ESC Congress 2011: Drugs, Devices Work Together

PARIS, France—Pharmacology took center stage last week at the European Society of Cardiology (ESC) Congress 2011, but devices were by no means absent from the discussion.

In fact, the overall message from the conference was that synergy between device development and medical therapy can help improve patient outcome, said American College of Cardiology president David R. Holmes Jr, MD, of the Mayo Clinic (Rochester, MN).

“Multiple issues are involved in treating any given patient. They are all parts of the same puzzle. We have to pay attention to all of them to improve outcome rather than just selecting device A. It’s a package,” he told TCTMD in an interview. While novel anticoagulants grabbed headlines at this year’s conference, pharmacology cannot stand alone, Dr. Holmes emphasized.

New Anticoagulants Make Their Case, or Miss the Mark

Among the many studies presented at ESC, those looking at factor Xa inhibitors garnered “incredible enthusiasm,” Dr. Holmes said, pointing out that cardiologists must weigh the potential efficacy of these new drugs vs. their tendency to increase bleeding.

The ARISTOTLE trial tested apixaban, an oral direct factor Xa inhibitor, against warfarin in more than 18,000 patients with atrial fibrillation (A-fib). Based on the results, apixiban is now the latest competitor to prove superior to warfarin by lowering the combined risk of stroke or systemic embolism by 21%. Moreover, the newer agent was found to reduce major bleeding by 31% and all-cause death by 11% compared with the older anticoagulant.

A substudy of ARISTOTLE that analyzed the effects of apixaban relative to the actual time that warfarin patients were within therapeutic range, meanwhile, found consistent superiority of apixaban over warfarin for the primary efficacy and safety endpoints as well as most others across the wide ranges in quality of warfarin management.

Darexaban, another oral factor Xa inhibitor, fared less well. In the RUBY-1 trial, 1,258 patients who had recent high-risk ACS with or without ST-segment elevation were randomized to standard therapy plus placebo or darexaban (cumulative doses of 10, 30, or 60 mg given as once or twice daily formulations). But the novel drug was linked to a twofold to fourfold increased risk of major bleeding at 6 months when added to aspirin and/or clopidogrel, with progressively higher risk at the larger darexaban doses. Unfortunately, it also failed to achieve any decrease in ischemic events, though the study was not powered for efficacy.

In addition, separate substudies of the ROCKET-AF and RE-LY trials found that 2 important categories of A-fib patients can realize the benefits of the latest anticoagulants proven superior to warfarin: Rivaroxaban performed well in those with moderate renal dysfunction, and dabigatran showed good outcomes in those needing concomitant antiplatelet therapy due to stenting or ACS.

Questions about concurrent use of anticoagulants and antiplatelet drugs are particularly relevant in ACS patients, noted Dr. Holmes, since many patients experiencing AMI also have A-fib. The results presented at ESC raise “issues then about whether use of those new drugs in place of warfarin would be as safe as what we’re currently doing for ACS patients,” he said.

Mixed Messages on Duration of Dual Antiplatelet Therapy

Other studies examined dual antiplatelet therapy (DAPT), seeking the best treatment duration and setting standards for the use of platelet function tests.

PRODIGY fell on the negative side of the debate over whether clopidogrel therapy should be extended after stenting with either BMS or DES. The randomized study of approximately 2,000 patients found that continuing DAPT for 2 years rather than 6 months not only fails to reduce ischemic events but doubles the risk of major bleeding.

After 24 months, there was no difference between the 2 groups for the primary endpoint (all-cause death, MI, or stroke), which was approximately 10% with either 6 or 24 months of DAPT. On the other hand, among patients receiving long-term DAPT, there was about a twofold greater risk of type 5 bleeding (fatal), type 3 bleeding (overt with hemoglobin drop or intracranial hemorrhage), or type 2 bleeding (overt and ‘actionable’), defined by Bleeding Academic Research Consortium criteria (HR 2.17; 95% CI 1.44-3.22; P = 0.00018).

A Japanese registry study similarly found that after DES implantation, prolonging DAPT beyond 4 months does not reduce ischemic events but does significantly increase bleeding from 4 months to 1 year (4.2% with thienopyridine use vs. 3.0% without; P = 0.04). The same pattern held true in patients who continued thienopyridine use to 13 months.

But a study involving AMI patients came to a different conclusion: In those who are prescribed clopidogrel, stopping the antiplatelet within the first year of treatment more than doubles the risk of death or nonfatal MI.

Researchers used national British data sets to track clopidogrel adherence among 7,543 UK patients discharged home after an NSTEMI or STEMI. Overall, 4,650 of the patients received a clopidogrel prescription within 3 months, comprising 69% of the NSTEMI patients and 63% of the STEMI patients. By 1 year, the percentages still on clopidogrel were roughly equal for the 2 indications at 53% and 54%, respectively.

Discontinuation of clopidogrel within the first year was associated with an increased risk of death and MI compared with never being prescribed the drug (adjusted HR 1.45; 95% CI 1.22-1.73) and remaining on clopidogrel (adjusted HR 2.62; 95% CI 2.17-3.17).

An analysis of the GRAVITAS trial, meanwhile, found that using a lower level of platelet aggregation to differentiate which patients are at risk for adverse events on clopidogrel could help bolster the prognostic value of platelet function tests.

The original trial defined high on-treatment platelet reactivity as a P2Y12 reactivity unit (PRU) value of at least 230 on the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). Using this cutpoint, 2,214 of 5,429 stable or unstable CAD patients enrolled in the trial were considered to have high residual platelet reactivity. Among them, high-dose clopidogrel (600-mg initial dose and 150 mg daily thereafter) did not reduce the primary composite of CV death, nonfatal MI, or stent thrombosis at 6 months compared with standard clopidogrel (no additional loading dose and 75 mg daily thereafter).

For the post hoc analysis, researchers examined how setting a lower threshold—208 PRU—would affect adverse event risk. Patients who achieved PRU levels of less than 208 were at significantly lower risk of suffering the primary endpoint at both 60 days (HR 0.18; 95% CI 0.04-0.79; P = 0.02) and 6 months (HR 0.43; 95% CI 0.23-0.82; P = 0.01). In comparison, the 230 PRU cutoff proved far less effective at predicting reduced risk at either time point, whether 60 days (HR 0.62; 95% CI 0.25-1.51; P = 0.30) or 6 months (HR 0.71; 95% CI 0.41-1.23; P = 0.22).

According to Dr. Holmes, the combined findings on anticoagulants and DAPT from ESC offer “a very nice picture that the care of patients will be improved by virtue of improvements in devices, in drugs, and in our understanding of the combination of drugs and devices.”

As the field advances, newer, better designed stents will lead to less stent thrombosis and, consequently, reduced need for long-term DAPT. Novel factor Xa inhibitors, meanwhile, will produce less bleeding, he predicted. Together, these shifts can enhance outcomes.

Best DES Still Being Debated

Several studies at last week’s conference offered continued evaluation of changing DES technology, Dr. Holmes noted.

“It has been thought that the evolution of DES technology has led to better and better devices that are safer with less stent thrombosis and probably better rates of target vessel revascularization,” he said, adding that the latest studies help substantiate that and create a consistent evidence base.

One Swedish study looked at data on 61,351 patients in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) between November 2006 and October 2010. In this real-world population, PCI with newer-generation DES significantly reduced restenosis and stent thrombosis compared first-generation DES at 2 years. Moreover, both DES generations increased survival over rates achieved with BMS.

The RESET trial—the largest randomized study to ever compare everolimus-eluting stents (EES) and sirolimus-eluting stents (SES)—provided fresh evidence that the newer devices match their predecessors. EES also appear to perform well when used in patients with insulin-treated diabetes.

RESET randomly assigned low-to-moderate-risk patients in Japan to receive either EES (n = 1,597) or SES (n = 1,600). Noninferiority criteria were met for both of the study’s co-primary endpoints (table 1).

Table 1. RESET: Primary Endpoints at 12 Months

 

Prespecified subgroup analyses found that patients with insulin-treated diabetes were less prone to TLR after EES vs. SES use (5.4% vs. 12.3%; HR 0.42; 95% CI 0.18-0.9; P = 0.03).

Two additional studies looked at EES. The Bern-Rotterdam Cohort Study found that EES curb the risk of very late stent thrombosis compared with first-generation DES in an all-comers population, while the EXAMINATION trial found that EES also outperform BMS in terms of repeat revascularization and stent thrombosis in STEMI patients.

Wide-Ranging Studies Cover IABP, TAVI, More

A randomized study of intra-aortic balloon pump (IABP) therapy, the CRISP-AMI trial, dampened hopes for extending its use. Current guidelines recommend IABP therapy in conjunction with PCI for patients with cardiogenic shock, and recent observational and preclinical studies have supported the concept in patients with STEMI without shock.

But CRISP-AMI found that IABP fails to reduce infarct size or improve clinical outcomes when added prior to primary PCI in patients with high-risk STEMI but no cardiogenic shock.

Interestingly, said Dr. Holmes, the trial did show a nonsignificant trend toward lower mortality with IABP. “It was almost as if there was a divergence between [the primary endpoint that was] measured—infarct size—and potential clinical outcome. We generally think that infarct size and mortality should probably track. The study was underpowered to [assess] that, but it opens up some interesting potential for the design of subsequent trials and whether we should use surrogate endpoints for clinical outcome in AMI,” he commented.

Continuing good news on transcatheter aortic valve implantation (TAVI) came from the FRANCE 2 registry, which provided up-to-date information from 2,419 patients enrolled at 33 French Centers. Devices manufactured by Edwards Lifesciences (Irvine, CA) and Medtronic (Minneapolis, MN) both showed high success rates with good sustained hemodynamic and clinical improvement.

Mortality stood at 9.9% by 30 days and at 17.2% by 6 months, with almost identical rates for the 2 valve types. When valves were implanted by the transfemoral route, the Edwards device performed somewhat better than the Medtronic device.

Intensive treatment also received high marks this week. The PACIFIC registry study, for example, found that Japanese patients with ACS have very good in-hospital and 1-year outcomes, likely due to routine treatment with PCI and optimal medical therapy.

Similarly, the Italian Elderly ACS Study, which randomized 313 NSTE ACS patients aged at least 75 years to either early aggressive or initially conservative approaches, found that the composite of all-cause mortality, MI, disabling stroke, and rehospitalization was numerically lower with intensive treatment at 1 year. Among patients who had elevated troponin levels, the association reached statistical significance (HR 0.43; 95% CI 0.23-0.80; P = 0.03). Early aggressive treatment was defined as angiography within 72 hours, while patients initially treated conservatively received angiography after evidence of refractory ischemia.

Another registry upheld the superiority of CABG in triple-vessel disease, finding that such patients generally fare better with surgery than with PCI.

Among 2,981 Japanese patients with triple-vessel disease who underwent a first coronary revascularization between 2005 and 2007, CABG reduced the likelihood of all-cause death, MI, or stroke within 3 years compared with PCI (15.2% vs. 18.3%; HR 1.47; 95% CI 1.13-1.92; P = 0.004). The disadvantage for PCI grew at both ends of the Syntax score spectrum; patients with scores below 23 had increased risk of the primary endpoint as did those with scores of at least 33. The fact that even patients in the lowest tertile did better with surgery came as a surprise to many.

Cholesterol Matters, Too

Drugs aimed at altering patients’ lipid profiles also produced some memorable findings.

In the phase II dal-VESSEL trial, the experimental agent dalcetrapib showed promise by decreasing cholesterol ester transfer protein (CETP) activity and increasing high-density cholesterol levels without adversely affecting either blood pressure or endothelial function in patients who already had or were at risk for CHD.

Researchers are reportedly eager to find a CETP inhibitor that achieves efficacy without producing dangerous side effects, because a previous agent, torcetrapib, reached phase III trials before being dropped because of an increase in deaths.

An analysis of patients in the lipid-lowering arm of the ASCOT study, known as ASCOT-LLA, provided unexpected news: Prior exposure to atorvastatin appears to impart a sustained mortality benefit in hypertensive patients with no history of CAD.

ASCOT-LLA was terminated early in 2003 when interim results showed atorvastatin had substantially reduced the composite of nonfatal MI and fatal CHD compared with placebo at a median of 3.3 years. Patients continued in ASCOT’s blood pressure-lowering arm for another 2.2 years before that study also was stopped.

By 2011, approximately 11 years after ASCOT-LLA was begun, patients initially assigned to the atorvastatin group still had a 14% lower likelihood of all-cause mortality despite the fact that cholesterol profiles were now exactly the same between the 2 groups. The difference was mainly driven by a 15% reduction in non-CV mortality.

 

Source:

Presentations at: European Society of Cardiology Congress; August 28-30, 2011; Paris, France.

 

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• ESC Congress 2010: Pharmacology Trials Take Center Stage
• ESC Congress 2009: Innovation and Optimization
• ESC 2008: Big PCI Issues Addressed, Take-Away Not Always Clear