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.

Gender No Predictor of Prolonged DAPT Benefit


Prolonged dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) effects don’t differ by gender, the PRODIGY investigators suggested.

On multivariable adjustment, recipients of extended and 6-month DAPT experienced similar rates of combined death, myocardial infarction, and cerebrovascular accidents at 2 years. This was true whether they were male (HR 1.08, 95% CI 0.766 to 1.522) or female (HR 1.013, 95% CI 0.588 to 1.748), reported Marco Valgimigli, MD, PhD, of Bern University Hospital in Switzerland, and colleagues.

 According to their study, published online in JACC: Cardiovascular Interventions, sex did not appear to play a role in the frequency of individual adverse outcomes. Notably, major bleeding occurred at similar rates across groups regardless of the definition used (included were the Bleeding Academic Research Consortium, Thrombolysis in Myocardial Infarction, and Global Use of Strategies to Open Occluded Coronary Arteries scales).

“Gender failed to emerge as a treatment modifier with respect to DAPT durationsuggesting that the decision-making on DAPT duration in female patients should weigh ischemic versus bleeding risks,” the authors concluded.

They noted that the longer duration won out in the landmark DAPT trial likely because of the selection of endpoints — stent thrombosis and the combination of MI and stroke.

While the secondary analysis of the PRODIGY trial, which randomized 1,970 patients to 6- or 24-month DAPT consisting of clopidogrel (Plavix) and aspirin, was only powered to find a 40% difference, it was in line with other trials that haven’t shown a significant impact on death or cardiovascular death, the researchers noted.

“When taken together, currently available studies suggest that the decision-making over DAPT duration towards either shorter or longer than conventional 12-month time frame should be a ‘patient by patient’ approach, aiming at balancing ischemic versus bleeding risks,” they concluded. “With that respect, whether gender per se should be taken into account in tailoring patient’s therapy is still unclear.”

 But what was clear from PRODIGY was that “gender should not be a primary covariate to be considered in the decision-making on DAPT duration after coronary stenting,” they added.

In the trial, women (n=459) were older and more likely to have hypertension, lower creatinine clearance, and acute coronary syndrome. Men, however, had a higher severity of coronary artery disease.

“The current findings suggest that men and women undergoing PCI have similar adjusted 2-year ischemic and bleeding outcomes, despite being characterized by different clinical presentation,” according to Valgimigli’s group.

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:

Bivalirudin Started during Emergency Transport for Primary PCI.


BACKGROUND

Bivalirudin, as compared with heparin and glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of bleeding and death in patients undergoing primary percutaneous coronary intervention (PCI). Whether these benefits persist in contemporary practice characterized by prehospital initiation of treatment, optional use of glycoprotein IIb/IIIa inhibitors and novel P2Y12 inhibitors, and radial-artery PCI access use is unknown.

METHODS

We randomly assigned 2218 patients with ST-segment elevation myocardial infarction (STEMI) who were being transported for primary PCI to receive either bivalirudin or unfractionated or low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors (control group). The primary outcome at 30 days was a composite of death or major bleeding not associated with coronary-artery bypass grafting (CABG), and the principal secondary outcome was a composite of death, reinfarction, or non-CABG major bleeding.

RESULTS

Bivalirudin, as compared with the control intervention, reduced the risk of the primary outcome (5.1% vs. 8.5%; relative risk, 0.60; 95% confidence interval [CI], 0.43 to 0.82; P=0.001) and the principal secondary outcome (6.6% vs. 9.2%; relative risk, 0.72; 95% CI, 0.54 to 0.96; P=0.02). Bivalirudin also reduced the risk of major bleeding (2.6% vs. 6.0%; relative risk, 0.43; 95% CI, 0.28 to 0.66; P<0.001). The risk of acute stent thrombosis was higher with bivalirudin (1.1% vs. 0.2%; relative risk, 6.11; 95% CI, 1.37 to 27.24; P=0.007). There was no significant difference in rates of death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). Results were consistent across subgroups of patients.

CONCLUSIONS

Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding but with an increase in acute stent thrombosis.

Source: NEJM

 

Bivalirudin During Transport for PCI in STEMI Lowers Bleeding, But Increases Stent Thrombi.


The direct thrombin inhibitor bivalirudin — when given to patients with ST-segment elevation myocardial infarction (STEMI) during transport for percutaneous coronary intervention (PCI) — is associated with lower rates of major bleeding after PCI. However, risks for early stent thrombosis are increased sixfold, according to a New England Journal of Medicine study. The drug’s maker participated in the study.

 Some 2200 patients with STEMI being transported to facilities for PCI were randomized en route to begin antithrombotic treatment with either bivalirudin or with heparin and optional glycoprotein inhibitors. By 30 days, the composite outcome of death or major bleeding was lower with bivalirudin (5.1% vs. 8.5%). However, the risk for stent thrombosis within 24 hours was higher with bivalirudin (1.1% vs. 0.2%).

An editorialist observes that the “clearest findings” after two bivalirudin trials are that the drug increases stent thrombosis while reducing bleeding complications. He writes that it’s “critical that clinicians weigh the relative importance of these events before selecting an antithrombotic strategy for their patients.”

Source: NEJM

Randomized Trial of Preventive Angioplasty in Myocardial Infarction.


Patients with acute ST-segment elevation myocardial infarction (STEMI) are effectively treated with emergency angioplasty, hereafter called percutaneous coronary intervention (PCI), to restore blood flow to the coronary artery that is judged to be causing the myocardial infarction (infarct artery, also known as culprit artery).1-5 These patients may have major stenoses in coronary arteries that were not responsible for the myocardial infarction,6 but the value of performing PCI in such arteries for the prevention of future cardiac events is not known.

Some physicians have taken the view that stenoses in noninfarct arteries may cause serious adverse cardiac events that could be avoided by performing preventive PCI during the initial procedure.7-12Others have suggested that medical therapy with antiplatelet, lipid-lowering, and blood-pressure–lowering drugs is sufficient and that the risks of preventive PCI outweigh the benefits.2-4,13-17

The aim of our single-blind, randomized study, called the Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial, was to determine whether performing preventive PCI as part of the procedure to treat the infarct artery would reduce the combined incidence of death from cardiac causes, nonfatal myocardial infarction, or refractory angina.

DISCUSSION

The results of this trial show that in patients with acute STEMI, the use of preventive PCI to treat noninfarct coronary-artery stenoses immediately after PCI in the infarct artery conferred a substantial advantage over not performing this additional procedure. The combined rate of cardiac death, nonfatal myocardial infarction, or refractory angina was reduced by 65%, an absolute risk reduction of 14 percentage points over 23 months. The effect was similar in magnitude and remained highly significant when the analysis was limited to cardiac death and nonfatal myocardial infarction.

In this trial, all decisions regarding the treatment of patients, other than the random assignments to the two study groups, were left to the discretion of the clinicians involved. The rates of use of drug-eluting stents and medical therapy were similar in the two groups. In the group receiving no preventive PCI, ischemia testing was performed in about one third of patients: 44 tests in asymptomatic patients (usually ≤6 weeks after the myocardial infarction) and 37 tests in patients with chest pain. In the preventive-PCI group, ischemia testing was performed in about one sixth of patients: 8 tests in asymptomatic patients and 31 tests in patients with chest pain. Although such testing was not a prespecified trial outcome, these findings suggest that preventive PCI may lead to less ischemia testing and that when such testing is performed, it tends to be in patients with symptoms.

Although refractory angina is a more subjective outcome than myocardial infarction or cardiac death, it was included as a component of the primary outcome because it is a serious symptomatic condition that warrants prevention. We sought to reduce bias in the assessment of this outcome by requiring that the diagnosis be confirmed with objective evidence of ischemia. The benefit of preventive PCI was also evident when the less subjective outcomes of cardiac death and nonfatal myocardial infarction were considered alone.

We decided against using revascularization as a primary outcome, since subsequent revascularization procedures could be prompted by the identification of stenosis in a noninfarct artery in the group receiving no preventive PCI during the initial procedure. This factor would also tend to underestimate the effect of preventive PCI on primary-outcome events by reducing the treatment difference between the two study groups. However, revascularization was retained as a secondary outcome to record the number of subsequent procedures in each group.

In our study, 13 patients did not receive their assigned treatment. In the group receiving no preventive PCI, 2 patients underwent PCI in a noninfarct artery (1 for unknown reasons and 1 because the operator treated what turned out to be a noninfarct right coronary artery and then had to treat the infarct circumflex artery). In the preventive-PCI group, 11 patients underwent PCI only in the infarct artery because the preventive PCI could not be completed owing to insufficient time (because of competing emergency PCIs) in 3 patients, failure of the noninfarct-artery PCI in 5 patients, and other complications in 3 patients. These deviations from the assigned treatment mean that the intention-to-treat analysis, adopted to ensure comparability of the two study groups, will tend to underestimate the benefit of preventive PCI. However, the results of the as-treated analysis were consistent with those of the intention-to-treat analysis.

In two other randomized trials, investigators have specifically assessed the value of preventive PCI in patients with acute STEMI undergoing PCI in the infarct artery. In one study, 69 patients were randomly assigned (in a 3:1 ratio) to preventive PCI (52 patients) or no preventive PCI (17 patients).20 At 1 year, in the preventive-PCI group, there were nonsignificant reductions in the rates of repeat revascularization (17% and 35%, respectively) and cardiac death or myocardial infarction (4% and 6%, respectively). In the other trial, 214 patients were randomly assigned to one of three groups: no preventive PCI (84 patients), immediate preventive PCI (65 patients), and staged preventive PCI performed during a second procedure about 40 days later (65 patients).7 At 2.5 years, the rate of repeat revascularization was less frequent in the immediate– and staged–preventive PCI groups combined, as compared with the group receiving no preventive PCI (11% and 33%, respectively), and there was a nonsignificant decrease in the rate of cardiac death (5% and 12%, respectively). These studies were limited by a lack of statistical power and a reliance on repeat revascularization as an outcome, which, as indicated above, may be subject to bias. However, the results of these studies are consistent with those of our study.

Current guidelines on the management of STEMI recommend infarct-artery-only PCI in patients with multivessel disease, owing to a lack of evidence with respect to the value of preventive PCI.2-5 This uncertainty has led to variations in practice, with some cardiologists performing immediate preventive PCI in spite of the guidelines, some delaying preventive PCI until recovery from the acute episode, and others limiting the procedure to patients with recurrent symptoms or evidence of ischemia. The results of this trial help resolve the uncertainty by making clear that preventive PCI is a better strategy than restricting a further intervention to those patients with refractory angina or a subsequent myocardial infarction. However, our findings do not address the question of immediate versus delayed (staged) preventive PCI, which would need to be clarified in a separate trial.

Several questions remain. First, are the benefits of preventive PCI applicable to patients with non-STEMI?21 Such patients tend to be difficult to study because, unlike those with STEMI (in whom the infarct artery is invariably identifiable), there is often uncertainty over which artery is the culprit. Second, do the benefits extend to coronary-artery stenoses of less than 50%? There is uncertainty over the level of stenosis at which the risks of PCI outweigh the benefits. Third, would a physiological measure of blood flow, such as fractional flow reserve,22,23 offer an advantage over angiographic visual assessment in guiding preventive PCI? Further research is needed to answer these questions.

In conclusion, in this randomized trial, we found that in patients undergoing emergency infarct-artery PCI for acute STEMI, preventive PCI of stenoses in noninfarct arteries reduced the risk of subsequent adverse cardiovascular events, as compared with PCI limited to the infarct artery.

 

Source: NEJM

 

 

 

Prasugrel versus clopidogrel for patients with unstable angina or non-ST-segment elevation myocardial infarction with or without angiography: a secondary, prespecified analysis of the TRILOGY ACS trial .


Wiviott SD et al. – Treatment with prasugrel and aspirin improves outcomes compared with clopidogrel and aspirin for patients with acute coronary syndrome who have had angiography and percutaneous coronary intervention; however, no clear benefit has been shown for patients managed first with drugs only. Authors assessed outcomes from the TRILOGY ACS trial based on whether or not patients had coronary angiography before treatment was chosen. Among patients who had angiography who took prasugrel there were fewer cardiovascular deaths, myocardial infarctions, or strokes than in those who took clopidogrel. This result needs to be corroborated, but it is consistent with previous trials of more versus less intensive antiplatelet treatment. When angiography is done for acute coronary syndrome and anatomic coronary disease confirmed, the benefits and risks of intensive antiplatelet treatment exist whether the patient is treated with drugs or percutaneous coronary intervention.

Methods

  • TRILOGY ACS (ClinicalTrials.gov number NCT00699998) was a randomised controlled trial, done at more than 800 sites worldwide.
  • Patients with non–ST–elevation acute coronary syndrome who were selected for management with revascularisation were randomly assigned to clopidogrel or prasugrel.
  • The primary endpoint was cardiovascular death, myocardial infarction, or stroke at 30 months.
  • In the present analysis we assessed differences in the primary endpoint by angiography status and whether the effects of treatment on the primary endpoint differed between patients who had angiography before enrolment and those who had not.

Results

  • 7243 patients younger than 75 years were included in the TRILOGY ACS primary analysis.
  • 3085 (43%) had angiography at baseline, 4158 (57%) had not.
  • Fewer patients who had angiography reached the primary endpoint at 30 months compared with those who did not have angiography, according to Kaplan–Meier analysis (281/3085 [12•8%] vs 480/4158 [16•5%], adjusted hazard ratio [HR] 0•63, 95% CI 0•53—0•75; p<0•0001).
  • The proportion of patients who reached the primary endpoint was lower in the prasugrel group than in the clopidogrel group for those who had angiography (122/1524 [10•7%] vs 159/1561 [14•9%], HR 0•77, 95% CI 0•61—0•98; p=0•032) but did not differ between groups in patients who did not have angiography (242/2096 [16•3%] vs 238/2062 [16•7%], HR 1•01, 0•84—1•20; p=0•94; pinteraction=0•08).
  • Overall, TIMI major bleeding and GUSTO severe bleeding were rare.
  • Bleeding outcomes tended to be higher with prasugrel but did not differ significantly between treatment groups in either angiography cohort.

Source: Lancet

Preventing Coronary Stent Thrombosis and Post-Stent Complications.


 

A structured review supports long-term low-dose aspirin plus a P2Y12-receptor inhibitor for 1 year.

More than 90% of percutaneous coronary interventions also involve stent placement. Stent thrombosis is a major complication of stent placement, and preventing it is the main goal of post-stent management. To determine the optimal approach to post-stent management, researchers conducted a structured literature review of 91 randomized trials, systematic reviews, and meta-analyses.

Dual antiplatelet therapy with long-term, low-dose aspirin (75–100 mg daily) plus a P2Y12-receptor inhibitor (usually clopidogrel) for 1 year after stent placement is the standard recommendation. Although this recommendation applies to both drug-eluting and bare-metal stents, a shorter duration of clopidogrel therapy (minimum of 1 month) is considered to be permissible for patients who have received bare-metal stents for nonacute coronary syndrome indications. Higher doses of aspirin (>200 mg daily) are associated with a twofold higher risk for bleeding, with no additional benefit. Risk for stent thrombosis continues beyond 1 year; however, studies of P2Y12-receptor inhibitor use beyond 1 year show no benefit in the face of elevated bleeding risk. Large clinical trials of shorter and longer durations of P2Y12-receptor inhibition are under way.

COMMENT

Three P2Y12-receptor inhibitors are available. However, adverse events have limited use of prasugrel (Effient) and ticagrelor (Brilinta). Studies of optimal clopidogrel dosing suggest that bleeding risk rises with higher doses; thus, the current recommendation is for a 300-mg loading dose followed by 75 mg daily. Because adding warfarin (i.e., for patients with atrial fibrillation or mechanical heart valves) is associated with two- to threefold higher risk for major bleeding complications, aspirin should be discontinued while patients receive warfarin. If at all possible, noncardiac elective surgery should be delayed until 1 full year of dual antiplatelet therapy with aspirin and clopidogrel is completed. Patients at high risk for bleeding should take proton-pump inhibitors while receiving dual antiplatelet therapy. Based on anticipated studies, clinicians soon might have more guidance for tailoring dual antiplatelet therapy duration to a patient’s specific clinical profile and type of stent.

Source: NEJM

High incidence of acute coronary occlusion in patients without protocol positive ST segment elevation referred to an open access primary angioplasty programme.


Abstract

Background Primary percutaneous coronary intervention (PPCI) programmes vary in admission criteria from open referral to acceptance of electrocardiogram (ECG) protocol positive patients only. Rigid criteria may result in some patients with acutely occluded coronary arteries not receiving timely reperfusion therapy.

Objective To compare the prevalence of acute coronary occlusion and, in these cases, single time point biomarker estimates of myocardial infarct size between patients presenting with protocol positive ECG changes and those presenting with less diagnostic changes in the primary angioplasty cohort of an open access PPCI programme.

Methods We retrospectively performed a single centre cross sectional analysis of consecutive patients receiving PPCI between January and August 2008. Cases were categorised according to presenting ECG—group A: protocol positive (ST segment elevation/left bundle branch block/posterior ST elevation myocardial infarction), group B: ST segment depression or T-wave inversion, or group C: minor ECG changes. Clinical characteristics, coronary flow grades and 12 h postprocedure troponin-I levels were reviewed.

Results During the study period there were 513 activations of the PPCI service, of which 390 underwent immediate angiography and 308 underwent PPCI. Of those undergoing PPCI, 221 (72%) were in group A, 41 (13%) in group B and 46 (15%) in group C. Prevalence of coronary occlusion was 75% in group A compared with 73% in group B and 63% in group C. Median 12 h postintervention troponin-I (25th–75th percentile) for those with coronary occlusion was significantly higher in group A patients; 28.9 μg/l (13.2–58.5) versus 18.1 μg/l (6.7–32.4) for group B (p=0.03); and 15.5 μg/l (3.8–22.0) for group C (p<0.001), suggesting greater infarct size in group A.

Conclusions A number of patients referred to an open access PPCI programme have protocol negative ECGs but myocardial infarction and acute coronary artery occlusion amenable to angioplasty.

Source: PMJ. BMJ

 

If Possible, STEMI Patients Should Go Straight to a Cath Lab.


Within a system designed to reduce time to reperfusion, mortality was lower in patients transported directly to a PCI-capable center than in those transferred from a non–PCI-capable center.

In the city of Ottawa, emergency medical system providers trained in electrocardiogram interpretation can triage patients with ST-segment-elevation myocardial infarction (STEMI) directly to a center with percutaneous coronary intervention (PCI) capability. In a registry study, investigators compared outcomes in 822 patients transported directly to a PCI-capable hospital with those in 567 patients transported initially to a non–PCI-capable hospital, then transferred for primary PCI.

The median door-to-balloon time was significantly shorter in patients transported directly for PCI (66 minutes) than in those transferred for PCI (117 minutes). At 180 days, all-cause mortality was lower in directly transported patients than in those first taken to a non–PCI-capable hospital (5.0% vs. 11.5%; P<0.001). After multivariable adjustment, direct transfer was associated with about a 50% reduction in mortality risk (odds ratio, 0.52; P=0.01).

Comment: This study strengthens evidence that standardized geographic protocols designed to reduce time to reperfusion for ST-segment-elevation myocardial infarction reduce mortality. The importance of prehospital STEMI diagnosis and systems for rapid transport and treatment are now reflected in guideline recommendations (JW Cardiol Jan 6 2010), and implementation of these practices should be a public-health priority.

Source: Journal Watch Cardiology

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