Great Debates of 2016 | By Debra L. Beck
CardioSource WorldNews | In ancient Rome, the gladiator games served as the West End and Broadway shows of the day, existing for their entertainment value. In this case, though, instead of “West Side Story,” you had actual armed combatants viciously fighting each other or animals, sometimes to the death. A defeated gladiator’s life was spared if he (or she, in an early attempt at workplace equality) was deemed to have fought well. Be glad you’re not a gladiator!
It may seem strange to fashion a medical conference debate forum after this brutal bit of history, but that’s what the European Society of Cardiology (ESC) did with “The Gladiators Arena,” debuted at this year’s (when in Rome…) conference.
However, while the gladiators of yore were often slaves or otherwise socially marginalized individuals, the ESC gladiators comprised an impressive group of top researchers and clinicians taking pro and con positions in traditional debate sessions on topical and controversial clinical questions facing cardiologists today. Fortunately, for the gladiators and viewers alike, the ESC arena proved more genteel and non-violent, with the fates of the combatants determined by a show of audience thumbs up or down – and the winner being crowned with a garland of leaves. Hail Caesar, indeed!
Will the moniker remain when the ESC’s annual meeting moves to Barcelona in 2017, or will we see a name change to something more Spain-centric? The Gaudi Games or Las Ramblas Rumble? Please, just not The Spanish Inquisition!
Should Guidelines “SPRINT” to Lower BP Targets?
With prevalence so high, hypertension walks around with a bull’s eye on its back. The 2013 European Society of Hypertension/European Society of Cardiology guidelines set a target blood pressure (BP) of < 140/90 mm Hg for all patients regardless of cardiovascular (CV) risk.1 There is a more conservative target for the elderly and some modest support for a more aggressive target of < 130 mm Hg in a few specific high CV risk situations.
Controversial updated U.S. guidelines suggested a BP goal of < 150/90 mm Hg for individuals aged 60 years or older and < 140/90 mm Hg for younger patients.2 However, a Scientific Statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension released in 2015, agreed with ESC and suggested a target of < 140/90 mm Hg for most patients with coronary artery disease and hypertension, including patients aged 65 to 79 years of age. The statement also suggested considering a BP level of < 130/80 mm Hg as “reasonable” in selected patients, including those with previous myocardial infarction (MI), stroke/transient ischemic attack (TIA), or coronary artery disease (CAD) risk equivalents.3
To date, only the Canadian hypertension guidelines, which are updated annually, have said that the lower target of < 120 mm Hg “should be considered” for high-risk individuals, age ≥ 50 years with systolic BP levels ≥130 mm Hg.4
Running into Controversy
Enter the SPRINT trial, presented at AHA.15 and published in November 2015, which showed that more intensive treatment to < 120 mm Hg reduced the rate of adverse clinical outcomes in patients at high cardiovascular risk compared to the standard < 140 mm Hg target.5 More aggressive treatment was associated with a significant reduction in the primary composite endpoint of myocardial infarction (MI), other acute coronary syndromes (ACS), stroke, heart failure (HF), or death from cardiovascular causes. While there were no significant differences in the rates of MI, other ACS events, or stroke between groups, acute decompensated HF was significantly reduced in the study arm. All-cause mortality was also significantly lower in the intensive-treatment group, but the patients in the study arm experienced higher rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure.
Not surprisingly, SPRINT has generated much discussion on whether BP targets should be officially lowered. In this debate session, SPRINT investigator William C. Cushman, MD, (University of Tennessee, Memphis) argued for lowering BP targets, while Sverre E. Kjeldsen, MD, PhD, (Oslo University Hospital Ullevaal, Oslo, Norway) argued against changing BP targets. The discussion was rounded out by introductory remarks given by Giuseppe Mancia, MD, (University of Milan, Italy) and concluding remarks from ESC program committee member Bryan Williams, MD, (University College London).
Dr. Mancia suggested that there is solid reasoning for the current BP targets, mainly that the trials done to date have showed benefit to treating BP to 140 mm Hg, with no trial showing benefit from active treatment to < 130 mm Hg. He also noted, however, that there are several remaining gaps in our knowledge of optimal BP targets. For example, there are very limited data on how to treat younger patients who have not yet accumulated much CV risk. Also unknown: how optimal BP targets might be specific to the individual patient or vary within a patient group, perhaps according to age or according to the presence or absence of organ damage.
For his part, Dr. Cushman mostly summarized the SPRINT findings and offered some thoughts as to where he might like to see the BP guidelines changed. (Certainly, applying the SPRINT results to the U.S. population would impact a lot of patients.)
The circles are proportional to the population sizes.
“I want to point out that in the intensive group, 62% were below 120. It wasn’t 80% below 120, but 80% were below 130,” he said, adding later, “I believe that SPRINT will change systolic blood pressure goal recommendations in hypertension guidelines. I’m not sure if those guidelines will decide for the goal to be less than 120 or less than 130.”
He noted the lack of heterogeneity in all major subgroups, both for the primary endpoint and for all-cause mortality, and the general indication that the benefits of more aggressive treatment outweighed “the relatively small risk” of adverse events.
After stating that his assigned task in the debate “is to attack,” Dr. Kjeldsen did so with gusto, not relenting before he presented strong criticisms of the trial’s design and interpretation, and even a suggestion of unethical behavior on the part of the researchers and others.
“We had great expectations,” he said about the SPRINT results when they were presented at last year’s AHA annual meeting. “I was sitting there in the front row expecting something fantastic. I was deeply disappointed there and increasingly disappointed during the year since.”
Dr. Kjeldsen’s first complaint was that SPRINT used a novel and unvalidated BP measuring technique, namely a programmed automated monitor that allowed for unattended BP measurement so as to reduce white coat hypertension. This sounds like a good idea, but since unattended BP measurements can stand as much as 20 mm Hg lower than usual office BP,6 he argued that the systolic target of 120 mm Hg used in SPRINT is really not as different as it sounds compared to the prevailing target of 140 mm Hg. (In his counter-comments, Dr. Cushman suggested the BP difference is “more on the order of 5 to 10 mm Hg, at the most, at least from most literature that I’m aware of.”)
Another issue raised was whether one of the main findings of SPRINT, the significant reduction seen in new onset HF with aggressive treatment, was really “an artifact” caused by up- and down-titration of diuretics in patients with very high risk of heart failure, as Dr. Kjeldsen suggested. (Dr. Cushman countered that the control patients “probably” received more diuretic treatment than they had before the study, as evidenced by their lower BPs during the study, but he added that the investigators are still looking closely at the effects of drug choices on outcomes.)
Pulling no punches, Dr. Kjeldsen finished his comments by questioning the way in which the SPRINT results were first released, referring to the decision of a “limited group of SPRINT investigators under the leadership of the NIH Director” to release top-drawer findings from SPRINT 2 months before the study’s publication and full release at the 2015 AHA meeting.
“Is it an ethical issue to announce sensational new data in a press release and potentially misinform the world for 2 months prior to the release of the data which can then be inspected by other experts and the community?” He went on to ask: “Will NIH repair the damage and issue a neutralizing statement?”
For all these reasons plus a few more, Dr. Kjeldsen concluded his comments by unequivocally stating that the SPRINT trial “should have no implications for guidelines or clinical practice.”
“We really do have to look at this data very carefully before we make big decisions about guidelines,” said Dr. Williams in his concluding remarks, made after the audience voted with their thumbs and awarded the winner’s garland to Dr. Kjeldsen. Dr. Williams summed it all up thus: “There is little doubt that more blood pressure lowering is better for patients at high risk because whatever the blood pressure was and whatever it ended up at, the people who got more of it, did better…The debate is how low should we go in the context of recommendations and guidelines? My own view is that the guidelines should remain conservative in that you can’t advocate levels of treatment that are potentially harmful to some [emphasis his], even if it benefits others.”
He also sent a little criticism back to the crowd who were eager to debate how low to go, noting that we do a “lamentable” job of lowering blood pressure altogether with less than 50% of patients achieving BP < 140 mm Hg, “and we’re here arguing whether we should try to go below 120. So, the first thing we should focus on is how to get blood pressure to 140 in the majority and then focus on getting it lower.”
Editor’s Note: You can access ACC’s comprehensive coverage and join the discussion of the SPRINT trial at ACC.org/Sprint.
Thromboembolic Prevention After TAVR: Antiplatelets or Anticoagulants
For all the progress made in technical refinement and patient selection in transcatheter aortic valve replacement (TAVR, or TAVI with the I for implantation for the Europeans), the issue of post-procedural anticoagulation remains a great unknown, with little or no high-quality evidence to guide clinicians.
While there is general consensus in the guidelines against long-term anticoagulation with a vitamin K antagonist (VKA) after TAVR,7,8 VKA use is recommended in the first 3 months, which some argue is also not appropriate.
“What we know is that we know very little about this issue,” said Lars Sondergaard, MD, DMSc, from Rigshospitalet in Copenhagen, Denmark. Arguing against antiplatelet therapy alone after TAVR, Dr. Sondergaard suggested that an antiplatelet only strategy is “too simple.”
In the opposite corner was Antonio Colombo, MD, FACC, from the Centro Cuore Columbus in Milan Italy, who was assigned to argue the “all we need are antiplatelet agents” side. Dr. Colombo started his remarks by saying, “For those people who are in a rush, I’ll just say that we have no answer because if we had an answer we would not be doing trials.”
Post-TAVR pharmacotherapy primarily consists of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for 1 to 6 months after implantation, and aspirin for life. If a patient has a pre-existing indication for oral anticoagulation (OAC), they are generally prescribed OAC or a novel oral anticoagulant (NOAC) for 3 to 6 months plus antiplatelet therapy and continued anticoagulation (with or without aspirin) for life.
Acknowledging the higher risk of ischemic stroke or peripheral embolism (compared to the normal population) in the first 90 days after valve replacement, the 2014 ACC/AHA guidelines assign a Class IIb recommendation for oral anticoagulation with a VKA to achieve a target international normalized ratio of 2.5 for the first 3 months after TAVR, even in the absence of other risk factors (Level of Evidence: B).7
Arguing against current recommendations, Dr. Colombo cited a recent meta-analysis by Masri et al. that compared VKA anticoagulation to antiplatelet therapy or no therapy in patients undergoing bioprosthetic valve implantation, 95% of which were aortic.9 Reviewing a total of 14 studies comprising 31,740 patients, and including two randomized trials, the authors found no significant differences in thromboembolic events, all-cause mortality, or the need for repeat surgery between those given VKAs and those receiving an antiplatelet or no therapy. However, there were significantly more bleeding events in those treated with warfarin.
Dr. Colombo noted that the incidence of clinically relevant transcatheter heart valve thrombosis is not well defined but appears to be quite low, somewhere around 1%. Referring to the stir caused by the Makkar et al. study published in 2015 in the New England Journal of Medicine,10 which showed that subclinical leaflet thrombosis was seen in 40% of bioprosthetic aortic valves, he stressed that reduced leaflet motion leading to symptoms was seen in less than 1% of patients, making it “a frequent event with rare clinical impact that, when it occurs, can be treated easily if necessary.” Five-year data from the PARTNER trial confirm that valve thrombosis is rare and there is no clear signal “so far” that there is a major issue with structural valve deterioration that requires re-intervention.
“But it occurs, and when it occurs it is possible to institute treatment and it is usually effective,” said Dr. Colombo. He cited a study published by his group that showed an incidence of transcatheter heart valve thrombosis of 0.61% out of 4,266 patients undergoing TAVR in 12 centers.11 “This may be a little underestimated, I admit, but you can round it up to 1%.”
The median time to transcatheter heart valve thrombosis was 181 days and the most common clinical presentation was exertional dyspnea in 65%, whereas 31% of patients had no worsening of symptoms. Echocardiography was “very instrumental” in showing increased valve gradient in 92% of patients.
“The good news is that 4 days of anticoagulation with heparin was most of the time sufficient to clear the valve of thrombotic material,” reported Dr. Colombo.
To further stress the downside of routine anticoagulation in TAVR patients, he cited a recent study by Abdul-Jawad Altisent et al. that showed that during 13 months of follow-up, the addition of one antiplatelet therapy to anticoagulation (in those with a clear indication for OAC after TAVR), increased bleeding from 15% to 24% (p=0.04).12 “The real problem is the addition of an antiplatelet to a vitamin K antagonist,” he explained.
He concluded his remarks thus: “Most TAVI patients are elderly with a high risk for bleeding and I see no reason to pay the price of bleeding to prevent a rare and treatable event.”
Countering this approach, Dr. Sondergaard suggested that TAVR patients are under continuous short- and long-term risk for thromboembolic events, which favors anticoagulation, although he also acknowledged that most TAVR patients are elderly and have comorbidities, which increase bleeding risk.
“I don’t think the ideal post-procedural antithrombotic therapy exists,” he said, “but we have to look at each individual and try to tailor the best medical treatment, and that is going to include anticoagulation for some of those patients.”
He also noted some evidence that the risk of structural valve deterioration is higher in the absence of continued OAC. In those with subclinical leaflet thrombosis, 3 months of VKA therapy will resolve it, he said, emphasizing that the data support VKAs in this regards, not NOACs or antiplatelet agents.
“Oral anticoagulation, but not antiplatelet therapy, protects against and resolves leaflet thrombosis” irrespective of whether there are symptoms, Dr. Sondergaard argued, in contradiction to Dr. Colombo’s argument that most leaflet thrombosis is subclinical and therefore not warranting OAC. In his coauthored New England Journal of Medicine paper that alerted the TAVR world to this issue,10 there was a nonsignificant trend towards increased thromboembolic risk with subclinical leaflet thrombosis, but these data need to be confirmed in larger studies, he noted. Along with protecting against leaflet thrombosis, VKA therapy for 3 to 6 months seems to guard against structural valve deterioration after bioprosthetic valve implantation, both in the surgical and transcatheter data.
Certainly, there is no arguing that patients with atrial fibrillation (AF) undergoing TAVR require continued OAC, and clinical trial data suggest that up to 40% of TAVR patients have pre-existing AF. But new-onset AF is also a significant issue to be considered, said Dr. Sondergaard. He cited unpublished data from NOTION-1 showing that after 2 months, all surgical AVR patients and 80% of TAVR patients had an episode of AF detected on continuous cardiac monitoring. For these individuals, antiplatelet therapy is inferior to OAC with regards to efficacy and safety, he said, and it is as efficient and safer than OAC plus antiplatelet therapy, citing the just published study by Abdul-Jawad Altisent et al.12 To balance competing risks of thromboembolism and bleeding, he suggested using the CHA2DS2-VASc and HAS-BLED scores and considering left atrial appendage occlusion so as to not compromise with OAC those at high risk for bleeding.
There are three ongoing trials that will offer much more information on this topic in the next few years—GALILEO, ATLANTIS, and POPULAR-TAVI. These studies will test multiple antiplatelet and anticoagulation options both in those with and without indications for OAC. In his concluding remarks, Dr. Windecker encouraged attendees to try to include their patients into one of these ongoing trials.
Stress Testing for Intermediate-risk Stable CAD
This debate session was provocatively named, “Stress testing thrown to the lions.” Stephan Windecker, MD, (University Hospital Bern, Switzerland) presented arguments supporting the use of invasive imaging for stable CAD as the standard approach, and Roxy Senior, MD, FACC, (Imperial College London, UK), argued against relying on angiography as “the standard.”
In her introductory review of the topic, Roxana Mehran, MD, FACC, (Icahn School of Medicine at Mt. Sinai, New York) noted that it is difficult to diagnose CAD based on symptoms alone. Clearly in those with unstable presentations, angiography is warranted, as it is in those with pre-test-probability > 85% for the presence of coronary stenosis. She added that the guideline-recommended CAD Consortium tool, as opposed to the old Diamond Forrester score, best estimates pre-test probability.
In a similar vein, among patients at low risk (< 15% likelihood of coronary stenosis), generally younger patients who perhaps present with atypical symptoms, there is consensus that these patients need no testing and no medication. The issue is the middle group—those with stable presentations and an intermediate likelihood of having significant CAD. Is there real value in stress testing or are they best served by invasive angiography?
Currently, the guidelines propose non-invasive testing for intermediate-risk patients, and this might entail treadmill exercise electrocardiogram, stress echo, stress magnetic resonance or nuclear medicine, or another noninvasive test.
“Unfortunately, the sensitivity and specificity [for the wide array of noninvasive tests available] is all over the map. There isn’t one noninvasive perfect test…to give you the perfect answer,” said Dr. Mehran. She added, however, that we do have solid evidence that noninvasive functional testing does have an important impact on the outcomes of patients with stable coronary disease, in that if you diagnose myocardial ischemia on such tests, this is correlated with a worse outcome.
So, why would we want to give up on noninvasive testing? Presenting his side, Dr. Windecker showed that there is substantial heterogeneity in the phenotype of stable CAD, with some being at much higher risk than others. Also, data, albeit mainly registry data, indicate that in the absence of stress testing, or in patients with negative stress tests, up to 40% were subsequently found to have obstructive coronary lesions, which he suggested would indicate that stress testing is of limited use.
Dr. Windecker also pointed out that coronary angiography is not only the gold standard for the diagnosis of obstructive CAD, but that it is a much lower-risk procedure than it once was (think, radial access) and that it allows for the immediate treatment of obstructive disease and ad hoc functional assessment by fractional flow reserve, when needed. Noninvasive testing, he noted, may offer less procedural risk, but it is associated with increased risk of adverse events occurring between the time of presentation and treatment.
He also noted “there is no single noninvasive test that performs adequately in all clinical settings, even in expert hands.” It is thought that anatomical testing is better to exclude CAD, but in terms of prognostic impact, the PROMISE study showed no difference in clinical outcomes between anatomical and functional testing.13
He concluded: “I would submit to you that you should consider coronary angiography as a noninvasive test equivalent in order to avoid inappropriate underuse.”
Dr. Senior’s first words of rebuttal were elegant: “When a patient comes with chest pain, what we need to exclude is myocardial ischemia. And where is the ischemia? It’s in the myocardium. So, look at the myocardium. You don’t have to look anywhere else, because that’s where the answer is. Not in the arteries.”
Dr. Senior went on to note that we have good outcomes data showing that a negative stress test is associated with a favorable prognosis, even in the absence of angiography, and that those with positive signs of ischemia on stress echocardiography need to be treated with intensive risk factor management and careful follow-up regardless of whether there is obstructive CAD or not.
So why, Dr. Senior continued, expose the patient to the risks of angiography and the possibility that they may have their hearts revascularized unnecessarily just because a lesion was found on angiography?
If there is no sign of ischemia on noninvasive testing, and no atherosclerosis on hybrid carotid ultrasound assessment (which he recommended), then “you don’t need any other major test to make a decision about this patient,” he concluded. Citing data from a paper he authored, Dr. Senior said that in intermediate pre-test probability patients, the preferred test is stress echocardiography.
While Dr. Windecker took criticism for his pro-angiography data coming mostly from registries, Dr. Senior took flak over the ongoing issue that stress testing performed in “regular” hands can confer very different outcomes to stress testing done by the “experts.”
All agreed that, at the end of the day (or the fight…), decisions must be tailored to the individual patients and take into account the expertise and culture of the clinical center, recognizing that some centers are better at noninvasive testing, while others excel in the catheterization laboratory. That said, the gathered crowd awarded the crown to Dr. Senior, showing a clear reluctance to abandon noninvasive testing.
Stay tuned next year to see if ESC brings a bit of WWE into the proceedings.
- Mancia G, et al. J Hypertens. 2013;31(7):1281-357.
- James PA, et al. JAMA 2014;311:507-20.
- Rosendorff C, et al. J Am Coll Cardiol 2015;65(18):1998-2038.
- Harris KC, et al. Can J Cardiol. 2016;32(5):589-97.
- The SPRINT Research Group. N Engl J Med 2015;373(22):2103-16.
- Filipovsky J, et al. Blood Press 2016;25:228-34.
- Nishimura RA, et al. J Am Coll Cardiol 2014;63(22):2438-88.
- Vahanian A, et al. Eur Heart J 2012;33(19):2451-96.
- Masri A, et al. Heart 2016 Aug 3. doi: 10.1136/heartjnl-2016-309630. [Epub ahead of print]
- Makkar RR, et al. N Engl J Med 2015;373(21):2015-24.
- Latib A, et al. Circ Cardiovasc Interv 2015;8:pii: e001779.
- Abdul-Jawad Altisent O, et al. JACC Cardiovasc Interv 2016;9(16):1706-17.
- Douglas PS, et al. N Engl J Med 2015;372:1291-300.
|Read the full November issue of CardioSource WorldNews at ACC.org/CSWN|
Keywords: CardioSource WorldNews, Blood Pressure, Coronary Artery Disease, Hypertension, Ischemic Attack, Transient, Myocardial Infarction, Prevalence, Stroke
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