NORSTENT

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Bonaa KH, et al. "Drug-Eluting or Bare-Metal Stents for Coronary Artery Disease". The New England Journal of Medicine. 2016. 375:1242-1252.
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Clinical Question

In patients with stable or unstable coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI), are contemporary second-generation drug-eluting stents (DES) superior to contemporary bare-metal stents (BMS) with regard to all-cause mortality or nonfatal MI?

Bottom Line

In patients with stable or unstable CAD undergoing PCI, contemporary second-generation DES are not superior to contemporary BMS in regards to a primary endpoint of all-cause mortality or nonfatal MI at 6 years. DES was associated with a 3% absolute reduction in any repeat revascularization as well as a 0.4% absolute reduction in stent thrombosis over this period.

Major Points

Multiple RCTs have demonstrated the superiority of drug-eluting stents (DES), coronary stents that provide continuous local delivery of pharmacologic inhibitors of neointimal proliferation, over traditional bare-metal stents (BMS), particularly with regard to stent restenosis, or late stent blockage due to endothelial growth within the stent.[1][2] As a result, implantation of DES has become the preferred method of coronary intervention even though the risk of late stent thrombosis (acute formation of clot within the stent, a rare but devastating outcome) appeared slightly higher with 1st generation DES compared to BMS.[3]. Subsequently, however, 2nd generation DES was developed, representing incremental improvement over 1st generation DES with structural advances allowing for improved outcomes overall as well as a lower risk of late stent thrombosis over 1st generation DES.[4] At the same time, however, BMS technology had also gradually improved, despite these stents usually being placed primarily in patients at higher risk of bleeding (due to the perceived need of a shorter duration of dual antiplatelet therapy due to the original studies demonstrating high risk of late stent thrombosis with DES). Prior to NORSTENT, a contemporary trial comparing 2nd generation DES with contemporary BMS was needed in order to determine comparative efficacy and safety particularly with regards to stent thrombosis.

The 2016 Norwegian Coronary Stent Trial (NORSTENT) randomized 9013 patients with either stable or unstable CAD undergoing PCI to either 2nd-generation DES or contemporary BMS placement to assess for a difference in the primary outcome of all-cause mortality or nonfatal MI. At 6 years, there was no difference in the primary outcome or its subcomponents. There was also no difference in angina-related quality of life between groups. However, there was a 3.3% absolute increase in any repeat revascularization in the BMS group as well as 0.4% absolute increase in definite stent thrombosis in the BMS group. Safety outcomes were similar with both DES and BMS.

The results of NORSTENT suggest that contemporary BMS has closed the gap somewhat compared to 2nd-generation DES, such that there is little difference between the two stent types with regard to major cardiovascular outcomes. As in previous trials, however, BMS remains associated with a higher rate of repeat revasularization at long-term follow-up, which is likely a result of increased restenosis rates with these stents (due to lack of intimal inhibition). Interestingly, however, NORSTENT also demonstrated a 0.4% absolute increase in stent thrombosis with BMS, which runs counter to previous data suggesting higher rates of stent thrombosis with (1st generation) DES compared to BMS. Given the high morbidity/mortality associated with stent thrombosis, this finding will require validation. Ultimately, however, NORSTENT suggests that DES may now be superior to BMS with regard to both stent restenosis as well as stent thrombosis, which if true will bring into serious question whether there remains any role for BMS in PCI.

Guidelines

As of October 2016, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, open-label, randomized controlled trial
  • N=9013
    • DES (n=4504)
    • BMS (n=4509)
  • Setting: 8 centers in Norway
  • Period: Sept 15, 2008 to Feb 14, 2011
  • Median follow-up: 9 years
  • Analysis: Intention-to-treat
  • Primary outcome: Death from any cause or nonfatal MI

Population

Inclusion Criteria

  • Age ≥18
  • Stable angina or acute coronary syndrome
  • Coronary lesions in native arteries or grafts amenable to stent implantation with DES or BMS

Exclusion Criteria

  • Previous stent placement
  • Bifurcation lesion requiring 2 stent technique
  • Serious medical condition other than CAD with life expectancy < 5 years
  • Intolerable side effects to any drug in use during PCI or contraindications to long-term dual antiplatelet therapy
  • On warfarin or other systemic anticoagulant

Baseline Characteristics

From the DES group.

  • Demographics: Age 63 years, Male 75.0%
  • Co-morbidities: BMI 27.1, Smoker 34.1%, DM 12.8%, HTN 42.9%, HLD 53.6%, Hx MI 9.6%, Hx stroke 3.9%, Hx CABG 6.5%
  • PCI Indication: Stable angina 29.1%, Unstable angina 12.6%, NSTEMI 31.2%, STEMI 26.7%
  • Lesion characteristics: Multivessel disease 40.3%, Type B2 or C 49.4%, Bifurcation 15.3%, CTO 4.0%, Ostial 7.4%, Calcified 23.1%, Thrombotic 23.1%
  • Index procedure characteristics: >1 procedure 6.5%, Radial approach 83.0%, # of lesions treated 1.4, # of stents implanted 1.7, Total stent length 28.5mm, Allocated stent implanted 98.6%, Angiographic success 97.6%

Interventions

  • Patients randomized 1:1 to DES or BMS after diagnostic angiography and before PCI
  • Patients received as many stents as clinically appropriate but only of the randomized stent type
  • Patients, operators, and clinicians providing clinical care were aware of the types of stents that were being placed
  • PCI was performed according to standard techniques at the discretion of each operator
  • All patients in both groups were prescribed aspirin at 75MG daily indefinitely and clopidogrel 75MG daily for 9 months after procedure regardless of stent type
  • Drugs for secondary prevention were prescribed according to current guidelines
  • Operators were encouarged to use the assigned type of stent if repeat PCI was required
  • Restenosis could be treated by balloon angioplasty, a cutting balloon, drug-eluting stents, or a combination of those methods at the discretion of the operator
  • Clinical follow-up of the patients was performed according to routine practice at the participating centers
    • There were no per-protocol follow-up visits
    • There was no routine angiography
    • A quality of life questionnaire was administered to a representative sample of 941 patients (10%) at baseline and was mailed to all patients at 6, 12, 24, 36, 48, and 60 months
    • Disease-specific health status and quality of life were assessed by means of a validated Norwegian translation of the Seattle Angina Questionnaire
  • Outcome events were collected by means of electronic linkage to the Norwegian Patient Registry and verified with discharge letters and medical-record notes identified by the electronic search
  • All outcomes were adjudicated by members of an endpoint committee of clinical and interventional cardiologists blinded to treatment assignment

Outcomes

Comparisons are DES vs. BMS.

Primary Outcome

Death or nonfatal MI
643 (16.6%) vs. 656 (17.1%) [HR 0.98; 95% CI 0.88-1.09; p=0.66]

Secondary Outcomes

Death
287 (7.5%) vs. 257 (7.4%) [HR 1.11; 95% CI 0.94-1.32; p=0.21]
Nonfatal MI
356 (9.8%) vs. 399 (10.5%) [HR 0.89; 95% CI 0.77-1.02; p=0.10]
Any revascularization
630 (16.5%) vs. 799 (19.8%) [HR 0.76; 95% CI 0.69-0.85; p<0.001]
Definite stent thrombosis
32 (0.8%) vs. 50 (1.2%) [HR 0.64; 95% CI 0.41-1.00; p=0.0498]

Subgroup Analysis

The results in the primary outcome were consistent in subgroups defined according to demographic, clinical, lesion, and procedural characteristics.

Adverse Events

Stroke
143 (3.4%) vs. 117 (3.0%) [HR 1.23; 95% CI 0.97-1.57; p=0.09]
BARC 3, 4, or 5 bleeding
225 (5.5%) vs. 229 (5.6%) [HR 0.99; 95% CI 0.82-1.18; p=0.88]

Criticisms

  • The trial was powered to detect a 3% absolute risk difference between BMS and DES in the primary outcome so a smaller difference cannot be ruled out by this study.
  • Stent implantation was not blinded to patients, interventionists, or clinicians, which allows for possibility of bias. This is somewhat mitigated by blinded outcomes adjudication.
  • It is unclear if FFR (fractional flow reserve) guidance, which is known to improve outcomes in PCI, was utilized in this study. Asymmetries in FFR use could lead to spurious differences in outcomes although this should be mitigated by adequate randomization.

Funding

  • The sponsors had no role in the design of the study, the gathering or analysis of the data, the writing of the manuscript, or the decision to submit the manuscript for publication

Further Reading

  1. Morice MC et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N. Engl. J. Med. 2002. 346:1773-80.
  2. Stettler C et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. Lancet 2007. 370:937-48.
  3. Lagerqvist B et al. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N. Engl. J. Med. 2007. 356:1009-19.
  4. Stefanini GG & Holmes DR Drug-eluting coronary-artery stents. N. Engl. J. Med. 2013. 368:254-65.