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JAMA. 2013;309(12):1241-1250
Background Case reports as early as the 1950s suggested chelation of lead might reduce angina. The popularity of chelation accelerated around the turn of the century. Small underpowered trials of chelation were inconclusive. Mainstream medicine considered chelation unproven and potentially hazardous.
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Chelation with disodium EDTA binds divalent and some trivalent cations, including calcium, magnesium, lead, cadmium, zinc, iron, aluminum, and copper, which facilitates their urinary excretion. High dose vitamins are often co-administered with chelation.
The NIH-funded Trial to Assess Chelation Therapy (TACT) trial was conducted to respond to the public health problem posed by EDTA chelation therapy: namely, that large numbers of patients could be exposed to undefined risks for unproven benefits. TACT was a double-blind placebo-controlled 2x2 factorial randomized trial enrolling 1708 patients to test chelation therapy.
Patients Eligibility for TACT required patients be older than 50 years, have a creatinine of 160/100 mm Hg, past intolerance to the chelation or vitamin components, chelation therapy within 5 years, coronary or carotid revascularization planned or having taken place within 6 months, cigarette smoking within 3 months, active heart failure or heart failure hospitalization within 6 months, or inability to tolerate 500-mL infusions weekly. Enrollment began in 2003 and follow-up continued until 2011. There were 134 sites; 60% of which were established chelation centers.
Baseline Characteristics The median age of patients was 65 years, 18% were women and the median body mass index was 30. More than 90% of patients had had either percutaneous coronary intervention or coronary bypass surgery. Approximately 31% of patients had diabetes. Use of guideline directed medications was typical of a well-treated population of post-MI patients. Procedures The active 10-component chelation solution consisted of up to 3 g of disodium EDTA; 7 g of ascorbic acid; 2 g of magnesium chloride; 100 mg of procaine; 2500 U of unfractionated heparin; 2 mEq of potassium chloride; 840 mg of sodium bicarbonate; 250 mg of pantothenic acid; 100 mg of thiamine; 100 mg of pyridoxine; and sterile water to make up 500 mL of solution. The identical-appearing placebo solution consisted of 500 mL of normal saline and 1.2% dextrose (2.5 g total).
The chelation or placebo infusions were administered through a peripheral intravenous line, weekly for the first 30 infusions, followed by an additional 10 infusions 2 to 8 weeks apart.
Patient also received an oral vitamin-mineral regimen vs an oral placebo.
In this review, we focus on the intention-to-treat comparison of EDTA chelation vs placebo.Endpoints The primary endpoint was a composite of death, reinfarction, stroke, coronary revascularization, or hospitalization for angina.
TACT trialists had planned to enroll 2300 patients over three years with a follow-up of one year. Enrollment was slow, and with permission from the data safety monitoring board (DSMB) enrollment was decreased to 1700 patients and follow-up was extended. The resultant power was 85% to detect a 25% reduction in the primary endpoint assuming a 2.5% per year event rate in the placebo arm.
Over the course of the trial, the DSMB requested 11 interim analyses of the data. Because of the increased monitoring, the level of statistical significance required for the primary endpoint was enhanced to a P value of less than 0.036.
Results After a median follow-up of 55 months, a primary end point occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio [HR]: 0.82 [95% CI: 0.69-0.99]; p= .035). There was no effect on total mortality (10% vs 11%, HR: 0.93, 95% CI: 0.70-1.25; p= 0.64). Myocardial infarction and coronary revascul

N Engl J Med 2012;366:9-19
Background Following an acute coronary syndrome, individuals have a substantially elevated risk of recurrent events, compared to a similar individual who did not experience ACS, despite the use of appropriate risk reducing therapies. This is termed “residual risk” and the concept has been mentioned in prior reviews. The quest to lower residual risk continues to be a major driver of new products and therapeutic concepts in cardiovascular medicine.
Rivaroxaban is an oral anticoagulant that directly and selectively inhibits factor Xa. Factor Xa initiates the final common pathway of the coagulation cascade resulting in the formation of thrombin. Thrombin promotes platelet aggregation.
At the time the trial was undertaken, both aspirin and thienopyridines were established agents that worked via different mechanisms, downstream of thrombin formation, to stop platelets from sticking together. Could the addition of an agent that inhibits thrombin formation, upstream of platelet activation and aggregation, reduce risk further without causing a prohibitive increase in bleeding risk?
A meta-analysis of small trials involving the use of warfarin, in addition to aspirin, suggested that warfarin, an indirect inhibitor of thrombin, could improve cardiovascular outcomes. And a phase 2 dose finding trial with rivaroxaban provided further support. Thus, the ATLAS ACS-TIMI 51 trial sought to test the hypothesis that adding rivaroxaban to standard therapies, at 2.5 or 5 mg twice daily, would reduce cardiovascular events compared to placebo.
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Patients Adults who had presented with an acute coronary syndrome (STEMI, NSTEMI or unstable angina). Patients under 55 years of age had to have either diabetes or a history of a previous MI. Patients were excluded if they had a platelet count Baseline characteristics Patients averaged 62 years of age with 36% greater than or equal to 65 and only 9% greater than or equal to 75. The majority of patients were either white (73%) or Asian (21%). Existing medical conditions were typical for an ACS population. The index diagnosis was a STEMI in 50% with the other half split fairly evenly between NSTEMI and UA. The majority of patients enrolled were from Eastern Europe (39%) and Asia (21%). Nearly all patients were on aspirin (99%) and a thienopyridine (93%) and 83% were on a statin drug.
Procedures Patients were enrolled within 7 days after hospital admission for an ACS. They had to be stable at the time of enrollment with the initial revascularization strategies completed. They were randomly assigned in a 1:1:1 fashion to twice daily rivaroxaban 2.5 mg, rivaroxaban 5 mg or placebo with a maximum follow-up of 31 months. All patients were to receive standard medical therapy. Patient follow-up occurred at 4 weeks, 12 weeks and every 12 weeks thereafter.
Endpoints The primary endpoint was a composite of death from cardiovascular causes, myocardial infarction, or stroke (ischemic, hemorrhagic, or stroke of uncertain cause). The primary safety endpoint was TIMI major bleeding not related to CABG surgery.
As prespecified by the investigators, the efficacy analyses were performed with the use of a modified intention-to-treat principle; however, they performed sensitivity efficacy analyses using a standard intention-to-treat approach. *Since the statistical significance of the main findings did not meaningfully change with either approach, we report the p-values based on the standard approach since using a modified approach is unconventional.
The investigators determined they would need 983 primary endpoint events to provide a power of 96% to detect a 22.5% relative reduction between the combined-dose group receiving rivaroxaban and the placebo group with a 2-sided alpha of 0.05. This would also yield a power of 90% to determine a relati

N Engl J Med 2010;363:930-942
Background By 2010, dual antiplatelet therapy had been established as beneficial during and after percutaneous coronary intervention for acute coronary syndromes. Optimal dosing however remained unknown. This included the best loading dose of clopidogrel and optimal dose of aspirin.
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The Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT–OASIS 7) trial was designed to determine whether a doubling of the loading and initial maintenance doses of clopidogrel is superior to the standard-dose regimen and whether higher-dose aspirin (300 to 325 mg daily) is superior to lower-dose aspirin (75 to 100 mg daily) in patients with acute coronary syndromes referred for an early invasive strategy.
Patients Adult patients who presented with a non-ST-segment elevation acute coronary syndrome (ACS) or an ST-segment elevation myocardial infarction. Patients had to have had coronary angiography with a plan to perform PCI within 72 hours. Major exclusion criteria were an increased risk of bleeding or active bleeding and a known allergy to clopidogrel or aspirin. 
Baseline Characteristics Nearly all patients had angiography. About 68% had PCI and 32% did not have PCI due to lack of significant (≤70%) stenosis. About a quarter of patients had coronary-artery bypass surgery. The average age of patients was 61 years; 27% female sex, and 70% had a diagnosis of unstable angina or NSTEMI. The median time to randomization in patients with unstable angina/NSTEMI was 3.4 days vs 0.6 days in patients with
STEMI. About 60% of patients were white, and 22% were Asian. The co-existing cardiac risk factors, such as smoking, hypertension, diabetes and previous MI were similar in all the trial arms, and typical of most trials at the time.
Procedures The CURRENT-OASIS 7 trial had 2x2 factorial design. First, comparing in a double-blind fashion, a double dose vs standard dose clopidogrel regimen. In the second component, patients were randomly assigned in an open-labeled fashion to higher- or lower-dose aspirin.
Immediately after randomization and before coronary angiography, patients randomly assigned to double-dose clopidogrel received a loading dose of 600 mg on day 1, followed by 150 mg once daily on days 2 through 7. Patients assigned to standard-dose clopidogrel received a 300-mg loading dose on day 1 before angiography, followed by 75 mg once daily on days 2 through 7. On days 8 through 30, both the double-dose and standard-dose groups received 75 mg of clopidogrel once daily.
Patients randomly assigned to lower-dose aspirin received 75 to 100 mg daily on days 2 through 30, and those randomly assigned to higher-dose aspirin received 300 to 325 mg daily on days 2 through 30. An initial loading dose of aspirin 300 mg was used in both arms on day 1. Other therapies, such as anti-thrombotics were left to the discretion of the treating doctors. Endpoints The primary endpoint was cardiovascular death, myocardial infarction, or stroke at 30 days. The sample-size calculation estimated an event rate of 11% at 30 days with standard-dose clopidogrel or lower-dose aspirin. That would have led to 14,000 patients to have 90% power to detect a 16% reduction in the primary endpoint. Lower-than expected event rates required an increase in sample size to 25,000 patients. This allowed for an 80% power to detect a 16% reduction in the primary endpoint.
Results  A primary outcome event occurred in 4.2% of patients in the double-dose clopidogrel group at 30 days, as compared with 4.4% in the standard-dose group (hazard ratio, 0.94, 95% confidence interval [CI], 0.83 to 1.06; P=0.30). The rate of death from any cause did not differ significantly between the double-dose and standard-dose groups (2.

N Engl J Med 2012;367:1297-1309
Background: In patients with acute coronary syndrome, clinical guidelines recommend early angiography particularly in those deemed moderate to high risk. However, a proportion of patients do not undergo revascularization, and these patients have poorer outcomes compared to those who do undergo revascularization.
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The TRITON-TIMI 38 trial demonstrated that prasugrel, when compared to clopidogrel, reduces ischemic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). Notably, in the TRITON-TIMI 38 trial, 99% of the patients underwent PCI at the time of randomization.
Expanding upon the findings of TRITON-TIMI 38, the TRILOGY ACS trial sought to test the hypothesis that aspirin plus prasugrel is superior to aspirin plus clopidogrel in patients with acute coronary syndrome, without ST segment elevation, who are managed medically without revascularization.
Patients: Patients were enrolled if they had unstable angina or non-ST elevation myocardial infarction and were treated medically without revascularization, within 10 days of the index event. Patients with non-ST elevation myocardial infarction had elevated cardiac biomarkers. Patients with unstable angina had ST-segment depression of more than 1 mm in two or more electrocardiographic leads and negative cardiac biomarkers. Patients had to have one of the following: age of 60 years or older, diabetes mellitus, prior myocardial infarction or prior revascularization with either PCI or coronary-artery bypass grafting (CABG). Main exclusion criteria were history of stroke or TIA (this group had net harm with prasugrel in TRITON-TIMI 38), renal failure requiring dialysis and patients taking oral anticoagulants.
Baseline characteristics: The trial enrolled 9,326 patients at 966 sites in 52 countries. The average age of patients was 66 years, with 78% were below 75 years old, and 61% were men. About 70% of the patients had non-ST elevation myocardial infraction as their index event. The average GRACE score was 122. About 82% had hypertension, 59% had hyperlipidemia, 38% had diabetes, 43% had prior myocardial infarction and 20% were current or recent smokers. The majority of patients were stable, with 88% classified as Killip class I.
Angiography before randomization was performed in 41% of the patients. Medications at randomization included beta-blockers in 78% of the patients, ACEi or ARB in 75%, statins in 83% and proton pump inhibitors in 25%.
Procedures: The trial was conducted as double-blind double-dummy study. Patients who underwent randomization within 72 hours after the first medical contact received a loading dose of 30mg of prasugrel followed by 10mg daily. The maintenance dose of prasugrel was 5mg daily for patients aged 75 years or older or patients who weighed less than 60 kg. Patients who underwent randomization after 72 hours of the first medical contact received open label clopidogrel before randomization and the maintenance study drug after randomization. Clopidogrel was given as a loading dose of 300mg followed by a maintenance dose of 75mg daily. Aspirin was given in all patients and the recommended dose was 100mg per day or less. Study drugs were given for a minimum of 6 months and a maximum of 30 months.
Endpoints: The primary efficacy endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke among patients Analysis was performed based on the intention-to-treat principle. The trial was event-driven. To ensure 90% power to detect 22% relative risk reduction of prasugrel over clopidogrel with a two-sided alpha of 5%, a total of 688 patients, Results: The trial randomized 4,663 patients to the prasugrel group and 4,663 patients to the clopidogrel group. The median duration of follow up

N Engl J Med 2009;361:1045-57.
Background Similar to Prasugrel, Ticagrelor is a direct-acting oral antagonist of the adenosine diphosphate receptor P2Y12. Unlike clopidogrel that requires transformation of the prodrug to the active metabolite, Ticagrelor provides faster and more consistent P2Y12 inhibition.
In the TRITON-TIMI 38 trial, Prasugrel compared to clopidogrel reduced myocardial infarction in patients with ACS but was associated with more major bleeding and subgroup interactions were evident for patients who were older, had a history of stroke or risk factors for bleeding and who were generally at higher risk for recurrent events.
The Study of Platelet Inhibition and Patient Outcomes (PLATO) sought to test the hypothesis that Ticagrelor is superior to clopidogrel for the prevention of vascular events and death in patients presenting with ACS.
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Patients Eligible patients were hospitalized for ACS, with or without ST-segment elevation (STE), whose onset of symptoms occurred within the previous 24 hours. For patients without STE, at least 2 of the following criteria were required: 1) ST-segment changes on ECG indicating ischemia, 2) a positive biomarker indicating myocardial necrosis, or 3) one or more risk factors including age ≥60 years, previous MI or CABG, CAD with stenosis of ≥50% in at least 2 vessels, history of ischemic stroke, TIA, carotid stenosis, cerebral revascularization, diabetes, peripheral arterial disease or CKD based on creatinine clearance Baseline characteristics The median age of patients was 62 years with 15% being ≥75 years and 72% were men; over 90% were white. The index event was UA or NSTEMI in approximately 60% and STEMI in 38%. Only 81% of patients underwent coronary angiography. PCI was performed in 64% of patients (was 99% in TRITON-TIMI 38) and CABG was performed in 10%. Interestingly, the majority of patients stented received only a bare metal stent (65%). 20% of patients had a prior MI, 25% had diabetes, 65% had hypertension and 36% were habitual smokers. Only 4% of patients had CKD defined as a creatinine clearance ≤60 ml/min or a history of ischemic stroke.
Procedures All drugs were administered in a double-blind, double-dummy fashion. Ticagrelor was given as a loading dose of 180 mg followed by 90 mg twice daily for all patients. For patients who had not been on clopidogrel for at least 5 days prior to randomization, a 300 mg loading dose of clopidogrel was given followed by a dose of 75 mg daily. Others in the clopidogrel group continued to receive a maintenance dose of 75 mg daily.
For patients undergoing PCI more than 24 hours after randomization, an additional dose of their study drug was given at the time of PCI, which was 300 mg of clopidogrel, at the investigator’s discretion, or 90 mg of ticagrelor. In patients undergoing CABG, it was recommended that the study drug be withheld for 5 days in the clopidogrel group and for 24 to 72 hours in the Ticagrelor group.
Outpatient visits occurred at 1, 3, 6, 9, and 12 months, with a safety follow-up visit 1 month after the end of treatment, which was scheduled to continue for 12 months. Notably, patients left the study at their 6- or 9- month visit if the targeted number of primary endpoint events had occurred by that time.
Endpoints The primary efficacy endpoint was the time to the first occurrence of a composite endpoint of death from vascular causes, myocardial infarction, or stroke. Investigators estimated that 1780 primary endpoint events would be required to achieve 90% power to detect a 13.5% relative risk reduction of the primary endpoint in the ticagrelor group, based on an event rate of 11% in the clopidogrel group at 12 months (≤9.5% vs 11%). The consistency of treatment effects over time was assessed from randomization to 30 days and from 31 to 360 days. The p