PERCUTANEOUS CORONARY INTERVENTION (PCI): A THERAPEUTIC MYTH?


Professor of Cardiovascular Science, Cardiovascular and Cell Sciences Research Institute,St George’s, University of London, UK

PCI IN PATIENTS WITH STABLE ISCHAEMIC HEART DISEASE – A THERAPEUTIC MYTH?

Contrary to expectations, large randomised studies have demonstrated percutaneous coronary intervention (PCI) not to reduce mortality or the incidence of acute myocardial infarctions in patients with stable coronary artery disease. Symptom relief is therefore considered to be the primary goal of PCI in patients with chronic stable angina. Very recently, however, the ORBITA study, a double blind multicentre randomised trial of PCI versus a placebo procedure for angina relief carried out in the UK and published in The Lancet, (1) showed that in patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time significantly compared with a placebo procedure.

ORBITA enrolled patients with ≥70% single-vessel coronary artery stenosis who received 6 weeks of medication optimisation followed by pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires and stress echocardiography. Patients were randomised to undergo PCI or a placebo procedure.  After 6 weeks of follow-up, the assessments carried out before randomisation were repeated at the final assessment. The authors assessed the difference in exercise time increment between groups.

230 patients with ischaemic symptoms were included in the study with 200 patients randomised as follows: 105 patients were assigned to PCI and 95 assigned to placebo procedure. Mean area coronary stenosis was 84·4% (SD 10·2), fractional flow reserve 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22).

The main result of the study, as reported by the authors, was that “no significant difference was observed in the primary endpoint of exercise time increment. There were no deaths and serious adverse events included the following:  pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group”.

The results of this study may change practice in relation to management of chronic stable angina. Contrary to current belief, jointly shared by Interventional cardiologists and patients with stable angina alike (12), PCI does not appear to be better than a placebo intervention for the management of symptomatic patients with stable angina. As discussed in the manuscript (1), “in the absence of blinding, the effect size of PCI on symptomatic endpoints can be overestimated because of the addition of the placebo effect to the true physiological effect of intervention”.14 It is worth noting that as indicated by the authors, “in all previous trials, both investigators and patients were aware of the treatment allocation” and this could have markedly affected the results.

Findings in the ORBITA study, particularly if further confirmed by larger studies, will have major implications for the future of coronary intervention worldwide. Comments from the interventional community regarding the ORBITA study findings are eagerly awaited.

References

  1. Al-Lamee R et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet 2018; 391: 31–40
  2. Kaptchuk TJ, Goldman P, Stone DA, Stason WB. Do medical devices have enhanced placebo effects? J Clin Epidemiol 2000; 53: 786−92
  3. Rothberg MB, Sivalingam SK, Kleppel R, Schweiger M, Hu B, Sepucha KR. Informed decision making for percutaneous coronary intervention for stable coronary disease. JAMA Intern Med 2015; 175: 1199−206.
  4. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995; 273: 408−12.

Longer Infusion Gives Bivalirudin the Upper Hand in PCI


Continued bivalirudin (Angiomax) infusion after primary percutaneous coronary intervention (PCI) may overcome its disadvantage in acute stent thrombosis rates compared with heparin while keeping the lower bleeding risk, according to a meta-analysis.

Bivalirudin use during PCI was tied to a doubling of acute stent thrombosis cases compared with heparin (risk ratio [RR] 2.36, 95% CI 1.46-3.02), found Rahman Shah, MD, of the University of Tennessee School of Medicine in Memphis, and colleagues.

 However, continuing with a full bivalirudin dose for 3 to 4 hours after PCI negated this effect (RR 0.90, 95% CI 0.32-2.54), the investigators reported online in JACC: Cardiovascular Interventions. There was no difference in acute stent thrombosis rates between patients who got heparin and full-dose bivalirudin in mixed-treatment models (odds ratio 0.97, 95% CI 0.36-2.21).

Post-procedural infusion of a low dose of bivalirudin failed to ameliorate the stent thrombosis disadvantage of the antithrombotic (RR 3.61, 95% CI 1.17-11.13).

At 30 days post-PCI, bivalirudin recipients had 47% lower odds of major bleedingcompared with their heparin counterparts. Those who got full-dose bivalirudin infusions were also less likely to have major bleeding (RR 0.29, 95% CI 0.16-0.53).

“While bivalirudin is associated with a greater risk of acute stent thrombosis than heparin post-primary PCI, this limitation may be mitigated by continuing full-dose bivalirudin (not reduced-dose bivalirudin) 3 to 4 hours postoperatively. The decrease in bleeding risk with bivalirudin compared to heparin is not compromised by this strategy,” Shah’s group concluded.

Marco Valgimigli, MD, PhD, and Giuseppe Gargiulo, MD, both of Bern University Hospital in Switzerland, called the results “potentially practice changing” and consistent with recommendations for bivalirudin in the U.S.

In an accompanying editorial, they recommended caution when interpreting the findings, however, due to the meta-analysis’ nonrandomized and unadjusted nature.

Shah’s investigation included five randomized controlled trials and 16,294 patients withacute coronary syndrome who underwent primary PCI.

Radial Access Safer in Ad Hoc PCI


Randomized trial shows similar efficacy, less bleeding

Action Points

Transradial access was as good as going through the groin for outcomes in ad hoc percutaneous coronary intervention reflecting real-world practice, and modestly reduced bleeding, a randomized trial from China showed.

The primary endpoint of major adverse cardiac or cerebrovascular event (MACCE)-free rate at 12 months came out 95.8% for radial compared to 95.5% for femoral access, which easily met the non-inferiority criterion (P≤0.001), Shigeru Saito, MD, of Shonan Kamakura General Hospital in Kanagawa, Japan, and colleagues found.

Transradial access came out superior for the secondary endpoint of freedom from major bleeding complications by the BARC DefinitionType 3 or 5 at one week (99.9% versus 99.0%,P<0.001 for superiority), Saito reported here at the opening late-breaking clinical trial session of theTranscatheter Cardiovascular Therapeutics meeting.

While the finding of less bleeding was not surprising, it was definitive, Saito suggested.

“After this result, everybody must follow the transradial approach as a first approach,” he told reporters at a press conference.

The DRAGON (Determination of the Radial versus Groin Coronary Angioplasty) trial included 2,042 patients getting ad hoc PCI at 25 hospitals in China randomized 2:1 to transradial versus transfemoral access.

In China, transradial accounts for about 95% of procedures, noted Run-Lin Gao, MD, of China’s National Center for Cardiovascular Diseases, who commented at the press conference.

So the findings might represent a best-case scenario of experienced radial operators, added press conference moderator and TCT co-director Roxana Mehran, MD, of Mount Sinai Hospital in New York City. While U.S. practice is increasingly moving toward radial access, it has still only reached about a quarter of procedures, she noted.

Still, Saito suggested that the findings could be “applied very easily to the U.S.,” despite differences between the two populations in things like body mass index.

Even in complex cases, there’s no reason not to take a transradial-first approach, agreedMarie-Claude Morice, MD, of Institut Cardiovasculaire Paris Sud in Massy, France.

Daniel I. Simon, MD, of University Hospitals’ Case Medical Center in Cleveland, Ohio, was a little more circumspect.

“There are two sort of diverging paths here,” he said at the press conference. “One is that interventions are getting more complex and… one of the things I’d hate to see is our trainees and fellows lose the techniques that you need from transfemoral catheterization to do some cases. Certainly the femoral will still be required for some procedures, but it certainly seems that you could make a very strong case in ST-segment elevation MI that this [transradial access] really should be the standard. That’s where I think the data is the most robust.”

FDA Approves Kengreal for Prevention in PCI


Indication for thrombotic risk reduction given after initial setbacks

The FDA granted the antiplatelet agent cangrelor (Kengreal) approval for prevention of thrombotic events in adults getting percutaneous coronary intervention (PCI) without use of other antiplatelet agents.

The label specified use “as an adjunct to PCI for reducing the risk of periprocedural myocardial infarction, repeat coronary revascularization, and stent thrombosis in patients who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor.”

That was a slight deviation from what the FDA advisory panel voted in favor of, which was use when “an oral P2Y12 platelet inhibitor prior to PCI is not feasible and when glycoprotein IIb/IIIa receptor antagonists are not anticipated to be used.”

The panel had expressed concern that approval of cangrelor as an alternative to preloading clopidogrel (Plavix) would further drive ad hoc PCI as a matter of convenience.

The drug had initially been turned down for a broad indication in prevention of thrombotic events associated with coronary stenting and for bridging patients whose existing antiplatelet regimen must be interrupted for surgery.

The second panel also had reservations about the single positive trial upon which approval could be based, the CHAMPION PHOENIX trial in which cangrelor reduced post-procedural cardiovascular events by 22% compared with clopidogrel (Plavix).

The FDA noted bleeding as the most serious risk with the drug, as with all antiplatelet agents. In the trial, serious bleeding was more common with cangrelor than clopidogrel, with rates of about one in 170 versus one in 275 patients.

The number needed to treat with cangrelor was 156 to prevent one MI, stent thrombosis, or revascularization. The number needed to harm was 461 to cause one additional GUSTO severe or moderate bleed or 198 to cause one additional TIMI major or minor bleed.

Drugmaker The Medicines Company said it expected cangrelor to be available for the U.S. market in July.

FDA Favorably Views Cangrelor in PCI for CAD Patients Ahead of Panel Meeting


The injectable antiplatelet agent cangrelor (the Medicines Company, Parsippany, NJ) may be one step closer to approval for use as an adjunct to PCI for reducing thrombotic events in patients with CAD, should the panel vote in concert with the briefing documents released today by the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA)[1]

Although official vote by the committee won’t come until the end of Wednesday, FDA reviewers are recommending that cangrelor be approved “in patients in whom treatment with an oral P2Y12 platelet inhibitor prior to PCI is not feasible and when glycoprotein IIb/IIIa–receptor antagonists are not anticipated to be used.” This is in contrast to last year’s vote.
In February 2014, the advisory committee voted 7 to 2 that cangrelor should not be approved because the risk/benefit profile was not sufficient enough. In addition, although the large CHAMPION-PHOENIX trial showed positive results, the previous CHAMPION-PLATFORM and CHAMPION-PCI trials were negative and weighed into the decision making of some of the panel members.

After requesting and receiving further sensitivity analyses and a more simplified application letter, the reviewers now state that PHOENIX is sufficient enough as a stand-alone trial to warrant approval.

“The benefit of cangrelor compared with clopidogrel is small, but the risk is smaller,” write the reviewers. “Treating 171 patients prevents one clinically meaningful periprocedural MI. In comparison, treating 1106 patients causes one GUSTO severe bleed, a safety factor of ~6.5-fold. Using a less severe bleed to assess benefit risk, such as a GUSTO moderate or TIMI minor bleed, still favors the use of cangrelor.”
Last year, the advisory committee also recommended unanimously that cangrelor not be approved as a “bridging” therapy for patients with stents who stop oral P2Y12 inhibitors because of surgery. The Medicines Company is no longer seeking to market the medication for that indication.

Mass. Sees Steep Drop in Revascularization


Rates fell over the past decade for both PCI and CABG

Coronary revascularization has declined dramatically over the past decade, according to a population-based study in Massachusetts.

The age- and sex-adjusted rate fell 39% from 2003 through 2012, from 423 per 100,000 population to 258 (P<0.001), Robert W. Yeh, MD, MBA, of Massachusetts General Hospital in Boston, and colleagues reported online in a research letter in JAMA Internal Medicine.

The drop was significant for both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG):
  • PCI: 318 to 200 per 100,000
  • CABG: 113 to 63 per 100,000

The exact reason for the trends wasn’t clear, but likely relates to dropping rates of myocardial infarction (MI) reported in multiple populations, “likely attributable to improved primary and secondary prevention.”

“These data have broad implications for regional health policy, training and provider accreditation, hospital resource allocation, and patient outcomes,” the researchers concluded.

The retrospective study included all 171,702 coronary revascularizations among Massachusetts residents seen at nonfederal hospitals from April 2003 through September 2012, whether inpatient or outpatient, and regardless of concomitant valve or aortic surgery. Only the first procedure per year per patient was counted.

PCI accounted for 76.9% of the procedures overall; CABG, 23.1%.

The biggest declines were in elective PCI (down from 206 to 109 per 100,000) and in isolated CABG (down from 90 to 45 per 100,000). All other categories except combined CABG and aortic or mitral valve surgery also declined significantly from 2003-2012.

From the American Heart Association:

CABG Again Outperforms PCI in Patients with Diabetes.


In patients with diabetes and heart disease, coronary artery bypass grafting reduces cardiovascular events more effectively than PCI with drug-eluting stents, according to a study presented at the American Heart Association meeting and published in the New England Journal of Medicine.

Some 1900 diabetic patients with multivessel disease were randomized either to undergo PCI with drug-eluting stents or CABG.

During roughly 4 years’ follow-up, the primary composite outcome — death from any cause, nonfatal MI, and nonfatal stroke — occurred more often with PCI than with CABG (5-year event rate: 27% vs. 19%). In particular, death and MI were more common with PCI, while stroke was more common with CABG.

In Journal Watch Cardiology, Harlan M. Krumholz calls the observed superiority of CABG a “blockbuster result.” He adds: “The excess risk for stroke, however, may give some people pause. The issue is ripe for shared decision making; these findings will greatly benefit patients and their doctors working together to make well-informed choices.”

Source:NEJM

 

Does Appropriateness of PCI Influence Procedural Outcomes?


An analysis of registry data reveals no such association, suggesting that patient selection and procedural performance should be assessed separately.

Appropriate use criteria (AUC) for percutaneous coronary intervention (PCI) have become a major quality metric for patient selection and resource utilization. In this analysis, investigators made use of the National Cardiovascular Data Registry to determine whether an association exists between adherence to AUC and in-hospital outcomes of PCI.

Included were 203,561 patients undergoing PCI for nonacute indications at 779 hospitals during 2009–2011. A total of 12.1% of the procedures were classified as inappropriate (range, 0%–56.6%). Compared with the hospital tertile with the lowest median rate of inappropriate PCI (5.3%), the tertile with the highest rate (20.0%) had similar risk-adjusted in-hospital mortality (0.3%; odds ratio, 1.12; P=0.35) and periprocedural bleeding rate (1.7%; OR, 1.02; P=0.07), as well as a similar rate of guideline-recommended medications provision at discharge (85.2%; P=0.58).

Comment: These investigators failed to find an association between inappropriate percutaneous coronary intervention and in-hospital outcomes, suggesting that patient selection for PCI by appropriate use criteria represents an aspect of PCI quality that differs from processes of care assessed by other metrics, including postprocedure outcomes. The wide range of variation in PCI appropriateness among hospitals is cause for concern, but these findings indicate that AUC adherence alone is an insufficient measure of the quality of PCI at any given hospital.

Source: Journal Watch Cardiology

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