The Take Home: ACC
This year, the American College of Cardiology Scientific Session was, for the first time, held virtually. The decision to cancel the annual live meeting and move to a virtual format was made in March amid COVID-19 concerns and increasing travel advisories and restrictions in response to the pandemic.
From March 28 to 30, late-breaking clinical trials and featured clinical research were presented via online webcasts, abstracts were made available via a web portal and sessions on a variety of topics were conducted by webcast.
Healio and Cardiology Today covered the virtual meeting and spoke with cardiologists for their perspective, including Radha Gopalan, MD, from Banner – University Medicine Heart Institute; Martha Gulati, MD, MS, FACC, FAHA, from University of Arizona College of Medicine – Phoenix and Banner – University Medicine Heart Institute; Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, from the University of Florida, Gainesville; Ashish Pershad, MD, from Banner – University Medicine Heart Institute; Michael J. Rinaldi, MD, from Atrium Health’s Sanger Heart & Vascular Institute; Viviany R. Taqueti, MD, MPH, FACC, from Brigham and Women’s Hospital and Harvard Medical School; and B. Hadley Wilson, MD, FACC, from Atrium Health’s Sanger Heart & Vascular Institute and the University of North Carolina School of Medicine.
Editor’s note: All coverage from ACC.20 can be found here .
VICTORIA
Gopalan: The VICTORIA trial is exciting in the sense that, for the first time, a large trial looked at the nitric oxide pathway in very sick patients with HF, comparing the novel oral soluble guanylate cyclase stimulator vericiguat (Merck/Bayer) with placebo.
Among 5,050 patients (mean age, 67 years; 24% women) with chronic HF after a worsening event, the primary outcome of first HF hospitalization or CV death occurred in 25.5% of patients assigned vericiguat vs. 38.5% in those assigned placebo during a median of 10.8 months (HR = 0.9; 95% CI, 0.82-0.98), which led to an absolute event reduction of 4.2 per 100 patient-years. Secondary efficacy outcomes favored vericiguat or were neutral.
Patients assigned vericiguat tended to have higher rates of symptomatic hypotension (9.1% vs. 7.9%; P = .12) and syncope (4% vs. 3.5%; P = .3) compared with those assigned placebo. This is an area that HF physicians struggle with daily. It should be carefully looked at because this could become a problem with regard to uptitrating the medication to the target dose of 10 mg daily.
We knew that if patients were on nitric oxide treatment in the very first HF trials, they did not show a significant benefit with ACE inhibitors. That was a subject of discussion for the past 25 years. In 2005, the A-HeFT trial was released looking at the nitric oxide pathway — isosorbide dinitrate — in combination with hydralazine in an African American population, and it showed that there was an additional 15% benefit in mortality.
That was exciting, but the VICTORIA trial patient population is different in that these are very sick patients who have required a hospitalization for decompensated HF. This is an important trial in the timeline of HF with reduced ejection fraction. Overall, I would categorize this as exciting and a win with modest results.
In VICTORIA, about 60% of patients were on triple therapy, which is a good thing. Most patients with HF when they are on triple therapy already have hypotension. When the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan (Entresto, Novartis) came out, we struggled to uptitrate the ARNI to target dose because of the development of hypotension, and this is still an issue. Now we are going to add an additional medicine. While an additional drug is very exciting and encouraging, it also poses difficulty for the clinician to uptitrate and comanage these coexisting medications.
One of the things we would like to see is more of a major impact on mortality benefit. Most of the benefits were derived from a reduction in HF hospitalizations.
VOYAGER PAD
Pepine: VOYAGER PAD is an important study because it provides randomized trial evidence for improving outcomes in the management of patients with peripheral artery disease.
Among more than 6,500 patients with PAD who were followed for a median of 28 months, the cumulative incidence of acute limb ischemia, major amputation for vascular cause, MI, ischemic stroke or CV death was 17.3% in those who received rivaroxaban (Xarelto, Bayer/Janssen) 2.5 mg twice daily on top of aspirin 100 mg daily compared with 19.9% in those who received a matching placebo plus aspirin (HR = 0.85; 95% CI, 0.76-0.96).
In terms of bleeding, the incidence of TIMI major bleeding, the primary safety endpoint, did not significantly differ between the two treatment groups, occurring in 2.7% of patients assigned rivaroxaban plus aspirin compared with 1.9% assigned aspirin only (HR = 1.43; 95% CI, 0.97-2.1). However, International Society on Thrombosis and Haemostasis (ISTH) major bleeding, a secondary endpoint, was higher with rivaroxaban (5.9% vs. 4.1%; HR = 1.42; 95% CI, 1.1-1.84).
The lack of a significant increase in TIMI major bleeding, particularly intracranial hemorrhage, is most encouraging. Providers will need to be reminded that the 2.5 mg twice-daily dosing of rivaroxaban, plus aspirin, is different compared with the usual once-daily dosing that we are accustomed to using for atrial fibrillation to prevent stroke and systemic embolization and for deep vein thrombosis prevention.
TAILOR PCI
Wilson: The biggest take-home message from TAILOR PCI is that genotyping for patients who are clopidogrel nonresponders failed to meet its primary endpoint at 1 year in this study of more than 5,302 patients (median age, 62 years; 76% men). That is further indication that the question of prophylactic genotyping is not settled in this patient population.
The primary analysis pertained to 1,849 patients — 903 of whom were assigned genotype-guided therapy and 946 of whom were assigned conventional therapy — who were carriers of loss-of-function alleles of CYP2C19 that results in an inability to metabolize clopidogrel to the active prodrug. Carriers of loss-of-function alleles in the genotype-guided group received ticagrelor (Brilinta, AstraZeneca) instead of clopidogrel; all patients in the conventional therapy group received clopidogrel.
In the main analysis, the primary endpoint of CV death, MI, stroke, definite or probable stent thrombosis or severe recurrent ischemia at 1 year after index PCI was reduced by 34% in the genetic screening group compared with the conventional therapy group (HR = 0.66; 95% CI, 0.43-1.02; number needed to treat to prevent one event in those with a loss-of-function variant, 55), which fell short of the goal of a 50% reduction.
However, the treatment effect significantly favored the genetic-guided group at 3 months (absolute difference, 2.1%; 95% CI, 1-3.4; HR = 0.21; P = .001).
There was no difference between the groups in TIMI major or minor bleeding.
We can go ahead and treat our patients as we are currently doing around the world with our pick of P2Y12 inhibitor post-stenting in this population and they should do well for the succeeding year after implantation with very low absolute risk and a nonsignificant difference in risk.
In practicality, there was improvement early on, but at 1 year, it leveled out. The potential benefit appeared greatest in the first 3 months but was not borne out over the succeeding year. As a result, most people are not likely to alter their treatment pattern following this trial and further study may be required to alter current guidelines. Any incidence of stent thrombosis is important and serious. To guard against this, ticagrelor is a superior agent to clopidogrel, as has been shown in previous studies.
SPYRAL HTN-OFF MED
Pershad: The SPYRAL HTN-OFF MED findings are significant, especially given the fact that many patients do not like to take medications. Hypertension is a lifelong disease and chronic ailment. Any dent you can make, in terms of lowering office systolic BP or ambulatory BP, is important.
The researchers evaluated 331 patients, half of whom were randomly assigned to catheter-delivered renal denervation (Symplicity Spyral, Medtronic), which delivers pulses of radiofrequency energy to the nerves in the arteries. The other half were assigned to a sham procedure.
The BP reductions reported with renal denervation compared with a sham procedure are significant, although at a short follow-up of only 3 months, at which point there was a significant 4.7 mm Hg reduction in patients’ 24-hour systolic ambulatory BP and a 9.2 mm Hg reduction in office systolic BP. Change in 24-hour systolic BP at 3 months, the primary efficacy endpoint, was 4 mm Hg (P < .001) and change in office systolic BP at 3 months, the secondary efficacy endpoint, was 6.6 mm Hg (P < .001).
If we find that this is a sustained effect of renal denervation, then I think it could have a positive impact on hypertension, for which there is an unmet clinical need. Improving BP over the long term will impact HF and stroke rates.
Randomized trial of e-cigarettes
Gulati: The findings of the E3 trial are interesting, but do not answer whether this is the magic that we have been looking for to help people quit smoking. I would call these preliminary data hopeful, but there are a lot of missing pieces.
In a trial of 376 tobacco cigarette users, those who were randomly assigned to nicotine e-cigarettes and smoking-cessation counseling were more likely to continue to abstain from smoking at 12 weeks than those who received counseling only (21.9% vs. 9.1%; RR = 2.5; 95% CI, 1.3-4.6).
When patients use e-cigarettes to quit smoking, I do not know what is in the e-cigarette. Additionally, my question is whether I am replacing one form of nicotine for another. And is it safer? And nicotine is addictive, so how will I wean them off e-cigarettes? What is the long-term safety of using an e-cigarette? And will this truly be better than other smoking-cessation aids we have available? We cannot tell this from 12 weeks of data. And if the participants use e-cigarettes for 52 weeks, there is the potential to addict them to e-cigarettes for life. I cannot tell them that is OK.
As a health care community, we are terrible at getting people to quit smoking, despite having different drugs and other techniques that we can use to help. The counseling part is always necessary.
These data will not change my personal clinical practice. I work with my patients to help them quit smoking, but with e-cigarettes there are a lot of unknowns. This year, all we are talking about is COVID-19, but last year what we were concerned about was e-cigarettes, especially in young people, and the associated lung effects. That has taken a back seat to everything else going on, and rightfully so, but we cannot forget that we do not know what people are inhaling.
E-cigarette companies were probably worried that this study would not come out in their favor. I have always believed that if a company wants to promote a product, then it should give unrestricted research grants to the right investigators to try to show that the product does what the company thinks it does. These companies should put their money where their mouth is, and they should want these studies if they want people to use their products.
CIAO
Taqueti: Ischemia with no obstructive CAD (INOCA) is a real clinical phenomenon. It has been underrecognized and understudied for years, but high-quality data from the ISCHEMIA trial suggest that it is common. In ISCHEMIA, more than 20% of patients who were enrolled, and ostensibly required to demonstrate moderate to severe ischemia on objective, core-lab-verified diagnostic testing, actually did not demonstrate obstructive CAD on very sensitive evaluation using coronary CTA. This is a remarkable finding, and a surprise to many in the field, though perhaps less so to those of us who have been seeing these patients and studying this phenomenon.
In the CIAO ancillary study, the cohort of 208 patients with INOCA excluded from ISCHEMIA had a much greater proportion of women than the cohort of 865 patients with obstructive CAD enrolled in ISCHEMIA (66% vs. 26%; P < .001). In addition, compared with the obstructive CAD cohort, the INOCA cohort was younger (63 years vs. 66 years; P = .004), less likely to have diabetes (19% vs. 33%; P < .001), less likely to have prior MI (2% vs. 15%; P < .001), less likely to be a current or former smoker (41% vs. 56%; P = .001) and more likely to have depression (19% vs. 9%; P < .001).
At enrollment, the Seattle Angina Questionnaire (SAQ)-7 score was higher in the INOCA cohort than the obstructive CAD cohort (83 vs. 78; P = .036) and the SAQ Angina Frequency score was lower in the INOCA cohort (90 vs. 100; P < .001).
The researchers smartly leveraged a subset of these patients identified as having INOCA — who were all essentially “screen failures” from the main ISCHEMIA trial — into a clinical registry to follow natural history of these patients longitudinally. But there were notable limitations. Only a small subset of patients with INOCA, approximately 17%, were included — that is, those who underwent stress echocardiography as their initial diagnostic test for ischemia prior to entry into the main trial. This is likely a highly selected group. There was no noninvasive or invasive testing for coronary microvascular dysfunction, which is thought to drive adverse CV outcomes in patients with INOCA.
Investigators found no significant correlation between reported angina and ischemic findings on stress echocardiography. This was true in the ISCHEMIA-CIAO and ISCHEMIA main cohorts. On longitudinal assessment, change in reported angina was also not correlated with change in ischemia in CIAO, despite overall improvements in both endpoints.
Most patients with INOCA were symptomatic of angina and/or dyspnea despite high prevalence of medical therapies, and had high prevalence of CV risk factors/comorbidities.
This study raises awareness of the importance of the INOCA phenotype and highlights the need for more precise diagnosis of coronary microvascular dysfunction, which can now be done noninvasively through clinically available and reimbursed positron emission tomography or other noninvasive and invasive imaging approaches. It also leaves many important questions unanswered. Only by better defining who has coronary microvascular dysfunction can we begin to target effective treatment strategies in a personalized and evidence-based way for our patients.
The bottom line is that INOCA is quite prevalent, in as many as 20% of patients with documented moderate-severe ischemia, and occurs in both women and men, but with a clear predominance in women, despite high use of existing medical therapies. More research and investment need to be done to improve outcomes in this emerging patient population.
POPULAR-TAVI
Rinaldi: POPULAR-TAVI is an important trial and will likely change practice. Currently, most patients undergoing transcatheter aortic valve replacement who also have an indication for oral anticoagulation therapy receive additional antiplatelet therapy with either aspirin or clopidogrel, but data supporting this strategy are lacking.
In this study, 313 patients undergoing TAVR with an indication for oral anticoagulation therapy, primarily AF, received oral anticoagulation with either warfarin or direct oral anticoagulation and were randomly assigned to 3 months of clopidogrel monotherapy or no clopidogrel. Aspirin was not administered.
The incidence of bleeding was higher in patients assigned clopidogrel plus oral anticoagulation compared with oral anticoagulation alone (34.6% vs. 21.7%; RR = 0.63; 95% CI, 0.43-0.9), as one would expect, but anticoagulation alone yielded no increase in ischemic events such as MI or stroke (RR = 0.77; 95% CI for superiority, 0.46-1.31). In fact, while the trial was underpowered to look at these events, these ischemic events were numerically lower in the oral anticoagulation therapy alone arm, which makes it unlikely that underpowering is missing an ischemic disadvantage.
Currently, most centers use 81 mg of aspirin as an adjuvant to oral anticoagulation therapy following TAVR. The extent of the disadvantage of adding clopidogrel in comparison to aspirin is unknown, but likely the outcomes would be similar.
While it would be nice to have additional studies that corroborate this, I would feel very comfortable eliminating antiplatelet therapy post-TAVR in patients receiving oral anticoagulation therapy who do not have a recently placed coronary stent.
These findings fit nicely with a variety of other studies in interventional cardiology that suggest less combination therapy results in less bleeding without the expense of higher ischemic events. – by Scott Buzby, Darlene Dobkowski, Katie Kalvaitis and Erik Swain
Disclosures: Gopalan, Gulati, Pepine, Pershad, Taqueti and Wilson report no relevant financial disclosures. Rinaldi reports he served on the advisory board for Abbott and Boston Scientific; conducted teaching courses for Abbott and Edwards; has spoken for Abbott, Boston Scientific and Edwards and has received a research grant from Boston Scientific.
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