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American College of Cardiology 68th Scientific Session and Exposition
The 68th Scientific Session and Exposition took place in New Orleans, Louisiana, March 16–18, 2019, and more than 17,000 cardiology health professionals attended the meeting. We review two sessions on atrial fibrillation, two on heart failure, two on hypertension, and one each on endocarditis and ST-elevation myocardial infarction.
Results of a Large-scale, App-based Study to Identify Atrial Fibrillation Using a Smartwatch: The Apple Heart Study
- Mintu Turakhia, MD, MAS, and Marco Perez, MD, Stanford University School of Medicine, Palo Alto, California
Findings from the Apple Heart Study (funded by Apple, Inc.) suggest that Apple Watch’s optical-sensor technology (photoplethysmography) may have clinical value for detecting atrial fibrillation (AF), according to Dr. Mintu Turakhia. The sensor, paired with a mobile app, identified AF with a high positive predictive value among 419,297 Apple Watch wearers with no prior diagnosis of AF, he said in a press briefing.
Using the sensor’s ability to intermittently detect subtle changes in blood flow, the watch generates a tachogram, plotting time between heartbeats. When an irregular tachogram is registered, sampling becomes more frequent, and if five out of six tachograms are irregular within 48 hours, a notification is sent to the user. Notified participants are prompted to contact a study physician (“Telehealth Doctor”) via the app, and, subsequent to a video consultation, may be sent an electrocardiogram (ECG) patch by mail. The patch is worn for up to seven days, then returned to the physician for analysis of the presence of AF. “The app continuously gathers data in the background without the wearer of the device doing anything,” Dr. Turakhia said. A survey of data was conducted at 90 days.
The single-arm, open-label Apple Heart Study included U.S. residents (22 years of age or older) without current AF, atrial flutter, or anticoagulant use, who own an iPhone (5S or higher) plus an Apple Watch (Series 1–3). The primary study goals were 1) to determine the proportion of participants receiving an irregular pulse notification that was subsequently verified through the ECG patch, 2) to determine how well the watch algorithm and ECG matched, and 3) to assess the percentage of patients receiving notification who actually sought medical help through the app.
Characteristics in subjects included diabetes in 5%, hypertension in 21%, prior stroke in 1%, and obesity in 38%. Of 658 subjects who were sent an ECG patch, 450 returned them, and among those, 34% were identified as having AF. Dr. Turakhia pointed out that early-stage AF often “…comes and goes, so that doesn’t mean that 66% didn’t have AF.” Among 450 participants who wore the Apple Watch and ECG patch simultaneously, the positive predictive value for AF for the tachogram was 71% and for notification, 84%. Around half of notified individuals contacted the study telehealth doctor, but many (57%) contacted physicians elsewhere, Dr. Turakhia said, regardless of whether or not they contacted the study doctor.
In subjects younger than 40 years of age, the notification rate was very low (0.16%). The rate was just over 3% in subjects older than 65 years, he pointed out.
Dr. Turakhia said that the findings provide the groundwork for future studies looking to leverage wearable technologies. “It really represents a paradigm shift for how clinical studies can be conducted. We don’t have to bring people into a brick- and-mortar clinic.”
In a Medpage Today commentary on March 20, Milton Packer, MD, wrote: “Overall, the chances of the Apple Watch detecting undiagnosed atrial fibrillation in this study were lower than the chance of a person being struck by lightning during their lifetime (0.03%)!” He also wrote that “the Apple device failed to correctly identify atrial fibrillation in a large proportion of people who actually had it,” and would likely create unnecessary anxiety in many others. He urged Apple to conduct a study that was adequately powered and structured to assess the device’s utility for affecting outcomes.
An Open-label, 2 x 2 Factorial, Randomized Trial To Evaluate the Safety of Apixaban Versus Vitamin-K Antagonist and Aspirin Versus Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention: Primary Results of the AUGUSTUS Trial
- Renato D. Lopes, MD, PhD, Professor of Medicine, Division of Cardiology at Duke University Medical Center, Durham, North Carolina
In AUGUSTUS, compared with regimens that include a vitamin-K antagonist (warfarin), aspirin, or both, an antithrombotic regimen with a P2Y12 inhibitor, such as clopidogrel plus apixaban without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in ischemic events. The trial included patients with atrial fibrillation (AF) who have acute coronary syndrome (ACS) or require a percutaneous coronary intervention (PCI), Dr. Renato Lopes said at a press briefing.
The trial population presents treatment challenges because of the twin hazards of stent thrombosis and stroke. Anticoagulants reduce stroke and thrombosis risk in patients with AF, but do not reduce stent-thrombosis risk or myocardial-infarction (MI) risk in patients with ACS. Dual antiplatelet therapy with a P2Y12 inhibitor and aspirin has been shown to reduce MI and stent thrombosis in patients with ACS, but not stroke associated with AF. Combining a blood thinner with dual antiplatelet therapy, however, increases the risk of life-threatening bleeding. Most AF clinical trials, Dr. Lopes pointed out, have excluded ACS, and most ACS trials have excluded patients with AF, creating a gap in understanding. The outstanding questions, he said, are whether a “next-generation” agent like apixaban is more effective than the vitamin-K antagonist and standard blood thinner warfarin at reducing bleeding episodes, and whether patients fare better if they take aspirin plus an antiplatelet agent, such as clopidogrel, in addition to a blood thinner. AUGUSTUS, Dr. Lopes said, is the first randomized, double-blinded, placebo-controlled trial to test aspirin withdrawal in a population at risk for bleeding, MI, strokes, and thrombosis.
All trial subjects (N = 4,614; median age, 70 years; 71% male) had AF requiring long-term anticoagulation with a platelet inhibitor and had experienced a recent ACS or were undergoing PCI within 14 days of enrollment. Ninety-two percent of subjects were taking clopidogrel, with most of the others taking prasugrel or ticagrelor. The trial was conducted in 33 countries.
Patients underwent two randomizations: the first, to apixaban or warfarin and the second, to daily baby aspirin or matching placebo. Warfarin assignment could not be blinded because of the need for monitoring. Treatment was for six months. The study’s primary endpoint was major or clinically relevant non-major bleeding, as defined by the International Society on Thrombosis and Haemostasis.
Major or clinically relevant non-major bleeding rates were 14.7% for warfarin and 10.5% for apixaban (Hazard Ratio [HR], 0.69; P < 0.001 for non-inferiority, P < 0.001 for superiority). For the endpoint of major or clinically relevant non-major bleeding, rates were 16.1% for aspirin and 9.0% for placebo (HR, 1.89; P < 0.001). The highest rate was in patients receiving warfarin plus aspirin (18.7%) and the lowest was in those receiving apixaban plus placebo (7.3%), an 11.4% absolute-risk reduction, with only nine patients needing treatment, Dr. Lopes said.
Death and hospitalization rates were also significantly reduced with apixaban (23.5%) versus warfarin (27.4%; HR, 0.83; P = 0.002). Ischemic outcomes were generally similar. The stroke rate, however, was 0.6% with apixaban and 1.1% with warfarin (HR, 0.50). Hospitalization rates were 22.5% for apixaban and 26.3% for warfarin (HR, 0.83).
“My impression is that this [clinical trial] is perhaps the last nail in the coffin for aspirin and warfarin, going forward,” said ACC-appointed expert Dhanunjaya Lakkireddy, MD.
Efficacy and Safety of Bempedoic Acid Added to Maximally Tolerated Statins in Patients With Hypercholesterolemia and High Cardiovascular Risk: The CLEAR Wisdom Trial
- Anne Carol Goldberg, MD, Washington University, St. Louis, Missouri
Bempedoic acid, an investigational drug, may be an additional, safe therapeutic option for high-cardiovascular risk patients with elevated LDL-cholesterol (LDL-C) who are already receiving maximally tolerated statins, according to results of the CLEAR Wisdom trial. Bempedoic acid, unlike statins, does not block the cholesterol production in muscles that is thought be a source of muscle pain, which prevents or limits statin dosing in about 10% of individuals taking high-dose statins, said Dr. Anne Carol Goldberg at a press briefing.
Treating patients who have atherosclerotic cardiovascular disease with the highest tolerated dose of a statin, with the goal of reducing LDL-C levels by at least 50%, is recommended by the ACC Blood Cholesterol Guideline published jointly with the American Heart Association in 2018, Dr. Goldberg noted.
CLEAR Wisdom, conducted at 86 sites in North America and Europe, was a phase 3, double-blind, placebo-controlled study enrolling 779 high-cardiovascular-risk patients (mean age, 64 years; 64% male) who were already receiving maximally tolerated statins plus other lipid-lowering therapy. Patients were randomized 2:1 to treatment with bempedoic acid 180 mg or placebo once daily for 52 weeks, in addition to maximally tolerated statin ± other lipid-lowering therapy. Pre-existing atherosclerotic cardiovascular disease and/or heterozygous familial hypercholesterolemia were exclusion criteria. All patients had a baseline LDL-C ≥ 100 mg/dL (2.6 mmol/L) at screening and ≥ 70 mg/dL (1.8 mmol/L) following placebo run-in while receiving maximally tolerated statins. The primary endpoint was a 12-week mean percentage change from baseline in LDL-C.
The primary endpoint was reported at a rate of +2.4% in the placebo group and -15.1% in the bempedoic acid group (P < 0.001). In patients already taking high-intensity statins, the bempedoic acid LDL-C reduction was 14.4%. For low-/moderate-intensity statins, the reduction was 14.9% and for those not taking statins, it was 24.6% (P < 0.001 for all).
Adjudicated treatment-emergent cardiovascular events, Dr. Goldberg reported, occurred at similar rates in both groups (10.1% and 8.2% for placebo and bempedoic acid, respectively).
Adverse-event rates, at 70.8% for placebo and 70.1% for bempedoic acid, were nearly identical, and study-drug discontinuation rates were similar at 8.6% for placebo and 10.9% for bempedoic acid. Fasting blood-glucose level increases, a concern with statins, did not occur with bempedoic acid.
Dr. Goldberg concluded, “The effect of bempedoic acid was durable at one year, and we observed no increase in adverse effects from the addition of bempedoic acid to statin therapy.” She added, “…this agent may add to the armamentarium of treatment options for high-risk patients with atherosclerotic cardiovascular disease whose LDL-C remains uncontrolled despite taking a maximally tolerated statin.”
Initiation of Angiotensin–Neprilysin Inhibition After Acute Decompensated Heart Failure: Results of the Open-Label Extension of the PIONEER-HF Trial
- Adam DeVore, MD, Duke Clinical Research Institute at Duke University, Durham, North Carolina
In patients with stabilized acute decompensated heart failure, in-hospital initiation of sacubitril/valsartan led to early improvement in post-discharge outcomes compared with enalapril. Analysis from PIONEER-HF, said Dr. Adam DeVore, also showed that, regardless of the timing of initiation, sacubitril/valsartan decreased N-terminal pro–B-type natriuretic peptide (NT–proBNP), an indicator of impaired cardiac function.
Previous reports revealed greater reductions in NT–proBNP (P < 0.001) and improved clinical outcomes (P = 0.007) at eight weeks compared with enalapril for in-hospital initiation of sacubitril/valsartan among 832 patients with heart failure (mean age, ~62 years; ~28% female) with reduced ejection fraction who had been hospitalized for acute decompensated heart failure. The mean left-ventricular ejection fraction was approximately 24.5%. The current analysis included patients from both arms of the double-blind portion of PIONEER-HF who were subsequently receiving open-label sacubitril/valsartan for four weeks. The goal was to describe changes in NT–proBNP in patients with heart failure with reduced ejection fraction who had been recently hospitalized for acute decompensated heart failure and were switching from enalapril to sacubitril/valsartan, and to compare the totality of clinical events during the 12-week study period by randomized treatment arm.
At baseline, NT–proBNP (pg/mL) was 2,883 in the sacubitril/valsartan arm and 2,536 in the enalapril arm. At the end of the open-label period, NT–proBNP levels were 1,218 and 1,630, respectively. Reductions were significantly greater in patients switching from in-hospital enalapril to sacubitril/valsartan (-35.8%) than in those continuing on sacubitril/valsartan (-18.5%; P < 0.0001).
Regarding safety, Dr. DeVore noted similarly worsening renal function in 8.6% of patients in the continuing sacubitril/valsartan group and in 9.6% of patients in the enalapril to sacubitril/valsartan group.
In the continuing sacubitril/valsartan group, rates of death, heart failure, hospitalization, or left-ventricular assist device implantation were significantly lower (HR, 0.67; [95% confidence interval [CI], 0.48–0.94]; P = 0.020).
Dr. DeVore concluded, “A strategy of in-hospital initiation of sacubitril/valsartan improved clinical outcomes over 12 weeks compared with a strategy of in-hospital initiation of enalapril followed by delayed sacubitril/valsartan.”
Effect of Dapagliflozin on Heart Failure and Mortality in Type-2 Diabetes Mellitus Based on Ejection Fraction
- Eri T. Kato, MD, PhD, Kyoto University Hospital, Kyoto, Japan
In DECLARE–TIMI 58, heart-failure hospitalizations and cardiovascular death and mortality were reduced with the SGLT2 inhibitor dapagliflozin in patients with reduced ejection-fraction heart failure. Fewer hospitalizations for heart failure, Dr. Eri Kato said in a press briefing, was the main driver of benefit.
Dapagliflozin and other SGLT2 inhibitors improve blood glucose levels, a well-known risk factor for heart failure, in patients with type-2 diabetes mellitus (T2DM), Dr. Kato noted. The relationship between left-ventricular ejection fraction and the benefits of SGLT2 inhibitors is not well understood, and the complex and multifactorial mechanisms behind the interplay between diabetes and heart failure are the subject of ongoing investigations. Dr. Kato’s new analysis is the first to examine whether left-ventricular ejection fraction predicts dapagliflozin’s benefits.
DECLARE–TIMI 58 investigators enrolled 17,160 patients with T2DM who had established or multiple-risk factors for atherosclerotic cardiovascular disease, randomizing them to dapagliflozin 10 mg or placebo. An analysis of dapagliflozin benefits with respect to the presence of heart failure with reduced ejection fraction (< 45%) was preplanned. Among the trial population, 671 patients met this criterion. Among the other 16,489 subjects, 1,316 had heart failure without reduced ejection fraction and 15,173 did not have heart failure.
Among patients with heart failure and reduced ejection fraction, the endpoint of cardiovascular death/heart-failure hospitalization was reported at rates of 27.1% for placebo and 17.9% for dapagliflozin (HR, 0.62 [0.45, 0.86]. Among the remaining patients, the outcome rates were 4.8% for placebo and 4.3% for dapagliflozin (HR, 0.88 [0.76, 1.02]). All-cause mortality rates in patients with heart failure and reduced ejection fraction were 17.3% for placebo and 11.3% for dapagliflozin, and were almost identical (5.5% and 5.4%, respectively) in patients without reduced ejection-fraction heart failure. Reductions in the rates of individual components (cardiovascular death/heart-failure hospitalization together or separately, all-cause death) were larger with ejection fractions below 30% and smaller with progressively higher ejection fractions.
Rates of serious adverse events (volume-depletion symptoms, acute renal failure) were similar for placebo and dapagliflozin.
“Treatment with dapagliflozin resulted in a lower rate of hospitalization for heart failure versus placebo in a broad spectrum of patients, including those with preserved ejection fraction. Dapagliflozin reduced cardiovascular death and all-cause mortality only in patients with heart failure with reduced ejection fraction,” Dr. Kato concluded.
Partial Oral Treatment of Left-Sided Infective Endocarditis–the POET Trial–Long-Term Follow-up
- Henning Bundgaard, MD, DMSc, Professor of Cardiology, The Heart Center, The National University Hospital, Rigshospitalet, Copenhagen, Denmark
Efficacy and safety are improved when patients with stabilized, left-sided infective endocarditis are switched from intravenous (IV) to oral antibiotic therapy, according to findings from the POET (Partial Oral Treatment of Endocarditis) trial. More than 50% of patients with endocarditis may be candidates for partial antibiotic treatment, said Dr. Henning Bundgaard at a press briefing.
Patients with pre-existing heart valve disease, previous endocarditis, prosthetic heart valves, or other implanted cardiac devices have an increased risk for infective endocarditis. Left-side infections in the mitral or aortic valve are the most common, he added, and men are twice as vulnerable to infective endocarditis compared with women.
The indicated six-week IV treatment for left-sided infective endocarditis often means a long hospital stay for the duration of treatment, which in itself entails an increased risk for complications, Dr. Bundgaard said. Oral antibiotics would allow patients to leave the hospital sooner and complete their treatment at home. POET was designed to test whether oral antibiotic therapy for left-sided infective endocarditis is at least as effective as IV treatment. POET included 400 patients with left-sided infective endocarditis in stable condition who had a satisfactory response to at least 10 days of IV antibiotic treatment, administered according to European Society of Cardiology guidelines. The subjects (average age, 67 years; 77% male) were all from Danish heart centers. The most common pathogen was Streptococcus spp (~49%), followed by Enterococcus faecalis (~24%).
Oral treatment entailed two antibiotics from different classes with different mechanisms, both with moderate–high bioavailability. Antibiotic treatment was discontinued in both groups after six weeks. The primary endpoint was a composite of six months or less of all-cause mortality, unplanned cardiac surgery, embolic events confirmed by imaging, and relapse of bacteremia with the primary pathogen.
Initial six-month data had shown similar efficacy and safety for both treatments. Dr. Bundgaard presented results from the 100% follow-up at a median of 3.5 years with blinded adjudication. The time from infective-endocarditis diagnosis to randomization was similar in both groups (17 days), but the length of hospital stay was 19 days in the IV-treatment group and 3 days in the oral-treatment group.
Reporting on the primary composite outcome, Dr. Bundgaard said the rate was 38.2% in the IV-treatment group and 26.4% in the oral-treatment group (HR, 0.64; 95% CI [0.45–0.91]; P = 0.01). One component among the composite endpoints accounted for the substantial difference: a significantly lower death rate in the oral-treatment group compared with the IV-treatment group (16.4% vs. 27.1%, respectively).
Efficacy of Ticagrelor Versus Clopidogrel After Fibrinolytic Therapy in Patients With ST-Elevation Myocardial Infarction (TREAT)
- Otavio Berwanger, MD, PhD, Director of the Academic Research Organization at Albert Einstein Hospital, São Paulo, Brazil
The frequency of major cardiovascular events at 12 months was similar when patients aged 75 years and younger with ST-elevation myocardial infarction (STEMI) who were given fibrinolytic therapy received either ticagrelor or clopidogrel as antiplatelet therapy, according to Dr. Otavio Berwanger, TREAT trial co-author, at a press briefing. Thirty-day trial results, he noted, had also shown similar rates of thrombolysis in myocardial infarction (TIMI) major bleeding (the primary endpoint) for both ticagrelor and clopidogrel (P < 0.001 for non-inferiority).
Most lower- and middle-income countries (and some higher-income countries), and locations where percutaneous coronary intervention is not always available, have common use of fibrinolytic therapy, Dr. Berwanger said. TREAT was conducted in 10 countries on five continents, and included a mix of countries at various income levels. The trial involved 3,800 patients (median age, 59 years; 77% male) treated for STEMI at more than 180 centers. All patients had received fibrinolytic therapy within 24 hours of their myocardial infarction (MI). Half of the participants were randomly assigned to 12 months of ticagrelor (180-mg loading dose; 90 mg b.i.d.) and half were assigned clopidogrel (300-mg loading dose; 75 mg q.d.).
TIMI major bleeding rates were 1.05% for ticagrelor and 1.22% for clopidogrel (P = 0.61) after 12 months, reported Dr. Berwanger. Secondary endpoints of major bleeding, as defined by Platelet Inhibition and Patient Outcomes (PLATO) and Bleeding Academic Research Consortium (BARC) types 3 to 5 definitions, were also similar (P = 0.21 and P = 0.43, respectively). Total bleeding was significantly higher for ticagrelor (HR, 1.69; P < 0.01), as were TIMI minimal bleeding (HR, 2.06; P < 0.01) and clinically significant bleeding (HR, 1.41; P = 0.03). Intracranial and fatal bleeding were almost identical between the groups.
Other endpoints were consistently similar, including the cumulative incidence for the combined endpoint of cardiovascular death, MI, stroke, severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events at 12 months (HR 0.88, favoring ticagrelor; P = 0.25). Combined cardiovascular stroke, MI, or stroke at 12 months was similar (HR 0.93, favoring ticagrelor; P = 0.53).
“Results suggest the safety of ticagrelor with regard to major bleeding, in comparison to clopidogrel, up to 12 months in fibrinolytic-treated STEMI patients,” Dr. Berwanger concluded, adding, “In this population under 75 years, administration of ticagrelor after fibrinolytic therapy may not reduce the frequency of major cardiovascular events at 12 months compared to clopidogrel.” He commented that combining TREAT and PLATO in a pooled analysis indicates a reduction in major cardiovascular events for ticagrelor.
“My hospital administrator would not thank me if I said I was going to start using ticagrelor for everybody,” observed Claire Duvernoy, MD, Professor of Medicine, University of Michigan and an ACC-appointed expert at the press briefing. Press conference moderator Roxanna Mehran, MD, noted that approximately 20% of patients who are put on ticagrelor are unable to tolerate it.
Primary Results of the Intensive Versus Standard Ambulatory Blood-Pressure Lowering to Lessen Functional Decline in the Elderly Trial (INFINITY)
- William B. White, MD, Professor of Medicine, University of Connecticut School of Medicine, Farmington, Connecticut
Preserved brain function and reduced cardiovascular events may be the benefit of more aggressive hypertension treatment in the elderly, according to findings from the INFINITY trial presented by Dr. William White at a press briefing.
Functional decline in older individuals with hypertension associated with subcortical microvascular disease of the brain shows up as white matter hyperintensity (WMH) on magnetic resonance imaging (MRI) scans. In prior research (Circulation 2011;124:2312–2319), Dr. White said, 24-hour systolic blood pressure has been a better predictor of the progression of microvascular disease of the brain than blood pressure measured in the clinical setting. INFINITY evaluated two levels of ambulatory systolic blood pressure in older subjects. Specifically, its primary objective was to demonstrate that maintaining 24-hour ambulatory systolic blood pressure at 130 mmHg is superior to maintaining it at 145 mmHg for the prevention of functional decline ensuing from accrual of microvascular disease of the brain. Changes from baseline in mobility parameters (e.g., gait speed) and cognitive function (executive function, processing speed) were the primary outcome measures. Secondary endpoints included changes from baseline in cognitive-function parameters and serious adverse events (SAEs) (cardiovascular, falls with injury, and syncope associated with orthostatic hypertension).
Among the 199 participants (average age, 81 years; ~54% female) average systolic blood pressure was ~150 mmHg. All participants had MRI evidence of cerebrovascular disease. Half were assigned to standard blood pressure control (145 mmHg) and half were assigned to 130 mmHg or lower on 24-hour ambulatory monitoring. Treatment, continued for three years, included a variety of antihypertensive drug classes.
At the end of the study period, average systolic blood pressure was 146.0 mmHg in the standard-treatment group and 130.9 mmHg in the intensive-treatment group. Changes in WMH lesion accrual from baseline were similar between intensive-treatment and standard-treatment groups: 21 ± 17 mL versus 20 ± 16 mL, respectively (P = 0.70). Intracranial cavity-volume increases from baseline, however, were significantly lower in patients receiving intensive treatment compared with patients receiving standard treatment (1,452 ± 145 mL vs. 1,503 ± 161 mL; P = 0.02).
In patients who maintained systolic blood pressure at 30 mmHg or lower, reductions in brain lesion numbers were more pronounced. However, those treated more intensively showed no significant differences in mobility parameters (gait speed, stair ascent/descent time, sit to stand time, supine to sit time, or unipedal balance). Among six cognitive parameters assessed, only change from baseline in sequential reaction time significantly favored intensive treatment (-23 ± 16 ms vs. +33 ± 15 ms; P < 0.01). Fall and syncope rates were similar between the groups.
Among SAEs (death, nonfatal cardiovascular events, falls, and syncope/near syncope), the only significant difference was fewer nonfatal cardiovascular events––MI, stroke, hospitalization for heart failure, and arrhythmia––in the intensive-treatment group compared with the standard-treatment group (4.1% vs. 17%; risk ratio, 0.24; P < 0.01).
“Intensive lowering of ambulatory blood pressure in older patients with hypertension reduced the accrual of subcortical white-matter disease, and there were fewer cardiovascular events in the intensive-treatment group,” Dr. White concluded. He noted also, “While this observation was not accompanied by differences in mobility or cognitive function, it is probable that three years was too short in duration to observe functional differences between the intensive- and standard-treatment groups.”