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Controversies in non-ST-elevation acute coronary syndromes and percutaneous coronary interventions
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Deepak L. Bhatt, MD, MPH

Despite all the attention paid to ST-segment-elevation myocardial infarction (MI), in terms of sheer numbers, non-ST-elevation MI and unstable angina are where the action is. Acute coronary syndromes account for 2.43 million hospital discharges per year. Of these, 0.46 million are for ST-elevation MI and 1.97 million are for non-ST-elevation MI and unstable angina.1,2

A number of recent studies have begun to answer some of the pressing questions about treating these types of acute coronary syndromes. In this article, I update the reader on these studies, along with recent findings regarding stenting and antiplatelet agents. As you will see, they are all interconnected.

TO CATHETERIZE IS BETTER THAN NOT TO CATHETERIZE

In the 1990s, a topic of debate was whether patients presenting with unstable angina or non-ST-elevation MI should routinely undergo catheterization or whether they would do just as well with a conservative approach, ie, undergoing catheterization only if they developed recurrent, spontaneous, or stress-induced ischemia. Now, the data are reasonably clear and favor an aggressive strategy.3

Mehta et al4 performed a meta-analysis of seven randomized controlled trials (N = 9,212 patients) of aggressive vs conservative angiography and revascularization for non-ST-elevation MI or unstable angina. The results favored the aggressive strategy. At 17 months of follow-up, death or MI had occurred in 7.4% of patients who received the aggressive therapy compared with 11.0% of those who received the conservative therapy, for an odds ratio of 0.82 (P = .001).

The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implemention of the ACC/AHA Guidelines?) Quality Improvement Initiative5 analyzed data from a registry of 17,926 patients with non-ST-elevation acute coronary syndrome who were at high risk because of positive cardiac markers or ischemic electrocardiographic changes. Overall, 2.0% of patients who received early invasive care (catheterization within the first 48 hours) died in the hospital compared with 6.2% of those who got no early invasive care, for an adjusted odds ratio of 0.63 (95% confidence interval [CI] 0.52–0.77).

The investigators also stratified the patients into those at low, medium, and high risk, using the criteria of the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin [eptifibatide] Therapy) risk score. There were fewer deaths with early invasive therapy in each risk group, and the risk reduction was greatest in the high-risk group.5

Bavry et al6 performed an updated meta-analysis of randomized trials. At a mean follow-up of 24 months, the relative risk of death from any cause was 0.75 in patients who received early invasive therapy.

In another meta-analysis, O’Donoghue et al7 found that the odds ratio of death, MI, or rehospitalization with acute coronary syndromes was 0.73 (95% CI 0.55–0.98) in men who received invasive vs conservative therapy; in women it was 0.81 (95% CI 0.65–1.01). In women, the benefit was statistically significant in those who had elevations of creatine kinase MB or troponin but not in those who did not, though the benefit in men appeared to be less dependent on the presence of biomarker abnormalities.

MUST ANGIOGRAPHY BE DONE IN THE FIRST 24 HOURS?

Although a number of trials showed that a routine invasive strategy leads to better outcomes than a conservative strategy, until recently we had no information as to whether the catheterization needed to be done early (eg, within the first 24 hours) or if it could be delayed a day or two while the patient received medical therapy.

Mehta et al8 conducted a trial to find out: the Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial. Patients were included if they had unstable angina or non-ST-elevation MI, presented to a hospital within 24 hours of the onset of symptoms, and had two of three high-risk features: age 60 years or older, elevated cardiac biomarkers, or electrocardiographic findings compatible with ischemia. All received standard medical therapy, and 3,031 were randomly assigned to undergo angiography either within 24 hours after randomization or 36 or more hours after randomization.

At 6 months, the primary outcome of death, new MI, or stroke had occurred in 9.6% of the patients in the early-intervention group and in 11.3% of those in the delayed-intervention group, but the difference was not statistically significant. However, the difference in the rate of a secondary end point, death, MI, or refractory ischemia, was statistically significant: 9.5% vs 12.9%, P = .003, owing mainly to less refractory ischemia with early intervention.

The patients were also stratified into two groups by baseline risk. The rate of the primary outcome was significantly lower with early intervention in high-risk patients, but not in those at intermediate or low risk. Thus, early intervention may be beneficial in patients at high risk, such as those with ongoing chest pain, but not necessarily in those at low risk.

LEAVE NO LESION BEHIND?

Coronary artery disease often affects more than one segment. Until recently, it was not known whether we should stent all stenotic segments in patients presenting with non-ST-elevation MI or unstable angina, or only the “culprit lesion.”

Shishehbor et al9 examined data from a Cleveland Clinic registry of 1,240 patients with acute coronary syndrome and multivessel coronary artery disease who underwent bare-metal stenting. The median follow-up was 2.3 years. Using a propensity model to match patients in the two groups with similar baseline characteristics, they found that the rate of repeat revascularization was less with multivessel intervention than with culprit-only stenting, as was the rate of the combined end point of death, MI, or revascularization, but not that of all-cause mortality or the composite of death or MI.

 

 

BARE-METAL VS DRUG-ELUTING STENTS: BALANCING THE RISKS AND BENEFITS

After a patient receives a stent, two bad things can happen: the artery can close up again either gradually, in a process called restenosis, or suddenly, via thrombosis.

Drug-eluting stents were invented to solve the problem of restenosis, and they work very well. Stone et al10 pooled the data from four double-blind trials of sirolimus (Rapamune) stents and five double-blind trials of paclitaxel (Taxol) stents and found that, at 4 years, the rates of target-lesion revascularization (for restenosis) were 7.8% with sirolimus stents vs 23.6% with bare-metal stents (P < .001), and 10.1% with paclitaxel stents vs 20.0% with bare-metal stents (P < .001).

Thrombosis was much less common in these studies, occurring in 1.2% of the sirolimus stent groups vs 0.6% of the bare-metal stent groups (P = .20), and in 1.3% of the paclitaxel stent groups vs 0.9% of the bare-metal stent groups (P = .30).10

However, drug-eluting stents appear to increase the risk of thrombosis later on, ie, after 1 year. Bavry et al,11 in a meta-analysis, calculated that when stent thrombosis occurred, the median time after implantation was 15.5 months with sirolimus stents vs 4 months with bare-metal stents (P = .0052), and 18 months with paclitaxel stents vs 3.5 months with bare-metal stents (P = .04). The absolute risk of very late stent thrombosis after 1 year was very low, with five events per 1,000 patients with drug-eluting stents vs no events with bare-metal stents (P = .02). Nevertheless, this finding has practical implications. How long must patients continue dual antiplatelet therapy? And what if a patient needs surgery a year later?

Restenosis is not always so gradual

Although stent thrombosis is serious and often fatal, bare-metal stent restenosis is not always benign either, despite the classic view that stent restenosis is a gradual process that results in exertional angina. Reviewing 1,186 cases of bare-metal stent restenosis in 984 patients at Cleveland Clinic, Chen et al12 reported that 9.5% of cases presented as acute MI (2.2% as ST-elevation MI and 7.3% as non-ST-elevation MI), and 26.4% as unstable angina requiring hospitalization.

A Mayo Clinic study13 corroborated these findings. The 10-year incidence of clinical bare-metal stent restenosis was 18.1%, and the incidence of MI was 2.1%. The 10-year rate of bare-metal stent thrombosis was 2%. Off-label use, primarily in saphenous vein grafts, increased the incidence; other correlates were prior MI, peripheral arterial disease, and ulcerated lesions.

Furthermore, bare-metal stent thrombosis can also occur later. We saw a case that occurred 13 years after the procedure, 3 days after the patient stopped taking aspirin because he was experiencing flu-like symptoms, ran out of aspirin, and felt too sick to go out and buy more. The presentation was with ST-elevation MI. The patient recovered after treatment with intracoronary abciximab (ReoPro), percutaneous thrombectomy, balloon angioplasty, and, eventually, bypass surgery.14

No difference in risk of death with drug-eluting vs bare-metal stents

Even though drug-eluting stents pose a slightly higher risk of thrombosis than bare-metal stents, the risk of death is no higher.15

I believe the reason is that there are competing risks, and that the higher risk of thrombosis with first-generation drug-eluting stents and the higher risk of restenosis with bare-metal stents essentially cancel each other out. For most patients, there is an absolute benefit with drug-eluting stents, which reduce the need for revascularization with no effect in terms of either increasing or decreasing the risk of MI or death. Second-generation drug-eluting stents may have advantages in reducing rates of death or MI compared with first-generation drug-eluting stents, though this remains to be proven conclusively.

The right revascularization for the right patient

Bavry and I16 developed an algorithm for deciding on revascularization, posing a series of questions:

  • Does the patient need any form of revascularization?
  • Is he or she at higher risk of both stent thrombosis and restenosis, as in patients with diabetes, diffuse multivessel disease with bifurcation lesions, or chronic total occlusions? If so, coronary artery bypass grafting remains an excellent option.
  • Does he or she have a low risk of restenosis, as in patients without diabetes with focal lesions in large vessels? If so, one could consider a bare-metal stent, which would probably be more cost-effective than a drug-eluting stent in this situation.
  • Does the patient have relative contraindications to drug-eluting stents? Examples are a history of noncompliance with medical therapy, financial issues such as lack of insurance that would make buying clopidogrel (Plavix) a problem, long-term anticoagulation, or anticipated need for surgery in the next few years.

If a drug-eluting stent is used, certain measures can help ensure that it is used optimally. It should often be placed under high pressure with a noncompliant balloon so that it achieves contact with the artery wall all around. One should consider intravascular ultrasonographic guidance to make sure the stent is well opposed if it is in a very calcified lesion. Dual antiplatelet therapy with clopidogrel and aspirin should be given for at least 1 year, and if there is no bleeding, perhaps longer, pending further data.16

LEAVE NO PLATELET ACTIVATED?

Platelets have several types of receptors that, when bound by their respective ligands, lead to platelet activation and aggregation and, ultimately, thrombus formation. Antagonists to some of these receptors are available or are being developed.17

For long-term therapy, blocking the process “upstream,” ie, preventing platelet activation, is better than blocking it “downstream,” ie, preventing aggregation. For example, clopidogrel, ticlopipine (Ticlid), and prasugrel (Effient) have active metabolites that bind to a subtype of the adenosine diphosphate receptor and prevent platelet activation, whereas the glycoprotein IIb/IIIa inhibitors such as abciximab work downstream, binding to a different receptor and preventing aggregation.18

 

 

Dual therapy for 1 year is the standard of care after acute coronary syndromes

The evidence for using dual antiplatelet therapy (ie, aspirin plus clopidogrel) in patients with acute coronary syndromes without ST-elevation is very well established.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,19 published in 2001, found a 20% relative risk reduction and a 2% absolute risk reduction in the incidence of MI, stroke, or cardiovascular death in patients randomly assigned to receive clopidogrel plus aspirin for 1 year vs aspirin alone for 1 year (P < .001). In the subgroup of patients who underwent percutaneous coronary intervention, the relative risk reduction in the incidence of MI or cardiovascular death at 1 year of follow-up was 31% (P = .002).20

As a result of these findings, the cardiology society guidelines21 recommend a year of dual antiplatelet therapy after acute coronary syndromes, regardless of whether the patient is treated medically, percutaneously, or surgically.

But what happens after clopidogrel is withdrawn? Ho et al22 retrospectively analyzed data from Veterans Affairs hospitals and found a spike in the incidence of death or MI in the first 90 days after stopping clopidogrel treatment. This was true in medically treated patients as well as in those treated with percutaneous coronary interventions, in those with or without diabetes mellitus, in those who received a drug-eluting stent or a bare-metal stent, and in those treated longer than 9 months.

The investigators concluded that there might be a “clopidogrel rebound effect.” However, I believe that a true rebound effect, such as after withdrawal of heparin or warfarin, is biologically unlikely with clopidogrel, since clopidogrel irreversibly binds to its receptor for the 7- to 10-day life span of the platelet. Rather, I believe the phenomenon must be due to withdrawal of protection in patients at risk.

In stable patients, dual therapy is not as beneficial

Would dual antiplatelet therapy with clopidogrel and aspirin also benefit patients at risk of atherothrombotic events but without acute coronary syndromes?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial23 included 15,603 patients with either clinically evident but stable cardiovascular disease or multiple risk factors for athero-thrombosis. They were randomly assigned to receive either clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin. At a median of 28 months, the groups did not differ significantly in the rate of MI, stroke, or death from cardiovascular causes.

However, the subgroup of patients who had documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease did appear to derive significant benefit from dual therapy.24 In this subgroup, the rate of MI, stroke, or cardiovascular death at a median follow-up of 27.6 months was 8.8% with placebo plus aspirin compared with 7.3% with clopidogrel plus aspirin, for a hazard ratio of 0.83 (95% CI 0.72–0.96, P = .01). Unstented patients with stable coronary artery disease but without prior MI derived no benefit.

Bleeding and thrombosis: The Scylla and Charybdis of antiplatelet therapy

However, with dual antiplatelet therapy, we steer between the Scylla of bleeding and the Charybdis of thrombosis.25

In the CHARISMA subgroup who had prior MI, ischemic stroke, or symptomatic peripheral arterial disease, the incidence of moderate or severe bleeding was higher with dual therapy than with aspirin alone, but the rates converged after about 1 year of treatment.24 Further, there was no difference in fatal bleeding or intracranial bleeding, although the rate of moderate bleeding (defined as the need for transfusion) was higher with dual therapy (2.0% vs 1.3%, P = .004).

I believe the data indicate that if a patient can tolerate dual antiplatelet therapy for 9 to 12 months without any bleeding issues, he or she is unlikely to have a major bleeding episode if dual therapy is continued beyond this time.

About half of bleeding events in patients on chronic antiplatelet therapy are gastrointestinal. To address this risk, in 2008 an expert committee from the American College of Cardiology, American College of Gastroenterology, and American Heart Association issued a consensus document26 in which they recommended assessing gastrointestinal risk factors in patients on antiplatelet therapy, such as history of ulcers (and testing for and treating Helicobacter pylori infection if present), history of gastrointestinal bleeding, concomitant anticoagulant therapy, and dual antiplatelet therapy. If any of these were present, the committee recommended considering a proton pump inhibitor. The committee also recommended a proton pump inhibitor for patients on antiplatelet therapy who have more than one of the following: age 60 years or more, corticosteroid use, or dyspepsia or gastroesophageal reflux symptoms.

Some ex vivo platelet studies and observational analyses have suggested that there might be an adverse interaction between clopidogrel and proton pump inhibitors due to a blunting of clopidogrel’s antiplatelet effect. A large randomized clinical trial was designed and launched to determine if a single-pill combination of the proton pump inhibitor omeprazole (Prilosec) and clopidogrel would be safer than clopidogrel alone when added to aspirin. Called COGENT-1 (Clopidogrel and the Optimization of GI Events Trial), it was halted early in 2009 when it lost its funding. However, preliminary data did not show an adverse interaction between clopidogrel and omeprazole.

What is the right dose of aspirin?

Steinhubl et al27 performed a post hoc observational analysis of data from the CHARISMA trial. Their findings suggested that higher doses of aspirin are not more effective than lower doses for chronic therapy. Furthermore, in the group receiving clopidogrel plus aspirin, the incidence of severe or life-threatening bleeding was significantly greater with aspirin doses higher than 100 mg than with doses lower than 100 mg, 2.6% vs 1.7%, P = .040.

A randomized, controlled trial called Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7)28 recently reported that higher-dose aspirin (ie, 325 mg) may be better than lower dose aspirin (ie, 81 mg) in patients with acute coronary syndromes undergoing percutaneous coronary intervention and receiving clopidogrel. During this 30-day study, there was no increase in overall bleeding with the higher dose of aspirin, though gastrointestinal bleeding was slightly increased.29 In a factorial design, the second part of this trial found that a higher-dose clopidogrel regimen reduced stent thrombosis.29

 

 

Should nonresponders get higher doses of clopidogrel?

In vitro, response to clopidogrel shows a normal bell-shaped distribution.30 In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?31

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.32

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.24

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

References
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  10. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med 2007; 356:998–1008.
  11. Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am J Med 2006; 119:1056–1061.
  12. Chen MS, John JM, Chew DP, Lee DS, Ellis SG, Bhatt DL. Bare metal stent restenosis is not a benign clinical entity. Am Heart J 2006; 151:1260–1264.
  13. Doyle B, Rihal CS, O’Sullivan CJ, et al. Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents. Circulation 2007; 116:2391–2398.
  14. Sarkees ML, Bavry AA, Galla JM, Bhatt DL. Bare metal stent thrombosis 13 years after implantation. Cardiovasc Revasc Med 2009; 10:58–91.
  15. Bavry AA, Bhatt DL. Appropriate use of drug-eluting stents: balancing the reduction in restenosis with the concern of late thrombosis. Lancet 2008; 371:2134–2143.
  16. Bavry AA, Bhatt DL. Drug-eluting stents: dual antiplatelet therapy for every survivor? Circulation 2007; 116:696–699.
  17. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007; 100:1261–1275.
  18. Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov 2003; 2:15–28.
  19. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494–502. Errata in N Engl J Med 2001; 345:1506 and N Engl J Med 2001; 345:1716.
  20. Mehta SR, Yusuf S, Peters RJ, et al; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358:527–533.
  21. Anderson JL, Adams CD, Antman EM, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction); american College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association of Cardiovascular and Pulmonary Rehabilitation; Society for Academic Emergency Medicine. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007; 50:e1–e157.
  22. Ho PM, Peterson ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA 2008; 299:532–539. Erratum in JAMA 2008; 299:2390.
  23. Bhatt DL, Fox KA, Hacke W, et al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354:1706–1717.
  24. Bhatt DL, Flather MD, Hacke W, et al; CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49:1982–1988.
  25. Bhatt DL. Intensifying platelet inhibition—navigating between Scylla and Charybdis. N Engl J Med 2007; 357:2078–2081.
  26. Bhatt DL, Scheiman J, Abraham NS, et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2008; 118:1894–1909.
  27. Steinhubl SR, Bhatt DL, Brennan DM, et al; CHARISMA Investigators. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann Intern Med 2009; 150:379–386.
  28. Mehta SR, Bassand JP, Chrolavicius S, et al; CURRENT-OASIS 7 Steering Committee. Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J 2008; 156:1080–1088.
  29. Mehta SR, Van de Werf F. A randomized comparison of a clopidogrel high loading and maintenance dose regimen versus standard dose and high versus low dose aspirin in 25,000 patients with acute coronary syndromes: results of the CURRENT OASIS 7 trial. Paper presented at the European Society of Cardiology Congress; August 30, 2009; Barcelona, Spain. Also available online at www.Escardio.org/congresses/esc-2009/congress-reports. Accessed December 12, 2009.
  30. Serebruany VL, Steinhubl SR, Berger PB, Malinin AT, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45:246–251.
  31. Bhatt DL. Prasugrel in clinical practice [perspective]. N Engl J Med 2009; 361:940–942.
  32. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001–2015.
  33. Bhatt DL, Lincoff AM, Gibson CM, et al; for the CHAMPION PLATFORM Investigators. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009 Nov 15(epub ahead of print).
  34. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patient sundergoing PCI. N Engl J Med 2009 Nov 17(epub ahead of print).
  35. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361:1045–1057.
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Author and Disclosure Information

Deepak L. Bhatt, MD, MPH
Chief of Cardiology, VA Boston Healthcare System; Director, Integrated Interventional Cardiovascular Program, Brigham and Women’s Hospital and the VA Boston Healthcare System; Senior Investigator, TIMI Study Group; Associate Professor of Medicine, Harvard Medical School, Boston, MA

Address: Deepak L. Bhatt, MD, MPH, VA Boston Healthcare System and Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis Street, PBB-146 Boston, MA 02115; e-mail [email protected]

Medical Grand Rounds articles are based on edited transcripts from Education Institute Department of Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

Dr. Bhatt has disclosed that he has been the principal investigator in several potentially related studies. His institution has received research funding from Astra Zeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, and The Medicines Company. This paper discusses offlabel and investigational uses of various drugs and stents.

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Cleveland Clinic Journal of Medicine - 77(2)
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Deepak L. Bhatt, MD, MPH
Chief of Cardiology, VA Boston Healthcare System; Director, Integrated Interventional Cardiovascular Program, Brigham and Women’s Hospital and the VA Boston Healthcare System; Senior Investigator, TIMI Study Group; Associate Professor of Medicine, Harvard Medical School, Boston, MA

Address: Deepak L. Bhatt, MD, MPH, VA Boston Healthcare System and Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis Street, PBB-146 Boston, MA 02115; e-mail [email protected]

Medical Grand Rounds articles are based on edited transcripts from Education Institute Department of Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

Dr. Bhatt has disclosed that he has been the principal investigator in several potentially related studies. His institution has received research funding from Astra Zeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, and The Medicines Company. This paper discusses offlabel and investigational uses of various drugs and stents.

Author and Disclosure Information

Deepak L. Bhatt, MD, MPH
Chief of Cardiology, VA Boston Healthcare System; Director, Integrated Interventional Cardiovascular Program, Brigham and Women’s Hospital and the VA Boston Healthcare System; Senior Investigator, TIMI Study Group; Associate Professor of Medicine, Harvard Medical School, Boston, MA

Address: Deepak L. Bhatt, MD, MPH, VA Boston Healthcare System and Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis Street, PBB-146 Boston, MA 02115; e-mail [email protected]

Medical Grand Rounds articles are based on edited transcripts from Education Institute Department of Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

Dr. Bhatt has disclosed that he has been the principal investigator in several potentially related studies. His institution has received research funding from Astra Zeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, and The Medicines Company. This paper discusses offlabel and investigational uses of various drugs and stents.

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Despite all the attention paid to ST-segment-elevation myocardial infarction (MI), in terms of sheer numbers, non-ST-elevation MI and unstable angina are where the action is. Acute coronary syndromes account for 2.43 million hospital discharges per year. Of these, 0.46 million are for ST-elevation MI and 1.97 million are for non-ST-elevation MI and unstable angina.1,2

A number of recent studies have begun to answer some of the pressing questions about treating these types of acute coronary syndromes. In this article, I update the reader on these studies, along with recent findings regarding stenting and antiplatelet agents. As you will see, they are all interconnected.

TO CATHETERIZE IS BETTER THAN NOT TO CATHETERIZE

In the 1990s, a topic of debate was whether patients presenting with unstable angina or non-ST-elevation MI should routinely undergo catheterization or whether they would do just as well with a conservative approach, ie, undergoing catheterization only if they developed recurrent, spontaneous, or stress-induced ischemia. Now, the data are reasonably clear and favor an aggressive strategy.3

Mehta et al4 performed a meta-analysis of seven randomized controlled trials (N = 9,212 patients) of aggressive vs conservative angiography and revascularization for non-ST-elevation MI or unstable angina. The results favored the aggressive strategy. At 17 months of follow-up, death or MI had occurred in 7.4% of patients who received the aggressive therapy compared with 11.0% of those who received the conservative therapy, for an odds ratio of 0.82 (P = .001).

The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implemention of the ACC/AHA Guidelines?) Quality Improvement Initiative5 analyzed data from a registry of 17,926 patients with non-ST-elevation acute coronary syndrome who were at high risk because of positive cardiac markers or ischemic electrocardiographic changes. Overall, 2.0% of patients who received early invasive care (catheterization within the first 48 hours) died in the hospital compared with 6.2% of those who got no early invasive care, for an adjusted odds ratio of 0.63 (95% confidence interval [CI] 0.52–0.77).

The investigators also stratified the patients into those at low, medium, and high risk, using the criteria of the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin [eptifibatide] Therapy) risk score. There were fewer deaths with early invasive therapy in each risk group, and the risk reduction was greatest in the high-risk group.5

Bavry et al6 performed an updated meta-analysis of randomized trials. At a mean follow-up of 24 months, the relative risk of death from any cause was 0.75 in patients who received early invasive therapy.

In another meta-analysis, O’Donoghue et al7 found that the odds ratio of death, MI, or rehospitalization with acute coronary syndromes was 0.73 (95% CI 0.55–0.98) in men who received invasive vs conservative therapy; in women it was 0.81 (95% CI 0.65–1.01). In women, the benefit was statistically significant in those who had elevations of creatine kinase MB or troponin but not in those who did not, though the benefit in men appeared to be less dependent on the presence of biomarker abnormalities.

MUST ANGIOGRAPHY BE DONE IN THE FIRST 24 HOURS?

Although a number of trials showed that a routine invasive strategy leads to better outcomes than a conservative strategy, until recently we had no information as to whether the catheterization needed to be done early (eg, within the first 24 hours) or if it could be delayed a day or two while the patient received medical therapy.

Mehta et al8 conducted a trial to find out: the Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial. Patients were included if they had unstable angina or non-ST-elevation MI, presented to a hospital within 24 hours of the onset of symptoms, and had two of three high-risk features: age 60 years or older, elevated cardiac biomarkers, or electrocardiographic findings compatible with ischemia. All received standard medical therapy, and 3,031 were randomly assigned to undergo angiography either within 24 hours after randomization or 36 or more hours after randomization.

At 6 months, the primary outcome of death, new MI, or stroke had occurred in 9.6% of the patients in the early-intervention group and in 11.3% of those in the delayed-intervention group, but the difference was not statistically significant. However, the difference in the rate of a secondary end point, death, MI, or refractory ischemia, was statistically significant: 9.5% vs 12.9%, P = .003, owing mainly to less refractory ischemia with early intervention.

The patients were also stratified into two groups by baseline risk. The rate of the primary outcome was significantly lower with early intervention in high-risk patients, but not in those at intermediate or low risk. Thus, early intervention may be beneficial in patients at high risk, such as those with ongoing chest pain, but not necessarily in those at low risk.

LEAVE NO LESION BEHIND?

Coronary artery disease often affects more than one segment. Until recently, it was not known whether we should stent all stenotic segments in patients presenting with non-ST-elevation MI or unstable angina, or only the “culprit lesion.”

Shishehbor et al9 examined data from a Cleveland Clinic registry of 1,240 patients with acute coronary syndrome and multivessel coronary artery disease who underwent bare-metal stenting. The median follow-up was 2.3 years. Using a propensity model to match patients in the two groups with similar baseline characteristics, they found that the rate of repeat revascularization was less with multivessel intervention than with culprit-only stenting, as was the rate of the combined end point of death, MI, or revascularization, but not that of all-cause mortality or the composite of death or MI.

 

 

BARE-METAL VS DRUG-ELUTING STENTS: BALANCING THE RISKS AND BENEFITS

After a patient receives a stent, two bad things can happen: the artery can close up again either gradually, in a process called restenosis, or suddenly, via thrombosis.

Drug-eluting stents were invented to solve the problem of restenosis, and they work very well. Stone et al10 pooled the data from four double-blind trials of sirolimus (Rapamune) stents and five double-blind trials of paclitaxel (Taxol) stents and found that, at 4 years, the rates of target-lesion revascularization (for restenosis) were 7.8% with sirolimus stents vs 23.6% with bare-metal stents (P < .001), and 10.1% with paclitaxel stents vs 20.0% with bare-metal stents (P < .001).

Thrombosis was much less common in these studies, occurring in 1.2% of the sirolimus stent groups vs 0.6% of the bare-metal stent groups (P = .20), and in 1.3% of the paclitaxel stent groups vs 0.9% of the bare-metal stent groups (P = .30).10

However, drug-eluting stents appear to increase the risk of thrombosis later on, ie, after 1 year. Bavry et al,11 in a meta-analysis, calculated that when stent thrombosis occurred, the median time after implantation was 15.5 months with sirolimus stents vs 4 months with bare-metal stents (P = .0052), and 18 months with paclitaxel stents vs 3.5 months with bare-metal stents (P = .04). The absolute risk of very late stent thrombosis after 1 year was very low, with five events per 1,000 patients with drug-eluting stents vs no events with bare-metal stents (P = .02). Nevertheless, this finding has practical implications. How long must patients continue dual antiplatelet therapy? And what if a patient needs surgery a year later?

Restenosis is not always so gradual

Although stent thrombosis is serious and often fatal, bare-metal stent restenosis is not always benign either, despite the classic view that stent restenosis is a gradual process that results in exertional angina. Reviewing 1,186 cases of bare-metal stent restenosis in 984 patients at Cleveland Clinic, Chen et al12 reported that 9.5% of cases presented as acute MI (2.2% as ST-elevation MI and 7.3% as non-ST-elevation MI), and 26.4% as unstable angina requiring hospitalization.

A Mayo Clinic study13 corroborated these findings. The 10-year incidence of clinical bare-metal stent restenosis was 18.1%, and the incidence of MI was 2.1%. The 10-year rate of bare-metal stent thrombosis was 2%. Off-label use, primarily in saphenous vein grafts, increased the incidence; other correlates were prior MI, peripheral arterial disease, and ulcerated lesions.

Furthermore, bare-metal stent thrombosis can also occur later. We saw a case that occurred 13 years after the procedure, 3 days after the patient stopped taking aspirin because he was experiencing flu-like symptoms, ran out of aspirin, and felt too sick to go out and buy more. The presentation was with ST-elevation MI. The patient recovered after treatment with intracoronary abciximab (ReoPro), percutaneous thrombectomy, balloon angioplasty, and, eventually, bypass surgery.14

No difference in risk of death with drug-eluting vs bare-metal stents

Even though drug-eluting stents pose a slightly higher risk of thrombosis than bare-metal stents, the risk of death is no higher.15

I believe the reason is that there are competing risks, and that the higher risk of thrombosis with first-generation drug-eluting stents and the higher risk of restenosis with bare-metal stents essentially cancel each other out. For most patients, there is an absolute benefit with drug-eluting stents, which reduce the need for revascularization with no effect in terms of either increasing or decreasing the risk of MI or death. Second-generation drug-eluting stents may have advantages in reducing rates of death or MI compared with first-generation drug-eluting stents, though this remains to be proven conclusively.

The right revascularization for the right patient

Bavry and I16 developed an algorithm for deciding on revascularization, posing a series of questions:

  • Does the patient need any form of revascularization?
  • Is he or she at higher risk of both stent thrombosis and restenosis, as in patients with diabetes, diffuse multivessel disease with bifurcation lesions, or chronic total occlusions? If so, coronary artery bypass grafting remains an excellent option.
  • Does he or she have a low risk of restenosis, as in patients without diabetes with focal lesions in large vessels? If so, one could consider a bare-metal stent, which would probably be more cost-effective than a drug-eluting stent in this situation.
  • Does the patient have relative contraindications to drug-eluting stents? Examples are a history of noncompliance with medical therapy, financial issues such as lack of insurance that would make buying clopidogrel (Plavix) a problem, long-term anticoagulation, or anticipated need for surgery in the next few years.

If a drug-eluting stent is used, certain measures can help ensure that it is used optimally. It should often be placed under high pressure with a noncompliant balloon so that it achieves contact with the artery wall all around. One should consider intravascular ultrasonographic guidance to make sure the stent is well opposed if it is in a very calcified lesion. Dual antiplatelet therapy with clopidogrel and aspirin should be given for at least 1 year, and if there is no bleeding, perhaps longer, pending further data.16

LEAVE NO PLATELET ACTIVATED?

Platelets have several types of receptors that, when bound by their respective ligands, lead to platelet activation and aggregation and, ultimately, thrombus formation. Antagonists to some of these receptors are available or are being developed.17

For long-term therapy, blocking the process “upstream,” ie, preventing platelet activation, is better than blocking it “downstream,” ie, preventing aggregation. For example, clopidogrel, ticlopipine (Ticlid), and prasugrel (Effient) have active metabolites that bind to a subtype of the adenosine diphosphate receptor and prevent platelet activation, whereas the glycoprotein IIb/IIIa inhibitors such as abciximab work downstream, binding to a different receptor and preventing aggregation.18

 

 

Dual therapy for 1 year is the standard of care after acute coronary syndromes

The evidence for using dual antiplatelet therapy (ie, aspirin plus clopidogrel) in patients with acute coronary syndromes without ST-elevation is very well established.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,19 published in 2001, found a 20% relative risk reduction and a 2% absolute risk reduction in the incidence of MI, stroke, or cardiovascular death in patients randomly assigned to receive clopidogrel plus aspirin for 1 year vs aspirin alone for 1 year (P < .001). In the subgroup of patients who underwent percutaneous coronary intervention, the relative risk reduction in the incidence of MI or cardiovascular death at 1 year of follow-up was 31% (P = .002).20

As a result of these findings, the cardiology society guidelines21 recommend a year of dual antiplatelet therapy after acute coronary syndromes, regardless of whether the patient is treated medically, percutaneously, or surgically.

But what happens after clopidogrel is withdrawn? Ho et al22 retrospectively analyzed data from Veterans Affairs hospitals and found a spike in the incidence of death or MI in the first 90 days after stopping clopidogrel treatment. This was true in medically treated patients as well as in those treated with percutaneous coronary interventions, in those with or without diabetes mellitus, in those who received a drug-eluting stent or a bare-metal stent, and in those treated longer than 9 months.

The investigators concluded that there might be a “clopidogrel rebound effect.” However, I believe that a true rebound effect, such as after withdrawal of heparin or warfarin, is biologically unlikely with clopidogrel, since clopidogrel irreversibly binds to its receptor for the 7- to 10-day life span of the platelet. Rather, I believe the phenomenon must be due to withdrawal of protection in patients at risk.

In stable patients, dual therapy is not as beneficial

Would dual antiplatelet therapy with clopidogrel and aspirin also benefit patients at risk of atherothrombotic events but without acute coronary syndromes?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial23 included 15,603 patients with either clinically evident but stable cardiovascular disease or multiple risk factors for athero-thrombosis. They were randomly assigned to receive either clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin. At a median of 28 months, the groups did not differ significantly in the rate of MI, stroke, or death from cardiovascular causes.

However, the subgroup of patients who had documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease did appear to derive significant benefit from dual therapy.24 In this subgroup, the rate of MI, stroke, or cardiovascular death at a median follow-up of 27.6 months was 8.8% with placebo plus aspirin compared with 7.3% with clopidogrel plus aspirin, for a hazard ratio of 0.83 (95% CI 0.72–0.96, P = .01). Unstented patients with stable coronary artery disease but without prior MI derived no benefit.

Bleeding and thrombosis: The Scylla and Charybdis of antiplatelet therapy

However, with dual antiplatelet therapy, we steer between the Scylla of bleeding and the Charybdis of thrombosis.25

In the CHARISMA subgroup who had prior MI, ischemic stroke, or symptomatic peripheral arterial disease, the incidence of moderate or severe bleeding was higher with dual therapy than with aspirin alone, but the rates converged after about 1 year of treatment.24 Further, there was no difference in fatal bleeding or intracranial bleeding, although the rate of moderate bleeding (defined as the need for transfusion) was higher with dual therapy (2.0% vs 1.3%, P = .004).

I believe the data indicate that if a patient can tolerate dual antiplatelet therapy for 9 to 12 months without any bleeding issues, he or she is unlikely to have a major bleeding episode if dual therapy is continued beyond this time.

About half of bleeding events in patients on chronic antiplatelet therapy are gastrointestinal. To address this risk, in 2008 an expert committee from the American College of Cardiology, American College of Gastroenterology, and American Heart Association issued a consensus document26 in which they recommended assessing gastrointestinal risk factors in patients on antiplatelet therapy, such as history of ulcers (and testing for and treating Helicobacter pylori infection if present), history of gastrointestinal bleeding, concomitant anticoagulant therapy, and dual antiplatelet therapy. If any of these were present, the committee recommended considering a proton pump inhibitor. The committee also recommended a proton pump inhibitor for patients on antiplatelet therapy who have more than one of the following: age 60 years or more, corticosteroid use, or dyspepsia or gastroesophageal reflux symptoms.

Some ex vivo platelet studies and observational analyses have suggested that there might be an adverse interaction between clopidogrel and proton pump inhibitors due to a blunting of clopidogrel’s antiplatelet effect. A large randomized clinical trial was designed and launched to determine if a single-pill combination of the proton pump inhibitor omeprazole (Prilosec) and clopidogrel would be safer than clopidogrel alone when added to aspirin. Called COGENT-1 (Clopidogrel and the Optimization of GI Events Trial), it was halted early in 2009 when it lost its funding. However, preliminary data did not show an adverse interaction between clopidogrel and omeprazole.

What is the right dose of aspirin?

Steinhubl et al27 performed a post hoc observational analysis of data from the CHARISMA trial. Their findings suggested that higher doses of aspirin are not more effective than lower doses for chronic therapy. Furthermore, in the group receiving clopidogrel plus aspirin, the incidence of severe or life-threatening bleeding was significantly greater with aspirin doses higher than 100 mg than with doses lower than 100 mg, 2.6% vs 1.7%, P = .040.

A randomized, controlled trial called Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7)28 recently reported that higher-dose aspirin (ie, 325 mg) may be better than lower dose aspirin (ie, 81 mg) in patients with acute coronary syndromes undergoing percutaneous coronary intervention and receiving clopidogrel. During this 30-day study, there was no increase in overall bleeding with the higher dose of aspirin, though gastrointestinal bleeding was slightly increased.29 In a factorial design, the second part of this trial found that a higher-dose clopidogrel regimen reduced stent thrombosis.29

 

 

Should nonresponders get higher doses of clopidogrel?

In vitro, response to clopidogrel shows a normal bell-shaped distribution.30 In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?31

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.32

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.24

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

Despite all the attention paid to ST-segment-elevation myocardial infarction (MI), in terms of sheer numbers, non-ST-elevation MI and unstable angina are where the action is. Acute coronary syndromes account for 2.43 million hospital discharges per year. Of these, 0.46 million are for ST-elevation MI and 1.97 million are for non-ST-elevation MI and unstable angina.1,2

A number of recent studies have begun to answer some of the pressing questions about treating these types of acute coronary syndromes. In this article, I update the reader on these studies, along with recent findings regarding stenting and antiplatelet agents. As you will see, they are all interconnected.

TO CATHETERIZE IS BETTER THAN NOT TO CATHETERIZE

In the 1990s, a topic of debate was whether patients presenting with unstable angina or non-ST-elevation MI should routinely undergo catheterization or whether they would do just as well with a conservative approach, ie, undergoing catheterization only if they developed recurrent, spontaneous, or stress-induced ischemia. Now, the data are reasonably clear and favor an aggressive strategy.3

Mehta et al4 performed a meta-analysis of seven randomized controlled trials (N = 9,212 patients) of aggressive vs conservative angiography and revascularization for non-ST-elevation MI or unstable angina. The results favored the aggressive strategy. At 17 months of follow-up, death or MI had occurred in 7.4% of patients who received the aggressive therapy compared with 11.0% of those who received the conservative therapy, for an odds ratio of 0.82 (P = .001).

The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implemention of the ACC/AHA Guidelines?) Quality Improvement Initiative5 analyzed data from a registry of 17,926 patients with non-ST-elevation acute coronary syndrome who were at high risk because of positive cardiac markers or ischemic electrocardiographic changes. Overall, 2.0% of patients who received early invasive care (catheterization within the first 48 hours) died in the hospital compared with 6.2% of those who got no early invasive care, for an adjusted odds ratio of 0.63 (95% confidence interval [CI] 0.52–0.77).

The investigators also stratified the patients into those at low, medium, and high risk, using the criteria of the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin [eptifibatide] Therapy) risk score. There were fewer deaths with early invasive therapy in each risk group, and the risk reduction was greatest in the high-risk group.5

Bavry et al6 performed an updated meta-analysis of randomized trials. At a mean follow-up of 24 months, the relative risk of death from any cause was 0.75 in patients who received early invasive therapy.

In another meta-analysis, O’Donoghue et al7 found that the odds ratio of death, MI, or rehospitalization with acute coronary syndromes was 0.73 (95% CI 0.55–0.98) in men who received invasive vs conservative therapy; in women it was 0.81 (95% CI 0.65–1.01). In women, the benefit was statistically significant in those who had elevations of creatine kinase MB or troponin but not in those who did not, though the benefit in men appeared to be less dependent on the presence of biomarker abnormalities.

MUST ANGIOGRAPHY BE DONE IN THE FIRST 24 HOURS?

Although a number of trials showed that a routine invasive strategy leads to better outcomes than a conservative strategy, until recently we had no information as to whether the catheterization needed to be done early (eg, within the first 24 hours) or if it could be delayed a day or two while the patient received medical therapy.

Mehta et al8 conducted a trial to find out: the Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial. Patients were included if they had unstable angina or non-ST-elevation MI, presented to a hospital within 24 hours of the onset of symptoms, and had two of three high-risk features: age 60 years or older, elevated cardiac biomarkers, or electrocardiographic findings compatible with ischemia. All received standard medical therapy, and 3,031 were randomly assigned to undergo angiography either within 24 hours after randomization or 36 or more hours after randomization.

At 6 months, the primary outcome of death, new MI, or stroke had occurred in 9.6% of the patients in the early-intervention group and in 11.3% of those in the delayed-intervention group, but the difference was not statistically significant. However, the difference in the rate of a secondary end point, death, MI, or refractory ischemia, was statistically significant: 9.5% vs 12.9%, P = .003, owing mainly to less refractory ischemia with early intervention.

The patients were also stratified into two groups by baseline risk. The rate of the primary outcome was significantly lower with early intervention in high-risk patients, but not in those at intermediate or low risk. Thus, early intervention may be beneficial in patients at high risk, such as those with ongoing chest pain, but not necessarily in those at low risk.

LEAVE NO LESION BEHIND?

Coronary artery disease often affects more than one segment. Until recently, it was not known whether we should stent all stenotic segments in patients presenting with non-ST-elevation MI or unstable angina, or only the “culprit lesion.”

Shishehbor et al9 examined data from a Cleveland Clinic registry of 1,240 patients with acute coronary syndrome and multivessel coronary artery disease who underwent bare-metal stenting. The median follow-up was 2.3 years. Using a propensity model to match patients in the two groups with similar baseline characteristics, they found that the rate of repeat revascularization was less with multivessel intervention than with culprit-only stenting, as was the rate of the combined end point of death, MI, or revascularization, but not that of all-cause mortality or the composite of death or MI.

 

 

BARE-METAL VS DRUG-ELUTING STENTS: BALANCING THE RISKS AND BENEFITS

After a patient receives a stent, two bad things can happen: the artery can close up again either gradually, in a process called restenosis, or suddenly, via thrombosis.

Drug-eluting stents were invented to solve the problem of restenosis, and they work very well. Stone et al10 pooled the data from four double-blind trials of sirolimus (Rapamune) stents and five double-blind trials of paclitaxel (Taxol) stents and found that, at 4 years, the rates of target-lesion revascularization (for restenosis) were 7.8% with sirolimus stents vs 23.6% with bare-metal stents (P < .001), and 10.1% with paclitaxel stents vs 20.0% with bare-metal stents (P < .001).

Thrombosis was much less common in these studies, occurring in 1.2% of the sirolimus stent groups vs 0.6% of the bare-metal stent groups (P = .20), and in 1.3% of the paclitaxel stent groups vs 0.9% of the bare-metal stent groups (P = .30).10

However, drug-eluting stents appear to increase the risk of thrombosis later on, ie, after 1 year. Bavry et al,11 in a meta-analysis, calculated that when stent thrombosis occurred, the median time after implantation was 15.5 months with sirolimus stents vs 4 months with bare-metal stents (P = .0052), and 18 months with paclitaxel stents vs 3.5 months with bare-metal stents (P = .04). The absolute risk of very late stent thrombosis after 1 year was very low, with five events per 1,000 patients with drug-eluting stents vs no events with bare-metal stents (P = .02). Nevertheless, this finding has practical implications. How long must patients continue dual antiplatelet therapy? And what if a patient needs surgery a year later?

Restenosis is not always so gradual

Although stent thrombosis is serious and often fatal, bare-metal stent restenosis is not always benign either, despite the classic view that stent restenosis is a gradual process that results in exertional angina. Reviewing 1,186 cases of bare-metal stent restenosis in 984 patients at Cleveland Clinic, Chen et al12 reported that 9.5% of cases presented as acute MI (2.2% as ST-elevation MI and 7.3% as non-ST-elevation MI), and 26.4% as unstable angina requiring hospitalization.

A Mayo Clinic study13 corroborated these findings. The 10-year incidence of clinical bare-metal stent restenosis was 18.1%, and the incidence of MI was 2.1%. The 10-year rate of bare-metal stent thrombosis was 2%. Off-label use, primarily in saphenous vein grafts, increased the incidence; other correlates were prior MI, peripheral arterial disease, and ulcerated lesions.

Furthermore, bare-metal stent thrombosis can also occur later. We saw a case that occurred 13 years after the procedure, 3 days after the patient stopped taking aspirin because he was experiencing flu-like symptoms, ran out of aspirin, and felt too sick to go out and buy more. The presentation was with ST-elevation MI. The patient recovered after treatment with intracoronary abciximab (ReoPro), percutaneous thrombectomy, balloon angioplasty, and, eventually, bypass surgery.14

No difference in risk of death with drug-eluting vs bare-metal stents

Even though drug-eluting stents pose a slightly higher risk of thrombosis than bare-metal stents, the risk of death is no higher.15

I believe the reason is that there are competing risks, and that the higher risk of thrombosis with first-generation drug-eluting stents and the higher risk of restenosis with bare-metal stents essentially cancel each other out. For most patients, there is an absolute benefit with drug-eluting stents, which reduce the need for revascularization with no effect in terms of either increasing or decreasing the risk of MI or death. Second-generation drug-eluting stents may have advantages in reducing rates of death or MI compared with first-generation drug-eluting stents, though this remains to be proven conclusively.

The right revascularization for the right patient

Bavry and I16 developed an algorithm for deciding on revascularization, posing a series of questions:

  • Does the patient need any form of revascularization?
  • Is he or she at higher risk of both stent thrombosis and restenosis, as in patients with diabetes, diffuse multivessel disease with bifurcation lesions, or chronic total occlusions? If so, coronary artery bypass grafting remains an excellent option.
  • Does he or she have a low risk of restenosis, as in patients without diabetes with focal lesions in large vessels? If so, one could consider a bare-metal stent, which would probably be more cost-effective than a drug-eluting stent in this situation.
  • Does the patient have relative contraindications to drug-eluting stents? Examples are a history of noncompliance with medical therapy, financial issues such as lack of insurance that would make buying clopidogrel (Plavix) a problem, long-term anticoagulation, or anticipated need for surgery in the next few years.

If a drug-eluting stent is used, certain measures can help ensure that it is used optimally. It should often be placed under high pressure with a noncompliant balloon so that it achieves contact with the artery wall all around. One should consider intravascular ultrasonographic guidance to make sure the stent is well opposed if it is in a very calcified lesion. Dual antiplatelet therapy with clopidogrel and aspirin should be given for at least 1 year, and if there is no bleeding, perhaps longer, pending further data.16

LEAVE NO PLATELET ACTIVATED?

Platelets have several types of receptors that, when bound by their respective ligands, lead to platelet activation and aggregation and, ultimately, thrombus formation. Antagonists to some of these receptors are available or are being developed.17

For long-term therapy, blocking the process “upstream,” ie, preventing platelet activation, is better than blocking it “downstream,” ie, preventing aggregation. For example, clopidogrel, ticlopipine (Ticlid), and prasugrel (Effient) have active metabolites that bind to a subtype of the adenosine diphosphate receptor and prevent platelet activation, whereas the glycoprotein IIb/IIIa inhibitors such as abciximab work downstream, binding to a different receptor and preventing aggregation.18

 

 

Dual therapy for 1 year is the standard of care after acute coronary syndromes

The evidence for using dual antiplatelet therapy (ie, aspirin plus clopidogrel) in patients with acute coronary syndromes without ST-elevation is very well established.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,19 published in 2001, found a 20% relative risk reduction and a 2% absolute risk reduction in the incidence of MI, stroke, or cardiovascular death in patients randomly assigned to receive clopidogrel plus aspirin for 1 year vs aspirin alone for 1 year (P < .001). In the subgroup of patients who underwent percutaneous coronary intervention, the relative risk reduction in the incidence of MI or cardiovascular death at 1 year of follow-up was 31% (P = .002).20

As a result of these findings, the cardiology society guidelines21 recommend a year of dual antiplatelet therapy after acute coronary syndromes, regardless of whether the patient is treated medically, percutaneously, or surgically.

But what happens after clopidogrel is withdrawn? Ho et al22 retrospectively analyzed data from Veterans Affairs hospitals and found a spike in the incidence of death or MI in the first 90 days after stopping clopidogrel treatment. This was true in medically treated patients as well as in those treated with percutaneous coronary interventions, in those with or without diabetes mellitus, in those who received a drug-eluting stent or a bare-metal stent, and in those treated longer than 9 months.

The investigators concluded that there might be a “clopidogrel rebound effect.” However, I believe that a true rebound effect, such as after withdrawal of heparin or warfarin, is biologically unlikely with clopidogrel, since clopidogrel irreversibly binds to its receptor for the 7- to 10-day life span of the platelet. Rather, I believe the phenomenon must be due to withdrawal of protection in patients at risk.

In stable patients, dual therapy is not as beneficial

Would dual antiplatelet therapy with clopidogrel and aspirin also benefit patients at risk of atherothrombotic events but without acute coronary syndromes?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial23 included 15,603 patients with either clinically evident but stable cardiovascular disease or multiple risk factors for athero-thrombosis. They were randomly assigned to receive either clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin. At a median of 28 months, the groups did not differ significantly in the rate of MI, stroke, or death from cardiovascular causes.

However, the subgroup of patients who had documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease did appear to derive significant benefit from dual therapy.24 In this subgroup, the rate of MI, stroke, or cardiovascular death at a median follow-up of 27.6 months was 8.8% with placebo plus aspirin compared with 7.3% with clopidogrel plus aspirin, for a hazard ratio of 0.83 (95% CI 0.72–0.96, P = .01). Unstented patients with stable coronary artery disease but without prior MI derived no benefit.

Bleeding and thrombosis: The Scylla and Charybdis of antiplatelet therapy

However, with dual antiplatelet therapy, we steer between the Scylla of bleeding and the Charybdis of thrombosis.25

In the CHARISMA subgroup who had prior MI, ischemic stroke, or symptomatic peripheral arterial disease, the incidence of moderate or severe bleeding was higher with dual therapy than with aspirin alone, but the rates converged after about 1 year of treatment.24 Further, there was no difference in fatal bleeding or intracranial bleeding, although the rate of moderate bleeding (defined as the need for transfusion) was higher with dual therapy (2.0% vs 1.3%, P = .004).

I believe the data indicate that if a patient can tolerate dual antiplatelet therapy for 9 to 12 months without any bleeding issues, he or she is unlikely to have a major bleeding episode if dual therapy is continued beyond this time.

About half of bleeding events in patients on chronic antiplatelet therapy are gastrointestinal. To address this risk, in 2008 an expert committee from the American College of Cardiology, American College of Gastroenterology, and American Heart Association issued a consensus document26 in which they recommended assessing gastrointestinal risk factors in patients on antiplatelet therapy, such as history of ulcers (and testing for and treating Helicobacter pylori infection if present), history of gastrointestinal bleeding, concomitant anticoagulant therapy, and dual antiplatelet therapy. If any of these were present, the committee recommended considering a proton pump inhibitor. The committee also recommended a proton pump inhibitor for patients on antiplatelet therapy who have more than one of the following: age 60 years or more, corticosteroid use, or dyspepsia or gastroesophageal reflux symptoms.

Some ex vivo platelet studies and observational analyses have suggested that there might be an adverse interaction between clopidogrel and proton pump inhibitors due to a blunting of clopidogrel’s antiplatelet effect. A large randomized clinical trial was designed and launched to determine if a single-pill combination of the proton pump inhibitor omeprazole (Prilosec) and clopidogrel would be safer than clopidogrel alone when added to aspirin. Called COGENT-1 (Clopidogrel and the Optimization of GI Events Trial), it was halted early in 2009 when it lost its funding. However, preliminary data did not show an adverse interaction between clopidogrel and omeprazole.

What is the right dose of aspirin?

Steinhubl et al27 performed a post hoc observational analysis of data from the CHARISMA trial. Their findings suggested that higher doses of aspirin are not more effective than lower doses for chronic therapy. Furthermore, in the group receiving clopidogrel plus aspirin, the incidence of severe or life-threatening bleeding was significantly greater with aspirin doses higher than 100 mg than with doses lower than 100 mg, 2.6% vs 1.7%, P = .040.

A randomized, controlled trial called Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7)28 recently reported that higher-dose aspirin (ie, 325 mg) may be better than lower dose aspirin (ie, 81 mg) in patients with acute coronary syndromes undergoing percutaneous coronary intervention and receiving clopidogrel. During this 30-day study, there was no increase in overall bleeding with the higher dose of aspirin, though gastrointestinal bleeding was slightly increased.29 In a factorial design, the second part of this trial found that a higher-dose clopidogrel regimen reduced stent thrombosis.29

 

 

Should nonresponders get higher doses of clopidogrel?

In vitro, response to clopidogrel shows a normal bell-shaped distribution.30 In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?31

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.32

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.24

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

References
  1. Wiviott SD, Morrow DA, Giugliano RP, et al. Performance of the Thrombolysis In Myocardial Infarction risk index for early acute coronary syndrome in the National Registry of Myocardial Infarction: a simple risk index predicts mortality in both ST and non-ST elevation myocardial infarction [abstract]. J Am Coll Cardiol 2003; 43( suppl 2):365A–366A.
  2. Thom T, Haase N, Rosamond W, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2006; 113:e85–e151. Errata in Circulation 2006; 113:e696 and Circulation 2006 114:e630.
  3. Bhatt DL. To cath or not to cath. That is no longer the question. JAMA 2005; 293:2935–2937.
  4. Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA 2005; 293:2908–2917.
  5. Bhatt DL, Roe MT, Peterson ED, et al; for the CRUSADE Investigators. Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. JAMA 2004; 292:2096–2104.
  6. Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL, Askari AT. Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials. J Am Coll Cardiol 2006; 48:1319–1325.
  7. O’Donoghue MO, Boden WE, Braunwald E, et al. Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST segment elevation myocardial infarction: a meta-analysis. JAMA 2008; 300:71–80.
  8. Mehta SR, Granger CB, Boden WE, et al; TIMACS Investigators. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med 2009; 360:2165–2175.
  9. Shishehbor MH, Lauer MS, Singh IM, et al. In unstable angina or non-ST-segment acute coronary syndrome, should patients with multivessel coronary artery disease undergo multivessel or culpritonly stenting? J Am Coll Cardiol 2007; 49:849–854.
  10. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med 2007; 356:998–1008.
  11. Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am J Med 2006; 119:1056–1061.
  12. Chen MS, John JM, Chew DP, Lee DS, Ellis SG, Bhatt DL. Bare metal stent restenosis is not a benign clinical entity. Am Heart J 2006; 151:1260–1264.
  13. Doyle B, Rihal CS, O’Sullivan CJ, et al. Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents. Circulation 2007; 116:2391–2398.
  14. Sarkees ML, Bavry AA, Galla JM, Bhatt DL. Bare metal stent thrombosis 13 years after implantation. Cardiovasc Revasc Med 2009; 10:58–91.
  15. Bavry AA, Bhatt DL. Appropriate use of drug-eluting stents: balancing the reduction in restenosis with the concern of late thrombosis. Lancet 2008; 371:2134–2143.
  16. Bavry AA, Bhatt DL. Drug-eluting stents: dual antiplatelet therapy for every survivor? Circulation 2007; 116:696–699.
  17. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007; 100:1261–1275.
  18. Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov 2003; 2:15–28.
  19. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494–502. Errata in N Engl J Med 2001; 345:1506 and N Engl J Med 2001; 345:1716.
  20. Mehta SR, Yusuf S, Peters RJ, et al; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358:527–533.
  21. Anderson JL, Adams CD, Antman EM, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction); american College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association of Cardiovascular and Pulmonary Rehabilitation; Society for Academic Emergency Medicine. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007; 50:e1–e157.
  22. Ho PM, Peterson ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA 2008; 299:532–539. Erratum in JAMA 2008; 299:2390.
  23. Bhatt DL, Fox KA, Hacke W, et al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354:1706–1717.
  24. Bhatt DL, Flather MD, Hacke W, et al; CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49:1982–1988.
  25. Bhatt DL. Intensifying platelet inhibition—navigating between Scylla and Charybdis. N Engl J Med 2007; 357:2078–2081.
  26. Bhatt DL, Scheiman J, Abraham NS, et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2008; 118:1894–1909.
  27. Steinhubl SR, Bhatt DL, Brennan DM, et al; CHARISMA Investigators. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann Intern Med 2009; 150:379–386.
  28. Mehta SR, Bassand JP, Chrolavicius S, et al; CURRENT-OASIS 7 Steering Committee. Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J 2008; 156:1080–1088.
  29. Mehta SR, Van de Werf F. A randomized comparison of a clopidogrel high loading and maintenance dose regimen versus standard dose and high versus low dose aspirin in 25,000 patients with acute coronary syndromes: results of the CURRENT OASIS 7 trial. Paper presented at the European Society of Cardiology Congress; August 30, 2009; Barcelona, Spain. Also available online at www.Escardio.org/congresses/esc-2009/congress-reports. Accessed December 12, 2009.
  30. Serebruany VL, Steinhubl SR, Berger PB, Malinin AT, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45:246–251.
  31. Bhatt DL. Prasugrel in clinical practice [perspective]. N Engl J Med 2009; 361:940–942.
  32. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001–2015.
  33. Bhatt DL, Lincoff AM, Gibson CM, et al; for the CHAMPION PLATFORM Investigators. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009 Nov 15(epub ahead of print).
  34. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patient sundergoing PCI. N Engl J Med 2009 Nov 17(epub ahead of print).
  35. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361:1045–1057.
  36. Bhatt DL. Ticagrelor in ACS—what does PLATO teach us? Nat Rev Cardiol 2009; 6:737–738.
References
  1. Wiviott SD, Morrow DA, Giugliano RP, et al. Performance of the Thrombolysis In Myocardial Infarction risk index for early acute coronary syndrome in the National Registry of Myocardial Infarction: a simple risk index predicts mortality in both ST and non-ST elevation myocardial infarction [abstract]. J Am Coll Cardiol 2003; 43( suppl 2):365A–366A.
  2. Thom T, Haase N, Rosamond W, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2006; 113:e85–e151. Errata in Circulation 2006; 113:e696 and Circulation 2006 114:e630.
  3. Bhatt DL. To cath or not to cath. That is no longer the question. JAMA 2005; 293:2935–2937.
  4. Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA 2005; 293:2908–2917.
  5. Bhatt DL, Roe MT, Peterson ED, et al; for the CRUSADE Investigators. Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. JAMA 2004; 292:2096–2104.
  6. Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL, Askari AT. Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials. J Am Coll Cardiol 2006; 48:1319–1325.
  7. O’Donoghue MO, Boden WE, Braunwald E, et al. Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST segment elevation myocardial infarction: a meta-analysis. JAMA 2008; 300:71–80.
  8. Mehta SR, Granger CB, Boden WE, et al; TIMACS Investigators. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med 2009; 360:2165–2175.
  9. Shishehbor MH, Lauer MS, Singh IM, et al. In unstable angina or non-ST-segment acute coronary syndrome, should patients with multivessel coronary artery disease undergo multivessel or culpritonly stenting? J Am Coll Cardiol 2007; 49:849–854.
  10. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med 2007; 356:998–1008.
  11. Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am J Med 2006; 119:1056–1061.
  12. Chen MS, John JM, Chew DP, Lee DS, Ellis SG, Bhatt DL. Bare metal stent restenosis is not a benign clinical entity. Am Heart J 2006; 151:1260–1264.
  13. Doyle B, Rihal CS, O’Sullivan CJ, et al. Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents. Circulation 2007; 116:2391–2398.
  14. Sarkees ML, Bavry AA, Galla JM, Bhatt DL. Bare metal stent thrombosis 13 years after implantation. Cardiovasc Revasc Med 2009; 10:58–91.
  15. Bavry AA, Bhatt DL. Appropriate use of drug-eluting stents: balancing the reduction in restenosis with the concern of late thrombosis. Lancet 2008; 371:2134–2143.
  16. Bavry AA, Bhatt DL. Drug-eluting stents: dual antiplatelet therapy for every survivor? Circulation 2007; 116:696–699.
  17. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007; 100:1261–1275.
  18. Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov 2003; 2:15–28.
  19. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494–502. Errata in N Engl J Med 2001; 345:1506 and N Engl J Med 2001; 345:1716.
  20. Mehta SR, Yusuf S, Peters RJ, et al; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358:527–533.
  21. Anderson JL, Adams CD, Antman EM, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction); american College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association of Cardiovascular and Pulmonary Rehabilitation; Society for Academic Emergency Medicine. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007; 50:e1–e157.
  22. Ho PM, Peterson ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA 2008; 299:532–539. Erratum in JAMA 2008; 299:2390.
  23. Bhatt DL, Fox KA, Hacke W, et al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354:1706–1717.
  24. Bhatt DL, Flather MD, Hacke W, et al; CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49:1982–1988.
  25. Bhatt DL. Intensifying platelet inhibition—navigating between Scylla and Charybdis. N Engl J Med 2007; 357:2078–2081.
  26. Bhatt DL, Scheiman J, Abraham NS, et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2008; 118:1894–1909.
  27. Steinhubl SR, Bhatt DL, Brennan DM, et al; CHARISMA Investigators. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann Intern Med 2009; 150:379–386.
  28. Mehta SR, Bassand JP, Chrolavicius S, et al; CURRENT-OASIS 7 Steering Committee. Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J 2008; 156:1080–1088.
  29. Mehta SR, Van de Werf F. A randomized comparison of a clopidogrel high loading and maintenance dose regimen versus standard dose and high versus low dose aspirin in 25,000 patients with acute coronary syndromes: results of the CURRENT OASIS 7 trial. Paper presented at the European Society of Cardiology Congress; August 30, 2009; Barcelona, Spain. Also available online at www.Escardio.org/congresses/esc-2009/congress-reports. Accessed December 12, 2009.
  30. Serebruany VL, Steinhubl SR, Berger PB, Malinin AT, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45:246–251.
  31. Bhatt DL. Prasugrel in clinical practice [perspective]. N Engl J Med 2009; 361:940–942.
  32. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001–2015.
  33. Bhatt DL, Lincoff AM, Gibson CM, et al; for the CHAMPION PLATFORM Investigators. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009 Nov 15(epub ahead of print).
  34. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patient sundergoing PCI. N Engl J Med 2009 Nov 17(epub ahead of print).
  35. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361:1045–1057.
  36. Bhatt DL. Ticagrelor in ACS—what does PLATO teach us? Nat Rev Cardiol 2009; 6:737–738.
Issue
Cleveland Clinic Journal of Medicine - 77(2)
Issue
Cleveland Clinic Journal of Medicine - 77(2)
Page Number
101-109
Page Number
101-109
Publications
Cleveland Clinic Journal of Medicine
Publications
Cleveland Clinic Journal of Medicine
Topics
Cardiology
Critical Care
Emergency Medicine
Drug Therapy
Vascular
Article Type
Article
Display Headline
Controversies in non-ST-elevation acute coronary syndromes and percutaneous coronary interventions
Display Headline
Controversies in non-ST-elevation acute coronary syndromes and percutaneous coronary interventions
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Inside the Article

KEY POINTS

  • The data favor an aggressive strategy of routine catheterization, rather than a conservative strategy of catheterization only if a patient develops recurrent, spontaneous, or stress-induced ischemia.
  • Early percutaneous intervention (within 24 hours) may be beneficial in patients at higher risk, but not necessarily in those at lower risk.
  • Drug-eluting stents appear safe, assuming dual antiplatelet therapy is used. It is unclear how long this therapy needs to be continued.
  • The choice of revascularization strategy—bypass surgery, bare-metal stent, or drug-eluting stent—should be individualized based on the risk of restenosis, thrombosis, and other factors.
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