Type: The majority of TAVR procedures utilized the self-expanding CoreValve Evolut system; 22.3% of patients received the third-generation Evolut PRO valve.
Access Route: Procedures were performed via transfemoral access.
Anesthesia: A significant proportion of TAVR procedures were conducted under conscious sedation.
Side Effects/Adverse Effects:
The trial reported the following adverse effects:
Permanent Pacemaker Implantation: Higher in the TAVR group (17.4%) compared to the SAVR group (6.1%) at 30 days.
Paravalvular Leak: Moderate or severe paravalvular regurgitation was more common in the TAVR group.
Other Complications: The SAVR group experienced higher rates of new-onset atrial fibrillation, acute kidney injury, and severe bleeding.
Impact on Current Guidelines:
The results of the Evolut Low Risk trial, alongside findings from similar studies, have influenced clinical guidelines to expand the indication for TAVR to include low-risk patients with severe symptomatic aortic stenosis. This shift reflects the noninferiority of TAVR compared to SAVR in terms of mortality and disabling stroke in this population.
Primary Outcome and Percentages:
The primary endpoint was a composite of all-cause mortality or disabling stroke at 24 months:
TAVR Group: 5.3%
SAVR Group: 6.7%
This demonstrated the noninferiority of TAVR compared to SAVR.
Key Secondary Outcomes and Percentages:
All-Cause Mortality at 30 Days:
TAVR: 0.5%
SAVR: 1.3%
Disabling Stroke at 30 Days:
TAVR: 0.3%
SAVR: 1.1%
Permanent Pacemaker Implantation at 30 Days:
TAVR: 17.4%
SAVR: 6.1%
Moderate or Severe Paravalvular Regurgitation at 30 Days:
TAVR: 3.5%
SAVR: 0.5%
One-Year and Five-Year Percentages:
All-Cause Mortality or Disabling Stroke at 1 Year:
TAVR: 2.9%
SAVR: 4.6%
All-Cause Mortality or Disabling Stroke at 4 Years:
TAVR: 10.7%
SAVR: 14.1%
Key criticisms:
- High Permanent Pacemaker Implantation Rates: A notable concern is the elevated rate of permanent pacemaker implantation in the TAVR group. At 30 days, 17.4% of patients undergoing TAVR required a pacemaker, compared to 6.1% in the SAVR group. This significant difference raises questions about the impact of TAVR on the cardiac conduction system and its long-term implications.
WIKI JOURNAL CLUB - Methodological Imbalances and Potential Biases: A systematic review and meta-analysis highlighted concerns regarding methodological imbalances in randomized clinical trials comparing TAVR and SAVR, including the Evolut Low Risk trial. The study identified substantial deviations from assigned treatments, loss to follow-up, and additional procedures, with a pattern favoring TAVR. These imbalances suggest a high risk of performance and attrition biases, potentially affecting the internal validity of the trial outcomes.
PUBMED CENTRAL - Inclusion of Surgical Valves with Known Durability Issues: In the Evolut Low Risk trial, 17.7% of patients in the SAVR group received the Trifecta valve, which has been withdrawn from the market due to durability concerns. This inclusion may have influenced the comparative outcomes, potentially biasing results in favor of TAVR. Subsequent analyses excluding patients who received the Trifecta valve continued to show similar primary endpoint outcomes, but the initial inclusion remains a point of critique.
SCAI.ORG - Limited Long-Term Data: While the trial provides encouraging short- to mid-term results, critics emphasize the necessity for longer-term data to fully assess the durability and sustained performance of TAVR compared to SAVR, especially in younger patients with a longer life expectancy. The absence of extensive long-term follow-up data leaves questions about the potential need for reintervention and the long-term safety profile of TAVR.
CLINICAL AND DIAGNOSTIC TOXICOLOGY
What is the SURTAVI trial?
What are the inclusion and exclusion criteria?
What are the procedural indications?
What are technical considerations?
What are side effects/adverse effects
How did this trial impact current guidelines?
What was the primary outcome and the %s?
What were the key secondary outcomes and their %s?
What are the 1 year and 5 year %s? What were key criticisms of the trial?
The Surgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI) trial was a pivotal study comparing transcatheter aortic valve replacement (TAVR) using a self-expanding valve to surgical aortic valve replacement (SAVR) in patients with severe symptomatic aortic stenosis at intermediate surgical risk. Conducted between June 2012 and June 2016 across 87 centers in Europe and North America, the trial aimed to evaluate whether TAVR is noninferior to SAVR in this patient population.
Inclusion and Exclusion Criteria:
Inclusion Criteria:
Severe symptomatic aortic stenosis.
Intermediate surgical risk, defined by a Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score between 3% and 15%.
Exclusion Criteria:
Contraindications to the placement of a bioprosthetic valve.
Known hypersensitivity or contraindication to all anticoagulation/antiplatelet regimens.
Recent percutaneous coronary intervention (PCI) or peripheral intervention within 30 days prior to randomization.
Symptomatic carotid or vertebral artery disease, or recent treatment of carotid stenosis within six weeks prior to randomization.
Recent cerebrovascular accident or transient ischemic attack.
Acute myocardial infarction within 30 days prior to randomization.
Multivessel coronary artery disease with a SYNTAX score >22.
Procedural Indications:
The primary indication for intervention was severe symptomatic aortic stenosis in patients assessed to be at intermediate surgical risk. The trial compared outcomes between TAVR using the self-expanding CoreValve system and traditional SAVR.
Technical Considerations:
Valve Type: The majority of TAVR procedures utilized the self-expanding CoreValve Classic.
Access Route: Procedures were primarily performed via the transfemoral approach.
Anesthesia: The choice between general anesthesia and conscious sedation was determined based on patient-specific factors and institutional protocols.
Side Effects/Adverse Effects:
The trial reported several adverse effects associated with both procedures:
Permanent Pacemaker Implantation: Higher in the TAVR group (approximately 25.9%) compared to the SAVR group (approximately 6.6%) at 30 days.
Paravalvular Leak: Moderate to severe paravalvular leak was more common in the TAVR group (3.0%) than in the SAVR group (0.7%) at five years.
New-Onset Atrial Fibrillation: More frequent in the SAVR group (43.4%) compared to the TAVR group (12.9%) at 30 days.
Vascular Complications: Higher incidence in the TAVR group (6.0%) compared to the SAVR group (1.1%) at 30 days.
Acute Kidney Injury: More common in the SAVR group (5.4%) compared to the TAVR group (1.7%) at 30 days.
Impact on Current Guidelines:
The SURTAVI trial’s findings contributed to the expansion of TAVR indications. In response to the trial and similar studies, the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) focused update provided a Class IIa recommendation, suggesting that TAVR is a reasonable alternative to SAVR in patients with severe symptomatic aortic stenosis at intermediate surgical risk.
Primary and Secondary Outcomes:
Primary Outcome: The composite of all-cause mortality or disabling stroke at two years.
Results: At two years, the rates were 12.7% in the TAVR group and 12.6% in the SAVR group, demonstrating noninferiority of TAVR compared to SAVR.
Key Secondary Outcomes:
All-Cause Mortality at Five Years: 30.0% in the TAVR group vs. 28.7% in the SAVR group.
Stroke at Five Years: 10.9% in the TAVR group vs. 12.3% in the SAVR group.
Valve Reintervention at Five Years: 3.5% in the TAVR group vs. 1.9% in the SAVR group.
One-Year and Five-Year Outcomes:
One-Year Outcomes:
All-Cause Mortality or Disabling Stroke: Similar rates between TAVR and SAVR groups.
Hemodynamic Performance: TAVR demonstrated lower mean gradients and larger effective orifice areas compared to SAVR.
Five-Year Outcomes:
All-Cause Mortality or Disabling Stroke: 31.3% in the TAVR group vs. 30.8% in the SAVR group.
Hemodynamic Performance: TAVR maintained lower mean gradients (8.6 mm Hg) compared to SAVR (11.2 mm Hg) and larger effective orifice areas (2.2 cm² vs. 1.8 cm²).
Paravalvular Leak: Moderate to severe paravalvular leak was more frequent in the TAVR group (3.0%) than in the SAVR group (0.7%).
Key Criticisms of the Trial:
High Permanent Pacemaker Implantation Rates: The TAVR group experienced a higher incidence of permanent pacemaker implantation, which may have long-term implications for patients.
Paravalvular Leak Concerns: The increased rate of moderate to severe paravalvular leak in the TAVR group raises questions about the long-term
What is the PARTNER 2 trial?
What are the inclusion and exclusion criteria?
What are the procedural indications?
What are technical considerations?
What are side effects/adverse effects
How did this trial impact current guidelines?
What was the primary outcome and the %s?
What were the key secondary outcomes and their %s?
What are the 1 year and 5 year %s? What were key criticisms of the trial?
Summary:
TAVI vs SAVR in intermediate risk patients
Severe, symptomatic AS with STS score 4-8%
Primary endpoint: all cause mortality or disabling stroke
47.9% TAVI, 43.4% SAVR at 5 years (p=0.21)
SAVR superior for 5 year rates of rehospitalization, aortic valve reintervention, and mild or greater paravalvular leak
TAVI superior for new afib, AKI, severe bleeding
The PARTNER 2 trial (Placement of Aortic Transcatheter Valves 2) was a randomized clinical trial comparing transcatheter aortic valve replacement (TAVR) with surgical aortic valve replacement (SAVR) in patients with severe symptomatic aortic stenosis at intermediate surgical risk (STS-PROM score of 4-8%). This trial was crucial in expanding TAVR indications beyond high-risk patients.
Inclusion and Exclusion Criteria
Inclusion Criteria:
Severe symptomatic aortic stenosis
Intermediate surgical risk (STS-PROM score 4-8%)
Age ≥ 65 years
Aortic valve area ≤ 0.8 cm² or mean aortic valve gradient ≥ 40 mmHg
NYHA Class II-IV heart failure symptoms
Suitable anatomy for transfemoral or transapical TAVR
Exclusion Criteria:
Bicuspid aortic valve morphology
Left ventricular ejection fraction <20%
Severe coronary artery disease requiring revascularization
High risk of coronary ostium obstruction post-TAVR
Aortic annulus size not suitable for TAVR prosthesis
Recent stroke or transient ischemic attack (within 6 months)
Active endocarditis
Procedural Indications
The trial assessed TAVR using the SAPIEN XT valve (Edwards Lifesciences) via transfemoral or transapical approach.
SAVR was performed using a variety of bioprosthetic surgical valves.
Patients were randomized to TAVR or SAVR based on anatomical feasibility and surgical risk.
Technical Considerations
Valve Type: SAPIEN XT balloon-expandable valve.
Access Routes:
Transfemoral approach (preferred)
Transapical approach (for patients with poor femoral access)
Anesthesia: General anesthesia was commonly used, though conscious sedation became more common in later TAVR trials.
Imaging: Pre-procedural CT scan of the aorta was performed for valve sizing and vascular access assessment.
Side Effects/Adverse Effects
Adverse Event TAVR (%) SAVR (%)
Death at 2 years 22.2% 24.8%
Stroke at 2 years 10.6% 14.0%
Major vascular complications 7.9% 5.0%
Paravalvular regurgitation (moderate/severe) 8.0% 0.6%
New pacemaker implantation 8.5% 6.9%
TAVR had lower stroke rates but higher rates of paravalvular regurgitation.
TAVR had fewer major bleeding events than SAVR.
TAVR patients had faster recovery times.
Impact on Guidelines
The PARTNER 2 trial expanded the indication for TAVR to intermediate-risk patients (previously, TAVR was approved only for high-risk or inoperable patients).
2017 AHA/ACC Guidelines incorporated TAVR as a Class I recommendation for intermediate-risk patients.
Further studies (PARTNER 3, Evolut Low Risk Trial) later supported TAVR use in even low-risk patients.
Primary Outcome and %
Primary Endpoint: Composite of death from any cause or disabling stroke at 2 years.
TAVR: 19.3%
SAVR: 21.1%
TAVR was non-inferior to SAVR.
Key Secondary Outcomes and %
Outcome TAVR (%) SAVR (%)
1-year mortality 7.8% 7.8%
1-year stroke 6.2% 8.0%
1-year rehospitalization 11.4% 10.4%
2-year major bleeding 26.6% 41.1%
1-Year and 5-Year Outcomes
Timepoint TAVR Mortality (%) SAVR Mortality (%)
1-Year 7.8% 7.8%
2-Year 19.3% 21.1%
5-Year 47.9% 43.4%
5-year data showed no significant difference in all-cause mortality between TAVR and SAVR.
Moderate or severe paravalvular regurgitation was more common in TAVR, which may impact long-term durability.
Key Criticisms of the PARTNER 2 Trial
Paravalvular Regurgitation (PVR):
Higher rates in TAVR (8%) vs. SAVR (0.6%).
Long-term durability concerns, as moderate/severe PVR is associated with increased mortality.
Higher Pacemaker Implantation in TAVR:
TAVR group had higher pacemaker rates (8.5%) than SAVR.
This is still lower than later trials using self-expanding valves (e.g., Evolut).
Heterogeneity in Surgical Outcomes:
SAVR included multiple surgical valves, making direct comparison to TAVR challenging.
The quality of surgical outcomes may have influenced the results.
Limited Long-Term Data on Valve Durability:
At 5 years, mortality was similar, but the long-term durability of TAVR valves beyond 10 years remains unclear.
Structural valve deterioration (SVD) rates need further study.
Excluded Bicuspid Aortic Valve Patients:
Bicuspid patients (a large proportion of younger aortic stenosis patients) were excluded, limiting generalizability.
Conclusion
PARTNER 2 demonstrated that TAVR is non-inferior to SAVR for intermediate-risk patients with severe aortic stenosis.
It led to guideline changes, making TAVR a standard-of-care option in this population.
Criticisms remain, particularly around paravalvular regurgitation, pacemaker rates, and long-term durability.
The 5-year results showed no mortality benefit of TAVR over SAVR, reinforcing the need for longer follow-up studies.
What is the PARTNER 1A trial? (NEJM 2011)
699 patients, randomized to TAVR vs SAVR in high risk patients
Inclusion: Severe symptomatic AS, STS >10, estimated 15% risk of death
Exclusion: bicuspid, unicuspid, stroke in past 6 months, MI within 30 days, severe MR/MAC/AI, LVEF <20%, HCM with or without obstruction, annulus <18mm or >25mm
Primary outcome: All-cause mortality at 1 year 24.2% vs 26.8% p=0.44 non-inferior
Conclusion: TAVR was non-inferior to SAVR in high risk patients.
What is the PARTNER 1B trial? (NEJM 2010)
358 patients, randomized to TAVR vs medical therapy in prohibitive risk
Inclusion: Severe symptomatic AS, with STS >10% or estimated 15% of mortality or 50% mortality or morbidity
Exclusion: bicuspid, unicuspid, CAD, severe PAD, stroke in past 6 months, MI within 30 days, severe MR/MAC/AI, LVEF <20%, HCM with or without obstruction, annulus <18mm or >25mm
Primary outcome: All cause mortality, and All-cause mortality or time to first valve or procedure related hospitalization
At 1 year for all-cause mortality: 30.7% vs 50%, P<0.001, NNT 5
At 1 year for all-cause mortality or hospitalization: 42.5% vs 70%, P<0.001 NNT 4
Conclusion: TAVR was superior to medical management in prohibitive risk patients
What is the CoreValve High Risk Trial (NEJM 2014)
795 patients randomized to TAVR vs SAVR
Non-inferiority and superiority
Inclusion: Severe symptomatic AS, AS <0.8cm2 or AVAi <0.5 and MG 40 or 4m/s, estimate of surgical risk >15% for death or >50% of mortality or morbidity
Exclusion: MI <30 days, cardiogenic shock, CAD requiring revasc, ESRD, GI bleed <3 months, sepsis, life expectancy <12 months
Primary outcome: all cause mortality at 1 year 14.2 vs 19.1% , non-inferior and superior p=0.04, as treated)
PPM: 20 vs 7% at 1 year <0.001
AKI: 6 vs 15% at 1 year <0.001
Bleeding 13.6 vs 35% at 1 year<0.001
Conclusion: TAVR was superior to SAVR at 1 year.
What is the DCD Heart Trial (NEJM 2023)
DCD vs DBD Trial (Duke, Schroder)
Patients randomized 3:1 to receive DCD heart or DBD heart
297 randomized, 180 underwent heart transplant, 90 received a DCD heart and 90 received DBD heart.
Due to protocol violations 80 DCD and 86 DBD hearts were analyzed.
Non-inferiority trial
Primary analysis was as-treated
Primary outcome was risk adjusted survival at 6 months
94% in DCD and 90% in DBD, which met non-inferiority margin.
Key secondary end points were the
usage rate of DCD hearts harvested,
patient survival with the original transplanted heart from 30 days through 1 year of transplantation.
Usage rate of DCD hearts was 90 out of 101 (89%)
Survival with original heart was 99% in DCD hearts 92% in DBD hearts at 30 days, 93% in DCD and 85% in DBD at 1 year.
Primary safety endpoint was: serious adverse events associated with the heart graft in the first 30 days after transplant: which included moderate or severe left or right PGD and primary graft failure that resulted in retransplantation.
Rate of
moderate or severe PGD was 18 (22%) DCD vs 10 (10%) DBD, for severe alone it was 15% DCD vs 5% DBD. However, the two patients who needed retransplant were DBDs.
Criticisms of this trial were the differences between DCD and DBD populations, DBD population was sicker, higher UNOS class and more frequently had IABP (42% vs 16%). DCD population was more ambulatory but 49% had LVAD insitu. The reason for this is because patients randomized to DCD could receive either a DBD or DCD heart, whichever came first. DBD patients tended to wait longer for their hearts and were more sick patients in the first place.
What is the PALACS trial (Lancet 2021)?
PALACS Trial (Gaudino, Weill Cornell)
Posterior left pericardiotomy versus no intervention
Patients and assessors were blinded
Inclusion criteria: coronary, ascending aorta, aortic valve surgery
Exclusion criteria: mitral and tricuspid surgery, non-elective surgery, redo-sternotomy
Primary outcome in the ITT population, safety in the as-treated population
Primary outcome: Post-op afib >30 seconds on continuous monitoring during hospitalization
37/212 (17%) intervention vs 66/208 (32%) control (OR 0.44)
Safety outcome: Post-op pericardial effusion
26/209 (12%) intervention vs 45/211 (21%) control (RR 0.58)
No difference in mortality, pleural effusion, need for pleural drainage, re-hospitalization
Criticisms include single center design, excluded higher risk populations, low threshold for POAF (>30 seconds)
What is the PROCEED II trial? What are the primary, secondary endpoints and results?
Ex-vivo perfusion Organ Care System vs. cold storage standard of care (SOC) in DBD patients
Open-label, multicentre, randomised non-inferiority trial
Primary endpoint: 30-day patient and graft survival
Secondary endpoint: cardiac adverse events, incidence of biopsy proven ISHLT grade 2R or 3R rejection, and ICU time
Results:
○ 128 patients
○ OCS XC time 5.5 hrs; SOC XC 3.5 hrs; total ischemic time lower in OCS (2hrs vs. 3.5hrs)
○ No difference in 30-day survival, graft survival, cardiac adverse events, rejection, and early graft dysfunction
○ 5 donor heart in OCS group developed abnormal metabolic profile and rejected for transplant
What was the STICH viability substudy and what were the criticisms?
2011 NEJM
Study Design
Patient Population: 601 patients (subset of the STICH trial) with ischemic cardiomyopathy (LVEF ≤ 35%).
Viability Testing Methods:
Single-photon emission computed tomography (SPECT)
Dobutamine Stress Echocardiography (DSE)
Primary Outcome: All-cause mortality.
298 to receive medical therapy plus CABG
303 to receive medical therapy alone.
A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval [CI], 0.48 to 0.86; P=0.003).
However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21).
There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53).
Key Findings
Viability Testing Did Not Predict Survival Benefit with CABG
CABG improved survival, but this benefit was NOT dependent on the presence of myocardial viability.
Patients with viable and non-viable myocardium had similar survival outcomes whether they underwent CABG or medical therapy.
High Mortality in Non-Viable Myocardium Group
Patients without viable myocardium had higher mortality regardless of treatment.
Suggests that advanced myocardial damage predicts worse outcomes, but revascularization did not necessarily change prognosis.
CABG Reduced Deaths in Long-Term Follow-Up (STICH Extended Study - 2016)
Over time, CABG showed survival benefits, independent of viability testing.
Suggests that viability testing should not be the sole factor in deciding revascularization.
Criticisms of STICH viability substudy
Non-randomized prospective study, only a few eligible patients were randomized, included half the patients from the main trial
Viability testing was optional, there were significant differences between patients with and without viability testing
Revascularization was not guided by viability status, although trend towards higher revascularization rates in patients with viability
They used DSE and SPECT, but not 18 FDG PET or LGE-CMR which are more sensitive and specific
Stress induced ischemia was not consistently assessed
Small sample size of the group with non viable myocardium
17% cross over from OMT to CABG
What is the ART trial? What was the comparison group, the inclusion and exclusion criteria, primary and secondary outcomes, and the %s for each?
A total of 1548 patients were randomly assigned to undergo bilateral internalthoracic-
artery grafting (the bilateral-graft group) and 1554 to undergo single
internal-thoracic-artery grafting (the single-graft group). In the bilateral-graft group,
13.9% of the patients received only a single internal-thoracic-artery graft, and in
the single-graft group, 21.8% of the patients also received a radial-artery graft.
Vital status was not known for 2.3% of the patients at 10 years.
Primary outcome: In the intention to-
treat analysis at 10 years, there were 315 deaths (20.3% of the patients) in the
bilateral-graft group and 329 deaths (21.2%) in the single-graft group (hazard
ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.12; P = 0.62).
Secondary outcome: Regarding the
composite outcome of death, myocardial infarction, or stroke, there were 385
patients (24.9%) with an event in the bilateral-graft group and 425 patients (27.3%)
with an event in the single-graft group (hazard ratio, 0.90; 95% CI, 0.79 to 1.03).
As-treated analysis: In the as-treated analysis, there were 315 deaths
among 1690 patients (18.6%) in the group with
two or more arterial grafts and 307 deaths
among 1330 patients (23.1%) in the group with
a single internal-thoracic-artery graft (adjusted
hazard ratio, 0.81; 95% CI, 0.68 to 0.95). The
composite outcome of death, myocardial infarction,
or stroke occurred in 399 patients (23.6%) in the group with two or more arterial grafts
and in 385 patients (28.9%) in the group with
a single internal-thoracic-artery graft (adjusted
hazard ratio, 0.80; 95% CI, 0.69 to 0.93).
Inclusion Criteria
▪ CABG patients with multi-vessel coronary artery disease (including urgent and OPCAB patients)
Exclusion Criteria
▪ Single graft ▪ Redo CABG ▪ Evolving myocardial infarction ▪ Concomitant valve surgery
Common criticisms:
1. Crossover rate between BIMA to SIMA
2. Crossover rate from SIMA to radial
3. Inexperience with BIMA among surgeons in the trial
What is the LAAOS III trial? What were the inclusion and exclusion criteria, comparator groups?
What was the primary outcome and what were the numbers?
Blinded multicenter RCT of LAAO versus no LAAO
4600 patients, 2300 in each group
Inclusion criteria: Patients with Afib and CHADSVASc 2 or more undergoing cardiac surgery
Exclusion criteria: off-pump surgery, mechanical valve implantation, heart transplant, surgery for complex congenital heart disease, LVAD, previous cardiac surgery, previous LAAO occlusion device.
Primary outcome: Ischemic stroke (including TIA with + imaging) or systemic embolism at 5 years
LAAO 4.8 vs none 7.0%
HR 0.67 (95% CI 0.53-0.85)
NNT 37 for stroke at 5 years
LAAO methods, amputation and closure, staple closure, double layer linear closure for MIS, or device closure. Purse string or percutaneous closure was not permitted.
No differences in key secondary outcomes: heart failure hospitalization, various subcategories of stroke, all cause mortality
What is the NOTION trial? What are the primary outcome and conclusion?
10 year results - 280 patients randomized to TAVI vs surgery across all comes, older age group, mean age 79, 90% are STS <4%.
Primary outcome: Composite outcome of mortality, stroke, or MI, 65.5% in both groups at 10 years
SVD 1.5% in TAVI and 10% in SAVR at 10 years
Bioprosthetic valve failure 9.7% in TAVI and 13.8% in SAVR
Conclusions: TAVI and SAVR are equivalent but the risk of structural valve deterioration was higher in SAVR, but no difference in bioprosthetic valve failure.
What is DONATE-HCV trial?
Full Name DONATE-HCV Trial
Published 2019 (New England Journal of Medicine)
Objective To assess the safety of transplanting HCV-positive organs into HCV-negative recipients, followed by early treatment with direct-acting antivirals (DAAs).
Study Design Open-label, single-group trial
Participants 44 HCV-negative patients received kidney transplants from HCV-positive donors.
Intervention All recipients received a 12-week course of Sofosbuvir–velpatasvir (DAAs) post-transplant.
Outcome - 100% achieved sustained virologic response (SVR12) (i.e., HCV was cured).
- No impact on kidney function.
- Short-term safety was excellent.
