Conference Coverage

Despite the cancellation of the American College of Cardiology (ACC) and World Congress of Cardiology live conference slated for March 28-30 in Chicago, the event went digital with ACC.20 World Congress of Cardiology VIRTUAL. A wealth of vital science and education was presented online. Featured here is a small sample of interesting findings presented during the 3-day event.

Natural history of ischemia with no obstructive coronary disease ‘ebbs and flows’

Ischemia with no obstructive coronary artery disease (INOCA) is common, comprising approximately 20% of participants with moderate or severe ischemia screened in the recent International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial. A new analysis of people who were screened for ISCHEMIA but did not qualify for inclusion because they had less than 50% stenosis on coronary angiography finds that their symptoms and stress test results change over time in the absence of any intervention.

The ancillary study to ISCHEMIA, known as Changes in Ischemia and Angina over One year among ISCHEMIA trial screen failures with non-obstructive coronary artery disease on CT angiography (CIAO-ISCHEMIA), demonstrated that the change in symptoms and the change in ischemia on their stress tests did not necessarily correlate, according to lead investigator Harmony R. Reynolds, MD, from the Sarah Ross Soter Center for Women’s Cardiovascular Disease at NYU Langone Health, New York City.

CIAO-ISCHEMIA enrolled 208 people who were screened for the ISCHEMIA trial but were found to have INOCA.

Angina frequency, as assessed by the Seattle Angina Questionnaire (SAQ AF), and ischemia were quantified at baseline and after 1 year, and were compared with those from the 865 patients enrolled in ISCHEMIA who had a stress echocardiogram and obstructive coronary artery disease (CAD) on coronary computed tomographic angiography. At baseline, the two groups of patients had similar amounts of ischemia on their stress tests.

INOCA patients in CIAO were far more likely than patients in ISCHEMIA to be female (66% vs 26%), consistent with findings from previous studies (P < .001). They were also less likely to have diabetes (19% vs 33%; P < .001), a prior myocardial infarction (2% vs 15%; P < .001), less likely to be current or former smokers (41% vs 56%; P = .001), and more likely to have a history of depression (19% vs 9%; P < .001).

Indications for stress testing in the INOCA patients were typical angina in 50%, atypical chest pain in 32%, and shortness of breath in 49%, with some overlap between indications. On stress echocardiography at enrollment, participants had a median of 4 ischemic segments. Some 44% of CIAO participants with INOCA and 58% of those enrolled in ISCHEMIA had anterior ischemia (P < .001).

The median SAQ AF score was 90 in patients with INOCA at enrollment compared with 100 in those with CAD at enrollment. CIAO participants with INOCA had more frequent angina; 14% of these patients had weekly angina weekly and 2.5% had daily angina, compared with 3.6% and 0.6%, respectively, among those in ISCHEMIA. CIAO patients were also more likely to have angina in the previous month; 41% of CIAO patients with INOCA reported no angina in the previous month compared with 62% of ISCHEMIA patients with CAD. 

At 1 year, in patients in CIAO, stress echocardiograms normalized in 50% of patients, and in 45% they were unchanged from baseline or worse. Angina symptoms improved in 42% and worsened in 14% and angina frequency improved by a clinically meaningful amount, defined as at least a 10-point improvement on the SAQ AF, in 39% of patients with INOCA, said Dr. Reynolds. Weekly angina was present in 7.6% at 1 year (compared with 14% at enrollment) and daily angina was present in 0.5% (compared with 2.5% at 1 year). The median number of antianginal medications was one at enrollment and at 1 year.

No correlation was found between 1-year changes in ischemia and angina, the primary endpoint of the study.

“There’s always the hypothesis that maybe plaque is diffuse and that is explaining the appearance of no obstructive disease [in patients with INOCA], but here we have CT so we are not just seeing the lumen but we’re seeing the wall,” said Dr. Reynolds.

The take-home message is that “there’s a lot of variability in symptoms and ischemia in these patients over time,” she said. “I believe that they probably came to medical attention and therefore got enrolled in ISCHEMIA because they were at a time when they were most symptomatic. We know that coronary flow reserve can change over time, and that spasm is inherently variable. I think there’s just an ebb and flow in the symptoms for these patients and in the stress test findings, and that is one of the challenges of taking care of them.”

CIAO-ISCHEMIA was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr. Reynolds disclosed, Research/Research Grants: Abbott Vascular, BioTelemetry Inc.

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Vaping added to counseling leads to higher smoking quit rates versus counseling alone

Adding electronic cigarette (e-cigarette) use to smoking cessation counseling more than doubles the percentage of those who successfully quit smoking at 12 weeks when compared with counseling alone. 

In a clinical trial of 376 smokers enrolled at 17 sites in Canada, 21.9% who were given nicotine-containing e-cigarettes in addition to counseling had quit smoking compared with 17.3% given nonnicotine e-cigarettes plus counseling and 9.1% who received counseling alone, reported Mark J. Eisenberg, MD, MPH, from Jewish General Hospital and McGill University, Montreal.

According to Dr. Eisenberg, even with the use of pharmacologic or behavioral therapy, more than two thirds of those attempting to quit return to smoking within 1 year. “For this reason, many smokers have adopted the use of e-cigarettes to quit smoking,” he said. “Nevertheless, the efficacy and safety of e-cigarettes for smoking cessation remain poorly delineated.”

The trial included active smokers who smoked at least 10 cigarettes/day and were motivated to quit. They were randomized to nicotine e-cigarettes, nonnicotine e-cigarettes, or no e-cigarettes. All three groups received smoking cessation counseling.

The primary endpoint was self-reported smoking abstinence in the past week and biochemical validation using expired-air carbon monoxide levels of 10 parts/million or less at 12 weeks, reduced from 52 weeks because of e-cigarette manufacturing delays.

Participants’ mean age was 52 years and 53% were male. Mean duration of smoking was 35 years, and the mean number of cigarettes smoked per day was 21. About 91% had failed at previous attempts to quit smoking, and 80% had used pharmacologic or behavioral therapy.

At each follow-up time point (1, 2, 4, 8, and 12 weeks), smoking abstinence was greater among the participants randomized to e-cigarettes. Compared with counseling alone, the 12-week results showed that nicotine e-cigarette users were 2.4 times more likely to quit smoking (95% confidence interval [CI], 1.3-4.6) and nonnicotine e-cigarette users were 1.9 times more likely to quit (95% CI, 1.0-3.8).

Among those who continued to smoke at 12 weeks, those in the nicotine e-cigarette arm smoked a mean of 5.7 fewer cigarettes/day than those who received counseling alone (95% CI, -8.0 to -3.3). Those who were randomized to nonnicotine e-cigarettes smoked a mean of 3.6 fewer cigarettes/day (95% CI, -6.3 to -1.0).

Smoking abstinence was more likely at each follow-up in those who received e-cigarettes compared with counseling alone, and it was most likely in those who received nicotine e-cigarettes. At 12 weeks, the rates of smoking abstinence were 5% in the nicotine e-cigarette arm, 3% in the nonnicotine e-cigarette arm, and 1% in the counseling-alone arm.

Few serious adverse events occurred: 1 in the nicotine e-cigarette arm (exacerbation of chronic obstructive pulmonary disease), 5 in the nonnicotine e-cigarette arm (appendicitis, neoplastic cecal lesion, myocardial infection, chest pain, and epistaxis), and 2 in the counseling-alone arm (critical limb ischemia and urinary tract infection). None were related to the treatment received.

Longer term follow-up will determine if the benefit of e-cigarettes persists over time, said Dr. Eisenberg, who indicated that the research team will continue to collect data for 1 year, with the last follow-up to be completed in September 2020.

Nancy Rigotti, MD, Massachusetts General Hospital, Boston, commented that the study provides important evidence regarding e-cigarettes, which is their efficacy for smoking cessation. “There’s a contentious debate going on about the relative benefits and harms of e-cigarettes for public health,” she said. “And the case for public health benefits rests on their ability to help smokers quit. Unfortunately at this point, there’s only a small body of high-quality evidence to answer this question, and an answer is urgently needed, so this new randomized controlled trial is an important contribution. Because it’s a relatively unselected group of smokers, that adds to its potential generalizability.”

Mark J. Eisenberg, MD, MPH, reported nothing to disclose; Nancy Rigotti, MD disclosed Consultant Fees/Honoraria Achieve Life Sciences, Pfizer.

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At 10 years, PCI equal to CABG for left main coronary artery disease

Data are limited on outcomes beyond 5 years in recipients of either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) who have left main coronary artery disease (LMCAD). Recently, a follow-up extension of the PRECOMBAT trial (Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease) examined 10-year outcomes and found no significant difference in rates of death, myocardial infarction (MI), stroke, or target vessel revascularization between patients who underwent PCI and those who underwent CABG, reported Duk-Woo Park, MD, of Asian Medical Center, Seoul, South Korea.

Prior studies, notably the EXCEL and NOBLE studies published in late 2019, showed conflicting results, he said, with some reporting “a trend of late catch-up or crossover in the incidence of the primary composite outcome or all-cause mortality favoring CABG over PCI during extended follow-up.”

PRECOMBAT also showed that more patients who underwent PCI had to have a repeat PCI than those who underwent CABG.

The clinical trial randomized 600 patients with unprotected LMCAD to either PCI with sirolimus-eluting stents or CABG at 13 medical centers in South Korea between 2004 and 2009. The primary outcome was occurrence of a major adverse cardiac or cerebrovascular event, defined as death from any cause, MI, stroke, or ischemia-driven target-vessel revascularization.

The mean age of patients at treatment was 62.3 years; 76.5% were men, 32% had diabetes mellitus, slightly more than half had hypertension, and approximately 40% had hyperlipidemia. Twice as many patients in the PCI arm had peripheral vascular disease than in the CABG arm (5% vs 2.3%). Approximately half of the patients enrolled had stable angina or silent ischemia.

About 40% in each arm had left main plus three-vessel disease and two thirds in each arm had bifurcation left main involvement. Complete revascularization was attained in 68.3% of the PCI arm and 70.3% of the CABG arm. The mean SYNTAX score was 24.4 in the PCI arm and 25.8 in the CABG arm.

In the PCI arm, a mean of 1.6 stents were implanted in the left main artery. Overall, the mean number of stents per patient was 2.7. The one-stent technique was used for treatment of bifurcation in 46.3% of patients. In the CABG group, the mean number of grafts per patient was also 2.7.

Follow-up results at 1 year and 5 years, published previously, reported no significant differences between the two groups for the primary endpoint or for any of its components; however, patients who underwent PCI were more likely to require a second PCI.

At 10 years, approximately, 96% in each arm had complete follow-up data. A primary outcome event occurred in 29.8% of the PCI group versus 24.7% of the CABG group (hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.93-1.69; P = 0.14).

The 10-year composite of death, MI, or stroke occurred in 18.2% of the PCI arm versus 17.5% of the CABG arm (HR, 1.00; 95% CI, 0.70-1.44; P = 0.98). Death from any cause occurred in 14.5% versus 13.8% of the PCI and CABG arms, respectively (HR, 1.13; 95% CI, 0.75-1.70; P = 0.57). Ischemia-driven target vessel revascularization was significantly more frequent after PCI than after CABG (16.1% vs 8.0%; HR, 1.98; 95% CI, 1.21-3.21; P = 0.006).

Dr. Park noted that the study was underpowered, owing to the limited number of patients and low event rates, and, thus, the results should be considered hypothesis generating, and they do highlight the need for further research.

“Because we evaluated the first-generation drug-eluting stents, our findings should be confirmed or refuted through longer follow-up of the trials involving contemporary drug-eluting stents,” he said.

“What these data definitely show is that if we have a patient who is not a good candidate for coronary revascularization surgically, we can expect an acceptable result with PCI in some high-risk patients, and this was actually a pretty low-risk group based on SYNTAX scores,” commented Marc R. Moon, MD, Washington University School of Medicine, St. Louis, who was not involved in the study.

The findings were published online in Circulation at the time of presentation. PRECOMBAT was funded by the Cardiovascular Research Foundation. Duk-Woo Park, MD reported nothing to disclose; Marc R. Moon, MD disclosed Consultant Fees/Honoraria MEDTRONIC.

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Enhancing cyclic guanosine monophosphate reduced heart failure hospitalization in patients with worsening disease

An investigational stimulator of guanylate cyclase, vericiguat, reduced the incidence of either cardiovascular (CV) death or heart failure hospitalization in a large randomized international phase III study of patients with worsening heart failure (HF) with reduced ejection fraction who were already receiving optimal standard of care.

In the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial, conducted in 600 centers across 42 countries, patients randomized to vericiguat plus standard of care experienced a 10% reduction in the primary endpoint of CV death plus HF hospitalization after a median follow-up of 10.8 months compared with patients randomized to placebo plus standard of care (hazard ratio [HR], 0.90; P = 0.019), reported Paul W. Armstrong, MD, from the Canadian VIGOUR Centre, University of Alberta.

Vericiguat enhances the production of cyclic guanosine monophosphate (GMP), which is a pathway that is critical for normal cardiac and vascular function not currently targeted by existing heart failure drugs. Vericiguat also restores nitric oxide sensitivity; nitric oxide exerts a favorable effect on vascular homeostasis through upregulation of cyclic GMP.

“VICTORIA enrolled a very high-risk HF population with significant unmet needs not well addressed by prior HF studies,” said Dr. Armstrong, who indicated that the findings from VICTORIA would apply to approximately the one fourth of patients with chronic HF who fit the inclusion criteria for the study.

VICTORIA enrolled 5,050 patients with New York Heart Association (NYHA) class II to IV chronic HF with an ejection fraction (EF) less than 45% (on guideline-based heart failure therapies) after a worsening event, defined as hospitalization for HF within the past 6 months or the need for intravenous diuretics within 3 months. Patients were randomized in a 1:1 ratio to vericiguat, titrated stepwise from 2.5 mg to a target of 10 mg once daily, or placebo in addition to standard HF treatments. Patients could be randomized as an inpatient or outpatient but must have met criteria for clinical stability.

Baseline characteristics were comparable between the 2 arms. Patients’ mean age was approximately 67, about one fourth were female, and about 40% had NYHA class III–IV HF. Mean EF at baseline was about 29%, and approximately 60% of patients were receiving triple guideline-directed drug therapy. About one third of patients enrolled had either an implantable cardioverter-defibrillator, biventricular pacemaker, or both devices.

The favorable effect of vericiguat on the primary endpoint appeared after approximately 3 months of treatment and persisted for the duration of the study. The absolute event reduction in the vericiguat arm relative to placebo was 4.2 per 100 patient years. The number needed to treat to prevent one primary outcome was 24.

The rate of CV mortality favored vericiguat but did not achieve statistical significance (HR, 0.93; P = 0.269). The rate of first hospitalization for HF was reduced significantly in the vericiguat arm versus placebo (HR, 0.90; P = 0.048). There was no significant difference between arms in all-cause mortality (HR, 0.95; P = 0.377).

Vericiguat was generally well-tolerated. Patients taking vericiguat had a numerically increased incidence of symptomatic hypotension (9.1% vs 7.9%; P = 0.121) and syncope (4% vs 3.5%; P = 0.303) compared with placebo. The rates of anemia were 7.6% in the vericiguat arm and 5.7% in the placebo arm. No adverse effects of vericiguat on either electrolytes or renal function was observed.

“Because vericiguat is a once daily medicine, easy to titrate, generally safe and well tolerated, without the need for monitoring renal function or electrolytes, it may play a useful role in patients with recent worsening HF,” Dr. Armstrong concluded. A separate study is underway to investigate whether vericiguat offers benefits for patients with HF with preserved ejection fraction.

Results of the study were published simultaneously online in The New England Journal of Medicine.

Clyde Yancy, MD, from Northwestern University Feinberg School of Medicine in Chicago, who was not involved in the study, noted that hospitalization for HF represents a major inflection point in the natural history HF, with a marked change in the risk for rehospitalization and death. “Until now, no therapies have attenuated this risk, except for more intensive process of care improvement strategies,” he said. “Now we have a therapy that may be the first one to change that natural history after a person with HF has had a worsening event.”

The risk of death, however, after HF hospitalization appears recalcitrant to any of the current medical therapies, and “that is still an issue that we have to address,” said Dr. Yancy.

Black patients constituted less than 5% of the study population, he pointed out, despite prevailing concerns that this unique patient population may exhibit diminished NO bioavailability.

Lynne Stevenson, MD, from Harvard Medical School, Boston, remarked that vericiguat is “not only a therapy for a new physiologic target but it’s also for a new population. Patients with recent HF hospitalization and decompensation have been actively excluded from all the trials that have shown benefit. VICTORIA finally addresses this population of decompensated patients.”

The VICTORIA trial was supported by Merck Sharp & Dohme, a subsidiary of Merck and Co., Inc.; and Bayer AG. Paul W. Armstrong, MD reported nothing to disclose; Clyde W. Yancy, MD reported Other: Abbott Laboratories.

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Wide gender gap in authorship of cardiovascular clinical trials

Women are grossly underrepresented in leadership of cardiovascular clinical trials, making up only 9.3% of first authors and 10% of senior authors. In addition, they account for only 10.1% of trials’ leadership committee members, according to a study led by Cleveland Clinic cardiologists.

These percentages can’t be considered surprising, given that women represent only 12% of board-certified cardiologists, 7.2% of interventionalists, and 6% of electrophysiologists.

Yet, despite the known disparity of women in cardiology, “women’s representation in clinical trial leadership is still much lower than would be expected,” said Leslie Cho, MD from the Women’s Cardiovascular Center at Cleveland Clinic, and co-author of the study, which was presented by Kara Denby, MD, also from Cleveland Clinic.

The researchers identified and evaluated all cardiovascular medicine studies published from 2014 to 2018 in three high-impact journals: Journal of the American Medical Association (n = 41), The Lancet (n = 70), and The New England Journal of Medicine (n = 89). After excluding trials that focused on emergency medicine, 200 trials were included in the analysis.

Across all three journals, women accounted for only 9.3% of first authors and 10.0% of last authors.

 “Women were far underrepresented on leadership committees — and women physicians [in contrast to nonphysician scientists] even more so,” said Dr. Cho. “Only 5% to 6% of committee members were women physicians, and the majority [55.5%] of committees did not include any women physicians.”

Women leaders were even rarer in large trials (those with > 500 enrollees) and in studies of procedural subspecialties (electrophysiology and interventional cardiology) versus nonprocedural subspecialties (clinical cardiology, cardiovascular imaging, heart failure, preventive cardiology and vascular medicine).

Five percent of committees had 25% or fewer members who were women and 5% of committees had no women members.

 “We didn’t look into why these disparities occur, but other studies have suggested possible explanations,” said Dr. Denby. “There could be an unconscious bias that results in inadvertent gender discrimination. Maybe it’s due to less industry recognition, slower rates of promotion or lower grant funding for women. Maybe it’s a cyclical problem, where having fewer women leaders leads to fewer women leaders being developed for the future.”

The issue is likely multifactorial. The authors advocate further research on the issue, particularly in light of evidence of at least moderately improved patient outcomes when women physicians are involved in care.

For example, a recent study reported fewer deaths among women with myocardial infarction when they were treated by a woman physician. Similar findings were reported in studies of elderly internal medicine patients and emergency department patients treated by women physicians or a combination of women and men physicians.

“Another study found that research quality is better when trials have first and senior authors of different genders,” says Dr. Denby. “With that in mind, the cardiovascular medical community may have an opportunity to strengthen its research by significantly increasing women’s inclusion in clinical trial leadership.”

These findings suggest that women may bring unique perspectives and insights to cardiovascular research and clinical trials in a diverse patient population, according to the authors.

The researchers also call for action to address the disparities now. Dr. Cho noted that this study’s findings parallel a well-recognized underrepresentation of female patients in clinical trials. “When the FDA looked at this,” she says, “they noticed that women were not even screened at similar rates even though they have a similar incidence of disease.”

An abundance of data suggests that having diverse representation improves quality of care as well as research, Dr. Cho added. “Perhaps with increased representation of women in trial leadership, we can finally have better representation of female patients in clinical trials,” Dr. Cho observed. “The best way forward is for the field to acknowledge that such disparity exists and actively work to overcome the disparities with action.”

A version of this story appears in ConsultQD.

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Personalized antiplatelet therapy after PCI based on genotyping barely misses primary endpoint

Genotyping-guided antiplatelet therapy following percutaneous coronary intervention (PCI) did not meet the stringent goal of halving the incidence of serious adverse cardiovascular events in the year following the procedure. However, the TAILOR-PCI trial did demonstrate a 34% reduction in such events at 1 year, in addition to a significant reduction in the number of events per patient, said Naveen L. Pereira, MD, from Mayo Clinic, Rochester, Minn.

TAILOR-PCI was designed to determine whether identifying carriers of the loss-of-function CYP2C19 allele and altering P2Y12 inhibitor therapy based on CYP2C19 genotype reduces the rate of ischemic outcomes.

In the United States, 30% to 35% of people carry the genetic variant that makes them less capable of metabolizing and, hence, activating the antiplatelet drug clopidogrel. This proportion increases to 50% among people of Asian heritage.

TAILOR-PCI was a two-arm, parallel, open-label, international multicenter randomized clinical trial designed to show superiority of genotyping-guided antiplatelet therapy. Eligible patients were 18 or older who underwent PCI for acute coronary syndrome or stable coronary artery disease and required 12 months of dual antiplatelet therapy.

The study had 2 arms.  A conventional therapy arm was prescribed clopidogrel after PCI, and at the end of 12 months, underwent genotyping that enabled identification of those who carried the loss of function CYPC19*2/*3 variants, and those who were noncarriers. “The reason that genotyping was performed at the end of 12 months was that if patients were identified to be poor metabolizers prior to the 12-month mark as per therapeutic guidelines, we would have to prescribe alternative antiplatelet drug therapy, therefore not allowing a comparison,” said Dr. Pereira. 

In the other arm, point-of-care genotyping that provided results within 60 minutes was performed and enabled identification of those patients who had loss of function variants for whom ticagrelor was prescribed and those who were noncarriers for whom clopidogrel was prescribed. 

To permit uniform comparison, both arms underwent genotyping by TaqMan assay at 12 months. No difference in ischemic outcomes was expected between conventional therapy and genotyping-guided therapy in patients who were noncarriers of the loss of function allele. The primary analysis, therefore, was undertaken only in those patients who had loss of function variants in the conventional arm who received clopidogrel and patients who had loss of function variants in the genotyping-guided arm who received ticagrelor.

Some 5,302 patients were randomized; 2,641 patients in the genotype-guided therapy arm (of whom 903 had loss of function variants) and 2,635 in the conventional therapy arm (of whom 946 had loss of function variants). Therefore, a total of 1,849 CYP2C19*2/*3 carriers were included in the primary analysis.

The primary end point was the composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis, and severe recurrent ischemia with 1 year after index PCI.

The average time to randomization after PCI was less than 5 hours in the CYP2C19*2/*3 carriers. Among loss-of-function carriers, 99% in the conventional therapy arm received clopidogrel and 85% in the genotype-guided therapy arm received ticagrelor and 15% received clopidogrel.

Event rates of 6% in the conventional therapy and 3% in the genotype-guided arm were assumed with a minimum detectable hazard ratio of 0.50 with 85% power.

The primary composite end point occurred in 4% of loss of function carriers in the genotyping-guided therapy group and 5.9% in the conventional therapy group, resulting in an adjusted hazard ratio of 0.66, which narrowly missed statistical significance (P = 0.056). 

A post hoc analysis demonstrated a risk reduction of 79% in the first 3 months compared with later time intervals, favoring genotyping-guided antiplatelet therapy (P = 0.001). “We now know from clinical practice and other studies that antiplatelet drug therapy is critical during the first 3 months after PCI,” said Dr. Pereira in a prepared statement released by ACC. “This finding suggests that the lion’s share of the benefit of genetically guided therapy may occur during this high-risk period. Because this wasn’t a preplanned analysis, we can’t draw firm conclusions from it, but it merits further study.” 

A prespecified sensitivity analysis that included multiple events per patient within the 12-month study period demonstrated a 40% reduction in ischemic events in favor of the genotyping-guided strategy, which was statistically significant (P = 0.011).

No significant difference in major and minor bleeding was observed between the two groups.

“They just missed the primary end point unfortunately,” commented Roxana Mehran, MD, from Mount Sinai School of Medicine, New York City, who was not involved in the study. “Maybe we should be looking beyond that P value. The investigators looked for a 50% reduction; they found a 34% reduction. Is that not good enough? To me it is; clinically it makes a great deal of sense in my mind.” 

The absolute risk reduction of 1.8% was “pretty good,” she added. “In the important vulnerable period up to 3 months, up to 6 months even, there was an important early benefit with genotyping, and that’s when it really counts.”

TAILOR-PCI was funded by the Mayo Clinic in collaboration with the National Heart, Lung, and Blood Institute. Spartan Bioscience, Inc, supplied the genetic tests used. Naveen L. Pereira, MD, reported no disclosures.

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Vascular dose of rivaroxaban added to aspirin reduces risk of ischemic events in patients with diabetes and atherosclerosis

Low-dose rivaroxaban plus aspirin reduced the risk of major cardiovascular events in patients with stable atherosclerosis, irrespective of the presence or absence of diabetes.

In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) Diabetes trial, a substudy of the parent COMPASS trial, the absolute reduction in the risk of achieving the primary efficacy endpoint, a composite of cardiovascular death, myocardial infarction (MI), or stroke, was numerically larger in the patients with diabetes than in those without diabetes, said Deepak L. Bhatt, MD, MPH, from Brigham and Women’s Hospital, Boston.

Data from the Reduction of Atherothrombosis for Continued Health (REACH) registry show that, compared with having risk factors alone, the presence of established atherosclerosis raises the risk of future cardiovascular events, and a history of ischemic events raises the risk even more. “The REACH registry taught us that polyvascular disease (ie, concomitant coronary artery disease and peripheral arterial disease or cerebrovascular disease) is a powerful driver of ischemic risk, as is diabetes mellitus,” said Dr. Bhatt.

COMPASS Diabetes tested a strategy of the combination of antiplatelet therapy and anticoagulation in 6,922 patients with diabetes and 11,356 patients without diabetes who were enrolled in the parent COMPASS trial, which included 27,395 patients. In the study, patients were randomly assigned to rivaroxaban at a dosage of 2.5 mg twice daily plus aspirin, 100 mg/day, or placebo plus aspirin. 

A significantly lower rate of the primary end point was observed with dual therapy versus placebo plus aspirin both in patients with diabetes (hazard ratio [HR] 0.74; P = .002) and in those without diabetes (HR 0.77, P = .005). The interaction P value was not significant (P = .77), “implying that the benefits of rivaroxaban plus aspirin were similar and consistent in those with and without diabetes,” said Dr. Bhatt. “However, due to the much greater absolute risk that patients with diabetes faced, their absolute risk reduction was numerically larger, 2.3%, vs 1.4% [at 3 years].”

Rate of death from any cause demonstrated a similar pattern, with consistent benefits to dual therapy versus controls in those with diabetes (HR 0.81; P = .05) and without diabetes (HR 0.84; P = .09), with a P value for interaction of .82). As with the primary endpoint, the numerical absolute risk reduction was larger in those with versus without diabetes (1.9%, versus 0.6%), constituting a threefold greater reduction in mortality in the subgroup with diabetes. 

On the endpoint of major vascular events, which encompassed CV death, MI, stroke, major adverse limb events, and major vascular amputation, the risk reduction with dual therapy was significant in those both with diabetes and without diabetes, with an HR of approximately 0.73 or 0.74 in both these subgroups, with an interaction P value that was not significant (P = .88). The absolute risk reduction was again numerically larger in those with versus without diabetes, 2.7% versus 1.7%.

As in the overall COMPASS trial, there was a significant increase in major bleeding with dual therapy versus monotherapy in patients with diabetes (HR 1.7; P = .0006) and without diabetes (HR 1.69; P < .0001). There was no significant increase detected in the rates of intercranial or fatal bleeding either in those with or without diabetes.

The net clinical benefit, an end point that combines cardiovascular death, MI, stroke, fatal bleeding, or symptomatic bleeding into a critical organ, favored dual therapy in patients with and without diabetes, though the absolute risk reduction was again numerically larger in patients with diabetes versus those without diabetes (2.7% versus 1.0%).

“Subgroup analysis indicated that the benefit of dual pathway inhibition on the primary end point was not predicated on a history of ischemic events or revascularization, but rather on the presence of atherosclerosis,” said Dr. Bhatt.

The diabetes subgroup was not specifically powered for safety or efficacy, Dr. Bhatt noted as a limitation, and early stopping of the trial further limited the power of subgroup analysis, “but the independent Data Safety Monitoring Board felt that the trial needed to be stopped due to overwhelming efficacy, including a reduction in all-cause mortality in the overall trial.”

Putting the data in context, Dr. Bhatt said that he wouldn’t add rivaroxaban to aspirin in patients who have had bleeding episodes on aspirin alone or other regimens more intensive than aspirin monotherapy.

“In patients that haven’t bled before, in particular if they’ve been exposed to more intense antithrombotic therapy, say dual antiplatelet therapy, I think those sorts of patients are good candidates for this vascular dose of rivaroxaban,” he said, cautioning that “there’s no free lunch” in that no antithrombotic regimen that has been shown to reduce the risk of ischemic events has been free of an increase in the incidence of major bleeding.

“The two haven't been successfully divorced,” he said. “So I think there needs to be careful patient assessment when initiating these forms of more potent, prolonged antithrombotic therapy and reassessment over time.”

COMPASS Diabetes is published in: Bhatt DL, Eikelboom JW Connolly SJ. The role of combination antiplatelet and anticoagulation therapy in diabetes and cardiovascular disease: insights from the COMPASS trial. Circulation 28 Mar 2020. doi:10.1161/CIRCULATIONAHA.120.046448. The REACH registry is published in: Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010; 304(12):1350-1357. doi:10.1001/jama.2010.1322. COMPASS was funded by Bayer. Dr. Bhatt has disclosed the following financial interests: Consultant Fees/Honoraria: Elsevier Practice Update Cardiology, Medtelligence/WebMD, MJH Life Sciences, WebMD; Officer, Director, Trustee, or Other Fiduciary Role: TobeSoft; Other: Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Journal of Invasive Cardiology, Medscape Cardiology, Merck & Co., Inc., PhaseBio, PLx Pharma, Regado Biosciences, Slack Publications/Cardiology Research Foundation Research/Research Grants Abbott, Afimmune, Amarin, Amgen Inc., Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Inc, Bristol Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly and Company, Ethicon, FlowCo, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, Novo Nordisk Inc., Pfizer Inc, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, The Medicines Company.

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Equal benefit and harm from 30 days of aspirin in patients with atrial fibrillation and a recent coronary event

In patients with atrial fibrillation (AF) and a recent acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI), adding apixaban to a P2Y12 inhibitor resulted in a lower rate of bleeding compared with a vitamin K antagonist (warfarin) with a reduced risk of death or rehospitalization. In both arms, the addition of aspirin resulted in an excess of bleeding without any difference in efficacy, according to a secondary analysis of the AUGUSTUS trial.

The objective of this post hoc analysis of AUGUSTUS was to explore the balance of risk (bleeding) and benefit (ischemic events) between randomization and 30 days and 6 months with aspirin and placebo.

The use of aspirin acutely and for up to 30 days resulted in an equal increase in severe bleeding, said lead investigator John Alexander, MD, from the Duke Clinical Research Institute, Durham, NC. From randomization to 30 days, the rates of major bleeding were 2.11% with aspirin and 1.14% with placebo, for an absolute difference of 0.97 (95% confidence interval [CI] 0.23–1.70). 

The rates of severe ischemic events—a composite of cardiovascular (CV) death, myocardial infarction (MI), stent thrombosis, or stroke—from randomization to 30 days were also similar, 1.66% in the aspirin arm and 2.57% in the placebo arm (absolute difference -0.91%, 95% CI -1.74 to -0.08).  

After 30 days, aspirin continued to increase bleeding without significantly reducing ischemic events. From 30 days to 6 months, rates of major bleeding were 3.71% with aspirin and 2.45% with placebo, an absolute difference of 1.25% (95% CI, 0.23–2.27), and the rates of CV death, MI, stent thrombosis, or stroke were 3.82% with aspirin and 3.99% with placebo, an absolute difference of -0.17% (95% CI, -1.33 to 0.98).

“Using aspirin up to 30 days might be reasonable, and these results should inform patient-centric shared decision-making regarding the ideal duration of aspirin after an ACS or PCI in patients with AF receiving oral anticoagulation,” said Dr. Alexander.

In AUGUSTUS, 4,614 patients with AF who had an indication for oral anticoagulation and an ACS or PCI or both with planned P2Y12 inhibitor use for at least 6 months were randomized to open-label apixaban, 5 mg twice daily, or a vitamin K antagonist with a target internationalized ratio of 2 to 3. Patients were also randomized to blinded aspirin, 81 mg/day, or matching placebo. All patients received a P2Y12 inhibitor. Most patients received aspirin acutely prior to randomization, which occurred a median of 6 days after ACS or PCI.

The mean patient age was 70.7; 29% were female, and 36% had diabetes. Mean CHA2DS2-VASc score was 4.0. Some 61% of patients enrolled had ACS as a qualifying event.
The overall AUGUSTUS results, published in 2019, demonstrated significantly less bleeding with placebo vs aspirin and no significant difference in the rate of the composite of death or hospitalization or the rate of ischemic events between patients assigned to aspirin and those assigned to placebo, although there was numerically more of some ischemic events (stent thrombosis, MI, and urgent revascularization) in patients assigned to placebo. Analysis of stent thrombosis events suggested that most of the increased risk with placebo was present within 30 days of randomization, prompting the current analysis.

As a limitation, patients received aspirin before randomization in both arms, which may have influenced subsequent bleeding or ischemic outcomes, said Dr. Alexander.

A manuscript of the results was accepted for publication in Circulation (in press).

Julia Indik, MD, PhD, from the University of Arizona Health Sciences, Tucson, who was not involved in the trial, calculated a number needed to treat with 30 days of aspirin to prevent one severe ischemic event to be about 100, which is approximately the same as the number needed to harm (severe bleeding event). She commented, therefore, that perhaps a duration of aspirin shorter than 30 days may improve the risk-benefit ratio, although further research is needed. 

“I can’t identify a shorter time period that would be reasonable, recognizing that what we did was post hoc,” responded Dr. Alexander.

The AUGUSTUS trial was funded by the Bristol-Myers Squibb/Pfizer Alliance. John H. Alexander, MD, FACC, Duke University Med Center Disclosures: Consultant Fees/Honoraria: AbbVie, Inc., Bayer, Bristol Myers Squibb, CryoLife, Inositec, Pfizer Inc, Portola, Quantum Genomics Research/Research Grants Boehringer Ingelheim, Bristol Myers Squibb, CryoLife , CSL Behring, GlaxoSmithKline. Julia H. Indik, MD, PhD, FACC, University of Arizona Medical Center Disclosures: Nothing to disclose.

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The CARAVAGGIO findings expand the range of patients with cancer-associated thrombosis who are eligible for DOAC therapy to include those with GI cancer

Twice-daily apixaban was noninferior to subcutaneous dalteparin in the prevention of recurrent venous thromboembolism (VTE) in patients with cancer.

Data from the randomized open-label phase III CARAVAGGIO trial demonstrated that the primary efficacy outcome, recurrent proximal deep vein thrombosis (DVT)/pulmonary embolism (PE), occurred in 5.6% of patients randomized to apixaban compared with 7.9% of those assigned to dalteparin over 6 months of follow-up (P for superiority = 0.08, P for noninferiority < 0.001), with no excessive risk of bleeding, including gastrointestinal (GI) bleeding, in the apixaban arm, announced Giancarlo Agnelli, MD, from the University of Perugia, Italy.

“The findings of the CARAVAGGIO expand the proportion of patients with cancer-associated thrombosis who are eligible for the treatment with the oral direct anticoagulants, including patients with GI cancer,” he said. “This is the only trial in cancer-associated thrombosis where a direct-acting oral anticoagulant is not associated with increased GI bleeding, in spite of the inclusion of a substantial proportion of GI cancers.” 

Major guidelines recommend the consideration of edoxaban and rivaroxaban for the treatment of VTE in patients with cancer, but the clinical benefit of these oral agents is limited by the high risk of bleeding, mainly at GI sites, associated with their use.

The aim of CARAVAGGIO—the largest study to evaluate the treatment of VTE in cancer—was to assess whether the direct oral anticoagulant apixaban is noninferior to subcutaneous dalteparin for preventing a recurrent VTE in patients with cancer and to evaluate the risk of bleeding. 

The multicenter study enrolled 1,170 patients who had symptomatic or incidental acute proximal DVT or PE and any type of cancer (active or recent history) other than basal cell or squamous cell carcinoma of the skin, primary brain tumor or known cerebral metastases, and acute leukemia. They were randomly assigned to oral apixaban (10 mg twice daily for first 7 days followed by 5 mg twice daily) or subcutaneous dalteparin (200 IU/kg of body weight once daily for the first month, followed by 150 IU/kg once daily). Treatment duration was 6 months. 

Mean age of patients was 67.2. Fifty-five percent had PE with or without DVT, and 45% had an isolated DVT. Most patients (80.3%) had symptomatic DVT or PE whereas 20% had incidental VTE. Some 97% in both treatment arms had an active cancer at the time of enrollment; 94.3% of patients in the apixaban arm and 91.0% in the dalteparin arm had a solid tumor, of which 32.6% and 32.3%, respectively, were located in the GI tract, including pancreatic and hepatobiliary cancer.

Occurrence of secondary efficacy outcomes were as follows:

• Recurrent DVT: 2.3% of the apixaban arm vs 2.6% of the dalteparin arm

• Recurrent PE: 3.3% of the apixaban arm compared with 5.5% of the dalteparin arm

• Fatal PE: 0.7% of the apixaban group compared with 0.5% of the dalteparin group.

The primary safety outcome, bleeding as defined by the European Medicines Agency, occurred in 3.8% of the apixaban group compared with 4.0% of the dalteparin group (P = 0.60). Rates of major GI bleeding were 1.9% in the apixaban arm vs 1.7% in the dalteparin arm. 

There was a numerical excess in clinically relevant nonmajor bleeding events in the apixaban arm vs the dalteparin arm of 9.0% vs. 6.0%, respectively, corresponding to a 42% relative increase in the apixaban arm. “The sites of bleeding in clinically relevant nonmajor bleeding were essentially the genitourinary tract and upper respiratory tract, so again, there was no increase in GI bleeding even when clinically relevant nonmajor bleeding was considered,” said Dr. Agnelli. 

The proportion of patients who were free of recurrent VTE, major bleeding events, and death during the study period was 73.3% in the apixaban arm and 68.6% in the dalteparin arm. 

This study was published simultaneously online in the New England Journal of Medicine at the time of presentation. The trial was an investigator-initiated study supported by the BMS-Pfizer Alliance. Giancarlo Agnelli, MD, reported nothing to disclose.

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Renal denervation offers non-drug treatment to lower blood pressure

A sham-controlled trial of catheter-based renal denervation in patients with hypertension significantly reduced ambulatory blood pressure and office blood pressure in the absence of medications.

In the SPYRAL-HTN OFF MED trial, the primary efficacy end point of change in average 24-hour systolic blood pressure (SBP), adjusted for SBP at study entry, was –3.9 mm Hg lower in the arm randomized to renal denervation than in the sham control group. Similarly, the secondary efficacy endpoint of change in average office blood pressure, adjusted for office blood pressure at study entry, was –6.5 mm Hg lower in the treatment arm. Both end points measured the change in blood pressure from baseline to 3 months.

“The blood pressure [reduction] is clinically meaningful after 6 months and it is always ‘on’ and particularly at times of the day when the high blood pressure is most closely associated with cardiovascular complications,” said lead investigator Michael Böhm, MD, from Saarland University Medical Center, Hamburg, Germany.

SPYRAL HTN-OFF MED, an international trial conducted at 44 sites in 9 countries, enrolled 331 patients (80 from a pilot trial) with an office SBP 150 mm Hg  or greater and less than 180 mm Hg and a mean 24-hour SBP of 140 mm Hg or greater to less than 170 mm Hg. Before double-blind randomization to the renal denervation or sham control group, patients were required to stop taking all antihypertensive medications for at least 3 weeks. 

The mean age of patients was 53; 67% were men, about 20% were black, 16% were current smokers, and approximately 5% had type 2 diabetes. Slightly more than half had a hypertension diagnosis longer than 5 years. Mean body mass index was 31 kg/m2.

Renal denervation was performed using the Symplicity Spyral catheter, which is a multi-electrode catheter with quadratic vessel contact for simultaneous ablation in up to 4four electrodes. In the treatment arm, the mean number of main renal arteries treated per patient was 2.2 and the mean number of branches treated per patient was 5.8. The mean total number of ablations was 46.9 per patient. The procedure was successful in all patients.

There were no deaths, strokes, or changes in renal function in the treatment arm during the 3-month follow-up period, with one hospitalization for hypertensive crisis/emergency. There was one stroke in the sham control arm.

Some 17.0% of patients in the sham arm met the safety escape criteria (office SBP greater than 180 mm Hg or safety reasons), allowing them to be placed back on antihypertensive medication, compared with 9.6% of the treatment arm (P = 0.049). At baseline and 3 months, 85.1% in the treatment arm and 89.7% in the sham control arm had no evidence of antihypertensive medication use by testing of urine and serum.

Bayesian analysis showed a greater than 99.9% probability of superiority in the treatment arm versus the sham control arm on the primary and secondary efficacy end points.

The effect of renal denervation may have been underestimated in this trial, said Dr. Böhm, because previous studies have shown further blood pressure reduction after 3 months. In addition, an excess of patients in the sham arm who met the safety escape criteria may have limited the study’s ability to show the effect of renal denervation in the treatment arm. 

Dhanunjaya Lakkireddy, MD, from the Kansas City Heart Rhythm Institute and Research Foundation, Overland Park, Kans., who was not involved in the study, commented that the reductions in blood pressure observed with renal denervation are “reasonably impressive for an antihypertensive study” but “are not enough to make a case for it to be a stand-alone therapy.” The true value of renal denervation, therefore, may lie as an adjunct to antihypertensive drug treatment.

A companion study, the SPYRAL-HTN ON MED trial, is testing the safety and effectiveness of renal denervation in patients taking up to 3 antihypertensive agents. It is expected to conclude in about 18 months. 

The SPYRAL HTN-OFF MED results were published simultaneously in The Lancet. Michael Böhm Disclosures: Consultant Fees/Honoraria: Amgen, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Inc, Bristol-Myers Squibb Company, MEDTRONIC, Vifor; Other: Servier.

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