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American Heart Association 2018 Scientific Sessions
The recent American Heart Association Scientific Sessions, held in Chicago, Illinois, hosted 12,432 health care professionals from November 10 to 12, 2018. We review key sessions on SGLT-2 inhibition, angiotensin receptor-neprilysin inhibition, withdrawal of pharmacotherapy in dilated cardiomyopathy, anti-thrombin therapy in heart failure, lipid lowering in subjects aged 75 years and older, and finally, an important nonpharmacotherapy session on endoscopic versus open saphenous vein harvesting.
The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial
- Stephen D. Wiviott, MD, Harvard Medical School, Boston, Massachusetts
SGLT-2 inhibitors produce moderate effects on atherosclerotic major adverse coronary events (MACE) and robust effects on heart failure risk and renal outcomes, Dr. Wiviott said in a press briefing. His conclusion was based on results from DECLARE-TIMI 58 with dapagliflozin and earlier SGLT-2 inhibitor trials.
Dapagliflozin, a selective SGLT-2 inhibitor that blocks glucose and sodium resorption in the kidneys, lowers blood sugar and blood pressure and reduces weight. Reduced cardiovascular and renal events, mostly in secondary prevention patients with known atherosclerotic cardiovascular disease, have been shown in prior cardiovascular outcomes trials with SGLT-2 inhibitors. Some safety concerns related to amputation, stroke, and diabetic ketoacidosis were raised in trials prior to DECLARE-TIMI 58.
DECLARE-TIMI 58, a phase 3b, randomized, double-blind, placebo-controlled trial, evaluated the cardiovascular safety and efficacy of dapagliflozin in patients with type-2 diabetes mellitus and either cardiovascular disease (ischemic heart disease, cerebrovascular disease, peripheral artery disease) (n = 6,974) or multiple risk factors (men aged 55 years or older/women aged 60 years or older, with dyslipidemia, hypertension, or current tobacco use) for cardiovascular disease (n = 10,186). Patients were randomized 1:1 to dapagliflozin 10 mg or matching placebo. The primary safety outcome was MACE (cardiovascular disease, myocardial infarction, ischemic stroke), and dual primary efficacy outcomes were MACE and the composite of hospitalization for heart failure or cardiovascular death.
The mean age was 64 years (37% female) and median follow-up was 4.2 years. The primary efficacy endpoint rate was 4.9% in the dapagliflozin arm and 5.8% in the placebo arm (hazard ratio [HR], 0.83 [0.73–0.95]; P = 0.005). Superiority was not shown for MACE with dapagliflozin (8.8 % vs. 9.4%; HR, 0.93 [0.84–1.03]; P = 0.17), but non-inferiority was demonstrated (P < 0.001).
The renal composite of a 40% decline in estimated glomerular filtration rate, end stage renal disease, renal death, or cardiovascular death favored dapagliflozin significantly (4.3% vs. 5.6%, HR, 0.76 [0.67–0.87]; P < 0.001). All-cause mortality was similar between groups (6.2% with dapagliflozin vs. 6.6% with placebo [P = 0.20]).
While genital infections and diabetic ketoacidosis were increased with dapagliflozin, hypoglycemia and bladder cancer rates were reduced, and rates for amputation, stroke, and fracture were similar between groups. Dapagliflozin was safe and generally well-tolerated, Dr. Wiviott said.
“These drugs should be used in patients who are similar to those in the DECLARE population for heart-failure risk reduction, irrespective of their effect on MACE outcomes,” commented discussant Javed Butler, MD, MPH, of the University of Mississippi in Oxford, Mississippi. He also recommended further study of SGLT-2 inhibitors among diabetes patients without risk factors or with manifest heart failure.
Angiotensin Receptor–Neprilysin Inhibition in Patients Hospitalized With Acute Decompensated Heart Failure: Primary Results of the PIONEER-HF Randomized, Controlled Trial
- Eric J. Velazquez, Yale University School of Medicine, New Haven, Connecticut
In the PIONEER-HF trial, eight weeks of sacubitril/valsartan compared to enalapril led to greater reductions in N-terminal pro–B-type natriuretic peptide (NT-proBNP) and re-hospitalizations for heart failure. The trial patients had hemodynamically stabilized heart failure and reduced ejection fractions, Dr. Velazquez said in a press briefing.
Acute decompensated heart failure with reduced ejection fraction is a leading cause of hospitalization (more than one million people annually in the U.S.) and is associated with substantial morbidity and mortality. While sacubitril/valsartan, a first-in-class angiotensin receptor–neprilysin inhibitor, has been shown to improve survival in ambulatory patients with chronic heart failure and reduced ejection fraction, it is unknown if in-hospital initiation of sacubitril/valsartan compared to enalapril is safe and effective in acute decompensated heart failure, Dr. Velazquez noted.
PIONEER HF, which was conducted at 129 U.S. sites, included patients with heart failure and reduced ejection fraction who were hospitalized for acute decompensated heart failure. After hemodynamic stabilization, 881 patients (mean age ~62 years, ~28% female) were randomly assigned to sacubitril–valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or enalapril (target dose, 10 mg twice daily). About one-third of the patients had no prior heart failure diagnosis. Time-averaged proportional change in the NT-proBNP concentration from baseline through weeks four and eight was the primary efficacy outcome. Key safety endpoints included worsening renal function, symptomatic hypotension, hyperkalemia, and angioedema.
In the primary efficacy analysis, NT-proBNP with sacubitril/valsartan was reduced by 29% more than with enalapril (CI 19%, 37%; P < 0.0001). Subgroup analysis showed the benefit of persisting with treatment in those patients with or without prior heart failure and with or without prior treatment with ACE inhibitors/ARBs. Safety analysis showed no significant differences between treatments for worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema.
The reduction in event rate with sacubitril/valsartan was significant (enalapril, 16.8%; sacubitril/valsartan, 9.3%; HR, 0.54 [0.37, 0.79]; P = 0.001) for the serious clinical composite endpoint of death, heart failure re-hospitalization, need for left-ventricular assist device, and transplant listing. Thirteen patients needed treatment to prevent one event. The key component in this analysis was re-hospitalization for heart failure (13.8% for enalapril, 8.0% for sacubitril/valsartan; HR, 0.56, P = 0.005).
“These results support the in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure and reduced ejection fraction, irrespective of prior ACEi/ARB use, or prior heart failure diagnosis,” Dr. Velazquez concluded.
Uptake of sacubitril/valsartan has been low (at about 15% of eligible patients), noted Larry A. Allen, MD, the discussant for PIONEER HF. Insufficient clinical trial evidence, the complicated process of switching over from enalapril, cost, and clinical inertia may account for this. Trial findings showed sacubitril/valsartan to be safe and effective. Limitations included the fact that the trial population was about 10 years younger than the typical patient, and the primary endpoint was a surrogate marker. The secondary endpoints, however, were clinical, impressive, and consistent with the PARADIGM trial findings. “PIONEER HF reinforces the importance and safety of aggressive, guidelines-directed medical therapy in most patients,” Dr. Allen concluded. He commented also that PIONEER HF offers an algorithm for inpatient and subsequent outpatient management in heart failure with reduced ejection fraction that is simpler for both clinicians and patients.
Withdrawal of Pharmacological Heart Failure Therapy in Recovered Dilated Cardiomyopathy (TRED-HF)–A Randomized Controlled Trial
- Brian P. Halliday, MD, Imperial College, London, United Kingdom
For patients who have recovered from dilated cardiomyopathy, withdrawing heart-failure pharmacotherapy is not a wise strategy, according to TRED-HF trial results. Improvement in function, Dr. Halliday said in a press briefing, indicates remission rather than permanent recovery, for most patients.
Side effects, intention to become pregnant, or financial constraints often cause responsive patients to ask whether they need to take the medications forever. The open-label, pilot, randomized TRED-HF trial was conducted to investigate the safety of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were currently asymptomatic with left-ventricular ejection fraction improved from below 40% to 50% or higher. Also, their left-ventricular end-diastolic volumes had normalized, and their NT-proBNP concentrations were below 250 ng/L.
Fifty-one patients (median age 54 years, 67% male) were randomly assigned (1:1) to staged withdrawal or continuation of treatment. After six months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within six months, defined by a reduction in left-ventricular ejection fraction of more than 10% and to less than 50%, an increase in left-ventricular end-diastolic volume by more than 10% and to higher than the normal range, a two-fold rise in NT-proBNP concentration and to more than 400 ng/L, or clinical evidence of heart failure. When any of these conditions were met, therapy was immediately re-introduced.
Dr. Halliday noted that median time from diagnoses for enrolled patients was 4.9 years and median left-ventricular ejection fraction was 25% at initial diagnosis. All patients at enrollment were in sinus rhythm (median left-ventricular ejection fraction, 60%; median NT-proBNP, 72 ng/L).
Among 25 patients who had therapy withdrawn, 11 (44%) relapsed in the randomized phase. Among 25 crossover patients, 9 (36%) relapsed. Half of the patients who began therapy withdrawal completed follow-up without re-initiation of treatment and 16 (32%) completed withdrawal without > 3% deterioration in left-ventricular ejection fraction. Patients who relapsed were asymptomatic at follow-up.
Serious adverse events in the withdrawal arm led to hospitalization in three patients (urinary sepsis, non-cardiac chest pain, and an elective procedure), but no deaths, heart failure hospitalizations, or major adverse coronary events.
“Withdrawal of therapy should not usually be attempted until predictors of relapse are defined, we gain a better understanding of the importance of specific therapies, and have monitoring in place,” Dr. Halliday concluded.
The probability that with longer-term follow-up, the 40% heart-failure recrudescence rate would be much higher was suggested by discussant Jane E. Wilcox, MD, of Northwestern University in Chicago, Illinois. She commented further that TRED-HF is a pilot study only, and the results are not definitive. “We are currently unable to identify true recovery, if it exists, and remission is an appropriate term for those patients fortunate to have improved ventricular function as a response to therapy. These patients should continue life-saving medical therapy without interruption.”
Primary Results of REDUCE-IT
- Deepak L. Bhatt, MD, MPH, Professor of Medicine, Harvard Medical School, Boston, Massachusetts
In hypercholesterolemic patients, icosapent ethyl 4 g/day compared with placebo reduced important cardiovascular events by 2% in REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl Trial). Icosapent ethyl, said Dr. Bhatt in a press briefing, is a highly purified, eicosapentaenoic acid ethyl ester that lowers triglyceride levels and also has antioxidative, anti-inflammatory, and other potentially anti-atherogenic properties.
Despite therapy with statins, Dr. Bhatt noted, residual cardiovascular risk remains, especially in patients with persistent hypertriglyceridemia. Although low-dose omega-3 mixtures have shown no significant cardiovascular benefits, JELIS (Japan Eicosapentaenoic Acid Lipid Intervention Study) results suggested a cardiovascular risk reduction in hypercholesterolemic patients receiving eicosapentaenoic acid.
Patients enrolled in REDUCE-IT (n = 8,179) were aged 45 years and older with established cardiovascular disease (70.7%), or aged 50 years and older with diabetes and one or more cardiovascular disease risk factors. All patients had been receiving statin therapy and had a fasting triglyceride level of 135 to 499 mg/dL (1.52 to 5.63 mmol/L) and a low-density lipoprotein cholesterol level of 41 to 100 mg/dL (1.06 to 2.59 mmol/L). The patients were randomly assigned to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary endpoint of the multicenter, randomized, double-blind, placebo-controlled trial was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary re-vascularization, or unstable angina.
The median age was 64 years (29% female), and the median baseline triglyceride level was 216 mg/dL. Triglyceride levels in the placebo group increased to 221 mg/dL after one year, while levels decreased by about 20% in the icosapent ethyl group (175.0 mg/dL).
Primary endpoint analysis at one year revealed highly significant benefit in the icosapent ethyl group. The composite endpoint rate was 28.3% in the placebo group and 23.0% in the icosapent ethyl group (HR, 0.75 [95% CI, 0.68–0.83]; P = 0.00000001). The rate for the key secondary endpoint of cardiovascular death, myocardial infarction, and stroke was also significantly reduced in the icosapent ethyl group (20.0% vs. 16.2%; HR, 0.74 [0.65–0.83]; P = 0.0000006). Dr. Bhatt pointed out a 20% reduction in death due to cardiovascular causes, a 31% reduction in myocardial infarction, and a 28% reduction in stroke, and noted that primary and secondary endpoint benefits were generally consistent across subgroups.
Treatment-emergent event rates were similar (icosapent ethyl, 81.8% vs. placebo, 81.3%). Bleeding-related disorders were more common in the icosapent ethyl group, however (2.7% vs. 2.1%; P = 0.06), and atrial fibrillation was more frequent (5.3% vs. 3.9%; P = 0.003). No fatal bleeding events were reported.
Discussant Carl E. Orringer, MD, noted that the REDUCE-IT findings add icosapent ethyl to ezetimibe and PCSK9 inhibitors to the list of agents, with randomized, controlled trial data supporting atherosclerotic cardiovascular disease risk reduction on top of maximally tolerated statins.
Effect of Rivaroxaban on Thromboembolic Events in Patients with Heart Failure, Sinus Rhythm, and Coronary Disease
- Barry Greenberg, MD, University of California-San Diego, La Jolla, California
For the primary clinical endpoints of death and cardiovascular events, rivaroxaban 2.5 mg twice daily compared with placebo failed in the COMMANDER HF trial. A post-hoc analysis, reported Dr. Greenberg in a press conference, did reveal significant reductions in thromboembolic events.
Following an episode of worsening heart failure, risks for hospital readmission and death remain high, Dr. Greenberg said. Activation of thrombin-related pathways may contribute to heart failure progression by inducing inflammation, endothelial dysfunction, and arterial and venous thrombosis. Prospective studies of warfarin in heart failure in patients with reduced ejection fraction, however, have failed to demonstrate overall benefit. He noted further that while therapies targeting a variety of mechanisms have, to date, failed to improve outcomes following heart failure hospitalizations, in trials that included heart failure patients, rivaroxaban in combination with antiplatelet agents (ATLAS ACS2 TIMI 51/COMPASS) has been shown to reduce adverse cardiovascular outcomes. Rivaroxaban, unlike warfarin, directly targets thrombin generation.
The COMMANDER HF hypothesis was that in patients with recent worsening of chronic heart failure, reduced ejection fraction, and coronary artery disease, rivaroxaban 2.5 mg twice daily added to background anti-platelet therapy would reduce rates of death and cardiovascular events.
Investigators enrolled 5,022 patients with chronic heart failure, left-ventricular ejection fraction of 40% or lower, coronary artery disease, increased plasma natriuretic peptide concentrations, and with no atrial fibrillation. The composite primary endpoint of all-cause mortality, myocardial infarction, and stroke was not reduced in the rivaroxaban arm (HR, 0.94). Analysis showed an endpoint driven by mortality that was attributed mostly to worsening heart failure. Numerical advantage for the classical thromboembolic events of myocardial infarction and stroke was seen among those patients receiving rivaroxaban. Dr. Greenberg underscored that the primary endpoint was driven by heart failure events not mediated by thrombin and therefore not amenable to rivaroxaban therapy.
The hypothesis for a COMMANDER-HF post-hoc analysis was that thromboembolic events pre-specified by the protocol (myocardial infarction, ischemic stroke, sudden/unwitnessed death, pulmonary embolism, or symptomatic deep vein thrombosis) would be reduced among those receiving rivaroxaban versus placebo. Dr. Greenberg reported that over a median follow-up of 19.6 months, 14.3% of patients experienced a thromboembolic event. The event rates per 100 patient years were 7.0 in the rivaroxaban arm and 8.5 in the placebo arm (HR, 0.83 [0.72, 0.96]; P = 0.013), with myocardial infarction (HR, 0.83) and ischemic stroke (HR, 0.64) driving the reduction.
“The findings of this post hoc analysis support the possibility that low-dose rivaroxaban may reduce the risk of thromboembolic events in HF patients,” Dr. Greenberg concluded.
Ezetimibe in Prevention of Cerebrovascular and Cardiovascular Events in Medium- to High-Risk, Elderly Patients With Elevated LDL-Cholesterol Yasuyoshi Ouchi, MD, PhD, Professor Emeritus, University of Tokyo, Tokyo, Japan
The results of the EWTOPIA75 trial offer the first evidence supporting primary prevention of cerebrovascular and cardiovascular events with lipid-lowering therapy in patients aged 75 years and older, Dr. Ouchi said in an oral presentation. Ezetimibe, in patients with no history of coronary artery disease, reduced the occurrence of a composite of atherosclerotic cardiovascular events.
The efficacy of lipid-lowering therapy with statins for high-risk patients is well established. However, there is no evidence about its clinical benefits in elderly Japanese patients (aged 75 years and older) with elevated low-density lipoprotein cholesterol (LDL-C) levels who have no history of coronary artery disease. The increase in elderly populations has been explosive in many countries and regions, including the U.S., Europe, Asia, and especially Japan, and many in these populations have hypercholesterolemia. Prospective, randomized, controlled trials in this elderly population are lacking, Dr. Ouchi observed.
The hypothesis tested in EWTOPIA75, a prospective, multi-center, open-label, blinded endpoint, randomized, controlled trial, was that LDL-C-lowering therapy for patients at or above 75 years of age with elevated LDL-C levels and no history of coronary artery disease can significantly prevent the occurrence of cerebrovascular and cardiovascular events. Ezetimibe inhibits cholesterol absorption in the intestine. All enrolled patients had LDL-C levels ≥ 140 mg/dL and one or more cardiovascular risk factors (diabetes, hypertension, smoking, low high-density lipoprotein (HDL) cholesterol levels, and high triglyceride levels). A composite of sudden cardiac death, fatal myocardial infarction, nonfatal myocardial infarction, coronary revascularization, fatal stroke, and/or nonfatal stroke was the primary endpoint.
The trial included 3,796 patients with a mean age of 80.7 years (male, 25.7%). Fifty-five percent were aged 75 to 79 years old and 31% were aged 80 to 84 years old. Mean LDL-C, HDL-C, and triglycerides at baseline were 161.6 ± 19.7 mg/dL, 56.8 ± 14.1 mg/dL, and 131.3 ± 55.3 mg/dL, respectively. Patients were randomly assigned to ezetimibe (ezetimibe 10 mg/day plus diet counseling) or to diet counseling alone.
One year after randomization, mean LDL-C levels were 126.1 ± 26.2 mg/dL and 144.0 ± 29.2 mg/dL in the ezetimibe and control groups, respectively. The difference was statistically significant (P = 0.001), Dr. Ouchi said.
After five years, the incidence of the composite primary endpoint was reduced significantly in the ezetimibe group (HR, 0.69 [95% CI, 0.504–0.862]; P = 0.002). The reduction was driven by a significant reduction in cardiac events (HR, 0.602 [95% CI, 0.370–0.979]; P = 0.041). Adverse-event rates were similar between the groups.
Noting that the trial did not have a placebo control, Dr. Ouchi remarked, “EWTOPIA75 had entirely objective endpoints in which investigators’ subjective judgments were not allowed.”
Randomized Endovein Graft Prospective (REGROUP) Trial
- Marco A. Zenati, MD, Professor of Surgery at Harvard Medical School, Boston, Massachusetts
In REGROUP, a study comparing endoscopic versus open vein-graft harvesting in coronary artery bypass graft (CABG) surgery, MACE rates were similar, but there were fewer complications and less pain with endoscopic vein-graft harvesting, Dr. Zenati reported at an AHA press briefing.
Endoscopic harvesting of saphenous veins for CABG surgery is associated with less pain, less infection, and better patient satisfaction. However, a 2009 study (New England Journal of Medicine, 361) showed endoscopic vein-graft harvesting versus open harvesting to be independently associated with vein-graft failure and adverse clinical outcomes including death (P = 0.005), and called for randomized clinical trials. Dr. Zenati noted that saphenous vein grafts are the most commonly used conduit for CABG surgery, and are harvested endoscopically in more than 70% of cases in North America.
REGROUP included the requirement that all endoscopic vein-graft harvesters had to have previously performed at least 100 procedures with less than a 5% rate of conversion to open procedures. Also, all patients had indications for elective or urgent on-pump CABG surgery using at least one vein graft. The REGROUP primary outcome was MACE (death, myocardial infarction, or repeat revascularization).
REGROUP investigators randomized 576 patients to endoscopic vein-graft harvesting and 574 to open vein-graft harvesting. The mean age was ~66 years (99.5% male). Harvest time was similar for endoscopic (57.5 minutes) and open vein harvesting (61.4 minutes), and most patients required three grafts.
After a median follow-up of 2.78 years, MACE rates were similar (P = 0.47; open, 15.5%; endoscopic, 13.9%) and its components of death (open, 8%; endoscopic, 6.4%), myocardial infarction (open, 5.9%; endoscopic, 4.7%) and revascularization (open, 6.1%; endoscopic, 5.4%).
Adverse-event rates, Dr. Zenati reported, favored endoscopic vein-graft harvesting, with fewer leg wound infections (1.4% vs. 3.1%), less need for a visiting nurse to dress leg wounds (1.2% vs. 3.7%), more patients reporting no leg incision pain (79.1% vs. 62.2%), and fewer antibiotics needed at six weeks (4.6% vs. 14.4%; P < 0.05 for all). Investigators also observed a trend toward more recurrent events with open vein-graft harvesting (HR, 1.29 [1.00 to 1.68]).
Dr. Zenati cited REGROUP’s lack of graft patency assessment by imaging and the predominantly male population as trial limitations. “Longer-term follow-up is required to examine whether additional differences emerge,” he commented.
AHA discussant Marc Ruel, MD, MPH, called REGROUP “definitive,” but pointed out that “expert” open vein-graft operators were not required, and very few radial arteries were used. The key question he posed (and which was deflected) was: “Which operation would you want for yourself?”
CIRT Results of Low-Dose Methotrexate for the Prevention of Atherosclerotic Events
- Paul Ridker, MD, Harvard Medical School, Boston, Massachusetts
In patients with stable coronary artery disease and either type-2 diabetes or metabolic syndrome, low-dose methotrexate plus folic acid compared with placebo did not reduce rates of myocardial infarction, stroke, or cardiovascular death. The Cardiovascular Inflammation Reduction Trial (CIRT) addressed the question, Dr. Ridker said at a press briefing, of whether inflammation reduction, in the absence of lipid lowering, can reduce cardiovascular event rates.
Inflammation is known to play a critical role in atherothrombosis, Dr. Ridker said. In prior research (the CANTOS trial), selective neutralization of interleukin-1β improved cardiovascular outcomes. Also, observational data have shown reduced events in patients with high cardiovascular risk with arthritis and psoriasis taking low-dose methotrexate. While the mechanism for methotrexate’s anti-inflammatory effects is uncertain, its safety record of over 40 years in older individuals with rheumatoid and psoriatic arthritis is enviable, Dr. Ridker commented. Also, these patients have similar comorbidities to those who have suffered a prior heart attack.
CIRT investigators enrolled 4,786 patients (mean age, ~66 years, ~19% female) at 417 U.S. and Canadian sites. All of the patients had suffered a documented myocardial infarction or had multi-vessel coronary artery disease. They had been on a stable, secondary prevention regimen for a minimum of 60 days. At baseline, median LDL-C and high-sensitivity C-reactive protein (hsCRP) levels were 68 mg/dL and 1.5 mg/L, respectively.
Subjects were randomized 1:1 to methotrexate (15–20 mg PO/week) plus 1 mg of folate daily, or placebo plus 1 mg of folate daily. All patients were treated with an aggressive standard of care. MACE (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) or MACE plus cardiovascular death was the primary endpoint.
MACE cumulative incidence rates after four years of follow-up were 3.46% for low-dose methotrexate and 3.43% for placebo (P = 0.91). The rates for MACE plus hospitalization for unstable angina requiring urgent revascularization were also similar, at 4.13% for methotrexate and 4.31% for placebo (P = 0.67).
In the methotrexate group, higher rates of malignancy (mainly non-basal cell skin cancer) were observed.
AHA discussant Sidney C. Smith, Jr, MD, Professor of Medicine at the University of North Carolina in Chapel Hill, commented, “CIRT is yet another testimony to the value of randomized controlled trials and the limitations of observational and animal data in determining the efficacy of drug interventions on patient outcomes.” In addition, Dr. Smith commended the AHA for presenting “negative” results.