Summary
Background
The ideal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is under debate. Lesion length is a well-recognized predictor of PCI complexity and long-term outcome.
Aim
To evaluate the determinants and impact on outcome of long-term DAPT in a retrospective cohort of patients treated for a long coronary lesion.
Methods
Patients ( n = 460) who underwent PCI for a long lesion (> 30 mm) were divided into two groups according to antiplatelet regimen at 1 year: patients who stopped DAPT before 1 year (single antiplatelet therapy group; n = 168) and patients who continued DAPT for longer than 1 year ( n = 292).
Results
Mean lesion length was 35.7 ± 7.1 mm. The proportion of patients who continued DAPT after 1 year was 63.5%. The main determinants of long-term DAPT were initial presentation as myocardial infarction and implantation of a drug-eluting stent. Median follow-up was 37.4 (23–51) months after the 1-year period following the index PCI. Long-term DAPT was highly associated with a lower risk of all-cause and cardiovascular mortality by multivariable analysis and after adjustment for other predictors: hazard ratios 0.11 (95% confidence interval 0.03–0.32) and 0.15 (95% confidence interval 0.04–0.62), respectively. No increase in major bleeding was noted.
Conclusion
In a contemporary practice, nearly two-thirds of patients who undergo PCI for a long lesion are treated with DAPT for several years. Our results suggest that long-term DAPT is beneficial in this subset of patients identified as being at high risk.
Résumé
Contexte
La durée exacte du maintien de la double anti-agrégation plaquettaire (DAAP) après une angioplastie coronaire percutanée (ACP) est débattue. La longueur des lésions coronaires traitées est un facteur bien connu de la complexité des ACP et du pronostic à long terme.
Objectifs
Nous avons réalisé une étude rétrospective des patients traités pour une longue lésion coronaire afin d’évaluer la proportion de patients traités par DAAP après 1 an dans cette population, les facteurs déterminants de cette prescription et l’impact sur le pronostic des patients.
Méthodes
Quatre cent soixante patients, ayant eu une ACP pour une lésion de plus de 30 mm, ont été inclus et divisés en 2 groupes en fonction de leur régime anti-agrégant plaquettaire à 1 an. Les patients ayant stoppé la DAAP avant 1 an (groupe MAPT ; n = 168) ont été comparés à ceux qui ont poursuivi la DAAP au-delà de 1 an (groupe DAPT ; n = 292).
Résultats
La longueur moyenne des lésions était de 35,7 ± 7,1 mm. La proportion de patients traités par DAAP après 1 an était de 63,5 %. Les facteurs déterminants de cette prescription étaient la présentation clinique initiale (syndrome coronaire aigu) et l’implantation d’un stent actif. Le délai médian de suivi était de 37,4 mois après la période de 1 an faisant suite à l’ACP initiale. Le traitement DAAP prolongé était associé à un taux plus faible de mortalité toute cause et cardiovasculaire en analyse multivariée : HR = 0,11 (0,03–0,32) et 0,15 (0,04–0,62), respectivement. On notait l’absence d’augmentation significative du risque de saignement.
Conclusion
Dans une pratique contemporaine, près de deux tiers des patients ayant une ACP pour une longue lésion coronaire sont traités par DAAP prolongée. Nos résultats suggèrent qu’une DAAP prolongée serait bénéfique dans cette population particulière identifiée à haut risque.
Introduction
Antiplatelet therapy is a cornerstone treatment in patients with coronary artery disease (CAD). Aspirin use has been known for some time to produce a significant reduction in morbidity and mortality rates in such patients, and is subsequently widely used in secondary prevention . In addition, dual antiplatelet therapy (DAPT), combining aspirin and a P2Y 12 receptor antagonist, is the treatment of choice for patients with acute manifestations of CAD, acute coronary syndromes and/or percutaneous coronary intervention (PCI) . According to the guidelines, DAPT should be continued in these settings for 6–12 months; thereafter, patients should be switched to single antiplatelet therapy (SAPT), which is currently the recommended lifelong treatment in patients with stable CAD .
In 2006, concerns were raised about the safety of first-generation drug-eluting stents (DESs) in terms of the risk of late/very late stent thrombosis and long-term mortality . Hence, the duration of DAPT after DES implantation has been increased progressively in clinical practice, with sometimes wide local differences. In low-risk populations, recent randomized trials have suggested that long-term DAPT (beyond 6–12 months) may not be beneficial in patients undergoing PCI with DES implantation . In contrast, several well-conducted registries and a substudy of the PRODIGY trial, focusing on the stent thrombosis issue and including higher-risk patients, have suggested that some individuals may require lifelong DAPT . To date, the exact duration of DAPT after DES implantation is largely the subject of debate in the literature. Some authors suggest individual adaptation of the duration of DAPT after PCI. The length of a coronary artery lesion is a well-recognized predictor of PCI complexity and long-term outcome, especially regarding the risk of stent thrombosis and death .
We therefore investigated a cohort of patients treated for a long coronary artery lesion (> 30 mm), to evaluate the proportion of patients receiving DAPT after 1 year in this specific population, the determinants of long-term DAPT and the impact of such a strategy on mortality.
Methods
Population and study design
Between April 2007 and December 2011, 573 patients were included in this retrospective cohort. Patients were eligible if they underwent successful PCI in our centre (Lille, France), with implantation of either at least one bare-metal stent or at least one DES for the treatment of a long lesion (defined as a lesion > 30 mm in length). In case of multiple stent implantations, all stents had to have been implanted using the overlap technique; patients with any gaps between several stents were excluded ( n = 2). For reasons of clarity and homogeneity, patients treated with different types of stents (especially bare-metal stents and DESs) for the same lesion were excluded ( n = 37). In addition, as previous anticoagulation treatment is often responsible for DAPT discontinuation within the first year after PCI, patients treated with vitamin K antagonists were excluded ( n = 32). Patients who experienced major bleeding and/or surgery within the first year after PCI were excluded for the same reason ( n = 10). Finally, patients who died and/or experienced an acute coronary syndrome and/or underwent another PCI within the first year after the index PCI were excluded ( n = 45). Only event-free patients at 1 year were included. One individual could fit different exclusion criteria.
The final population ( n = 460) was divided in two groups according to the antiplatelet regimen that patients were receiving 1 year after PCI ( Fig. 1 ). Patients who stopped DAPT before 1 year (SAPT group; n = 168) were compared with those who continued DAPT after 1 year (DAPT group; n = 292). The median duration of DAPT in the SAPT group was 10.8 months (6.5–12 months).
Percutaneous coronary intervention procedures
PCI with coronary stent implantation was performed in accordance with the standard technique used in our catheterization laboratory, and all patients gave informed consent . All patients were pretreated with an intravenous bolus of aspirin (250–500 mg) and an intravenous bolus of heparin (50–70 IU/kg); they also received a loading dose of clopidogrel (300–600 mg). The use of glycoprotein IIb/IIIa inhibitors was at the discretion of the physician. After the procedure, patients were treated with aspirin 75 mg and clopidogrel 75 mg once daily until the discontinuation of DAPT (i.e. clopidogrel).
Data collection
Baseline characteristics were indexed after systematic in-hospital chart review. Index coronary angiograms were reviewed by two experienced interventional cardiologists blinded to patient outcome (C.D. and G.L.).
All patients or their immediate family were interviewed by telephone. In case of inaccurate and/or incomplete answers, general practitioners and cardiologists were contacted to complete information. Of note, information on antiplatelet therapy and antithrombotic regimens was carefully collected. When clopidogrel discontinuation occurred, we obtained the exact date of DAPT discontinuation in 77% of cases. For the remaining patients, the exact month of discontinuation was available in all cases; in these cases, the 15th of the month was automatically indexed as the date of DAPT discontinuation. A date of cessation was subsequently available for 100% of the patients who stopped DAPT within the first year after PCI.
Objective, follow-up, definitions and endpoints
The main objective of the present study was to assess the impact of long-term DAPT on prognosis in patients treated for a long coronary artery lesion.
Clinical follow-up was performed at outpatient office visits or by telephone contact with the patient and/or their general practitioner or cardiologist. The median follow-up was 37.4 months (23–51 months) after the 1-year period following the index PCI in the overall population, 35.7 months (18–52 months) in the SAPT group and 38.3 months (22–54 months) in the DAPT group. We collected data on death, stent thrombosis and bleeding. All clinical events were adjudicated blindly by at least two investigators in all cases and by three investigators in case of disagreement, according to prespecified definitions. In case of new hospitalization, data were obtained by a systematic review of the discharge letter. The cause of death was determined after a detailed review of the circumstances of death, and was classified as cardiovascular or non-cardiovascular. Deaths from unknown causes were classified as cardiovascular. Major bleeding was defined as the occurrence of a fatal haemorrhage and/or an intracranial haemorrhage and/or a need for transfusion and/or a decrease in the haemoglobin concentration of ≥ 5 g/dL or a ≥ 15% decrease in haematocrit. Minor bleeding was defined as the occurrence of a peripheral vascular complication and/or other symptomatic haemorrhagic complication without any major bleeding definition criteria and/or a decrease in the haemoglobin concentration of 3 g/dL (but < 5 g/dL) or a 10% (but < 15%) decrease in haematocrit.
The primary endpoint was all-cause death; secondary endpoints were cardiovascular death and bleeding.
Statistical analysis
Continuous variables are expressed as means ± standard deviations. Categorical variables are expressed as absolute numbers and percentages. Durations are expressed as medians with 25th and 75th percentiles.
To evaluate predictors of long-term DAPT, baseline characteristics in the SAPT and DAPT groups were compared using the Chi 2 test or Fisher’s test for categorical variables and Student’s unpaired t -test for continuous variables, as appropriate.
To evaluate the impact of long-term DAPT on patient outcomes, predictors of events were analysed using a univariate Cox analysis; a multivariable analysis was then performed. All data with a P value < 0.2 in the univariate analysis were entered in a forward stepwise manner into a Cox multivariable model, with entry and retention set at a significance level of 0.05. Cox proportional hazard analyses were performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Co-linearity was excluded by means of a correlation matrix between candidate predictors. Cumulative event rates in both groups (SAPT and DAPT) were estimated using the Kaplan–Meier method and compared using the log-rank test.
All statistical analyses were performed using SPSS ® software for Windows, version 20.0 (SPSS Inc., Chicago, IL, USA). Statistical significance was assumed at a P value < 0.05.
The authors had full access to the data and take responsibility for their integrity. All authors have read and agree to the manuscript as written.
Results
Population
Baseline clinical, procedural and angiographical characteristics are summarized in Tables 1–3 . In the overall population ( n = 460), the mean age was 65.7 ± 12 years, 76.9% of patients were men and 33.2% were diabetics. Only 30% of patients had a history of myocardial infarction, 15.9% had a history of PCI and 9.5% had a history of coronary artery bypass graft surgery. The mean left ventricular ejection fraction (LVEF) was 51.8 ± 8.9%.
| Overall population ( n = 460) | SAPT ( n = 168) | DAPT ( n = 292) | P | |
|---|---|---|---|---|
| Men | 354 (76.9) | 126 (75.0) | 228 (78.1) | 0.59 |
| Age (years) | 65.7 ± 12.0 | 66.3 ± 12.8 | 64.5 ± 11.6 | 0.13 |
| Dyslipidaemia | 293 (63.7) | 101 (60.1) | 192 (65.7) | 0.55 |
| Smokers | 160 (34.8) | 59 (35.1) | 101 (34.6) | 0.74 |
| Hypertension | 267 (58.0) | 99 (58.9) | 168 (57.5) | 0.70 |
| Cardiovascular heredity | 143 (31.1) | 49 (29.2) | 94 (32.2) | 0.36 |
| Body mass index (kg/m 2 ) | 28.7 ± 13.9 | 27.9 ± 5.5 | 29.2 ± 16.9 | 0.32 |
| Diabetes | 153 (33.2) | 49 (29.2) | 104 (35.6) | 0.24 |
| Stroke | 18 (3.9) | 4 (2.4) | 14 (4.8) | 0.21 |
| History of CAD | 222 (48.3) | 75 (44.6) | 147 (50.3) | 0.29 |
| Prior myocardial infarction | 138 (30.0) | 46 (27.4) | 92 (31.5) | |
| Prior PCI | 73 (15.9) | 53 (31.5) | 20 (6.8) | |
| Prior CABG | 44 (9.5) | 19 (11.3) | 25 (8.6) | |
| Peripheral vascular disease | 47 (10.2) | 13 (7.7) | 34 (11.6) | 0.32 |
| Renal failure (creatinine clearance ≤ 60 mL/min) | 38 (8.3) | 16 (9.5) | 22 (7.5) | 0.30 |
| Initial clinical presentation as myocardial infarction | 166 (36.1) | 74 (44.0) | 92 (31.5) | 0.004 |
| With ST-segment elevation | 89 (19.5) | 39 (23.2) | 50 (17.1) | |
| Without ST-segment elevation | 77 (16.5) | 35 (21.5) | 42 (14.4) | |
| LVEF (%) | 51.8 ± 8.9 | 51.4 ± 9.5 | 52 ± 8.4 | 0.57 |
| LVEF ≥ 45% | 223 (48.5) | 83 (49.4) | 140 (47.9) | 0.71 |
| Creatinine (mg/L) | 9.9 ± 3.9 | 10.3 ± 5.3 | 9.6 ± 2.9 | 0.06 |
| Total cholesterol (mmol/L) | 4.4 ± 1.3 | 4.6 ± 1.3 | 4.3 ± 1.3 | 0.28 |
| LDL cholesterol (mmol/L) | 2.5 ± 1.1 | 2.6 ± 0.1.1 | 2.4 ± 1.1 | 0.13 |
| HDL cholesterol (mmol/L) | 1.2 ± 0.5 | 1.2 ± 0.5 | 1.2 ± 0.5 | 0.67 |
| Triglycerides (mmol/L) | 2.5 ± 1.1 | 1.7 ± 0.9 | 2.9 ± 1.2 | 0.42 |
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