souffert un infarctus du myocarde à Québec,
Canada
Avant-propos
Nous avons révisé les études démontrant que le traitement de la dyslipidémie chez les patients souffrant de maladie coronarienne est bénéfique pour réduire la récidive d’événements cardiovasculaires. Malgré des données probantes convaincantes, il est possible que les effets bénéfiques des statines ne soient pas aussi présents dans la « vraie vie », puisqu’il a été observé qu’une grande proportion des patients à haut risque d’événements cardiovasculaires ne soient pas traités selon les recommandations de la Société canadienne de cardiologie. En effet, l’étude de cohorte DYSIS a observé que près de 40% des patients à haut risque d’événements cardiovasculaires n’atteignaient pas les cibles lipidiques recommandées(118). Qu’en est-t-il de la population de la ville de Québec? Ceci a été la prémisse à la réalisation de notre étude intitulée « Factors Associated with Failure to Achieve Target Lipid Levels after Myocardial Infarction in Quebec, Canada » qui sera présentée dans les prochaines pages. L’objectif de notre étude rétrospective était d’évaluer, chez des patients de la région de Québec et ayant subi un infarctus aigu du myocarde avec surélévation du segment ST, la proportion des patients n’ayant pas atteint la cible lipidique recommandée à 1 an après l’événement coronarien aigu et de déterminer quels étaient les déterminants cliniques liés à une non-atteinte de ces cibles lipidiques. Nous avons inclus dans cette étude 539 patients ayant subi un infarctus aigu du myocarde avec élévation du segment ST et qui ont été traités à l’Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). Tous ces patients ont été traités avec une statine. Le dosage et le type de statine prescrite a été laissé à la discrétion du cardiologue traitant. Un bilan lipidique a été prélevé lors de leur séjour hospitalier et 12 mois plus tard. Une revue des dossiers lors du séjour hospitalier a permis de relever les comorbidités des patients. Les patients ont été séparés en 2 groupes, selon qu’ils aient ou non atteints la cible lipidique recommandée à 1 an. Une comparaison a été réalisée entre; 1) la proportion de patients ayant ou non atteint le taux de cholestérol-LDL recommandée à 1 an, 2) la proportion de
42
patients ayant été traités avec une haute dose ou une dose modérée de statine et, 3) les caractéristiques cliniques des 2 groupes. Finalement, les facteurs cliniques qui prédisaient la non-atteinte de la cible recommandée ont été déterminés par une analyse multivariée. Cette étude permettait de mieux comprendre les facteurs liés à la non-atteinte des cibles lipidiques recommandées dans notre région pour améliorer la prise en charge de la dyslipidémie des patients québécois souffrant de maladie coronarienne.
Cet article a été soumis au « Canadian Journal of Cardiology » le 15 mai 2018. Le Dr Géraldine Ong en est l’auteur principal. Ses rôles dans la réalisation du travail ont été : revue de dossiers médicaux, collecte des données, recrutement de patients, obtention du consentement éclairé, développement du protocole, analyse des données, préparation et rédaction du manuscrit, présentation lors de congrès (Congrès canadien de cardiologie). Dr Jean-Pierre Déry (développement du protocole, analyse des données, révision du manuscrit), Monsieur Serge Simard (analyse des données, révision du manuscrit), Madame Mélanie Roy (collecte des données, recrutement de patients, obtention du consentement éclairé, analyse des données) et le Dr Paul Poirier (développement du protocole, analyse des données, préparation et révision du manuscrit,) en sont les coauteurs.
Notez que le présent chapitre consiste en un article rédigé en anglais.
43
Titre de l’article: « Factors Associated with Failure to Achieve
Target Lipid Levels after Myocardial Infarction in Quebec,
Canada »
Géraldine Ong MD, Jean-Pierre Déry MD, Serge Simard M.Sc., Mélanie Roy M.Sc., Paul Poirier MD PhD
Résumé
Les lignes directrices canadiennes actuelles recommandent l'utilisation d’un traitement hypolipidémiant agressif pour atteindre la cible de cholestérol-LDL <2,0 mmol/L dans le but de réduire les événements cardiovasculaires chez les patients maladie coronarienne athérosclérotique. Malgré ces recommandations, le traitement sous-optimal de la dyslipidémie chez ces patients demeure prévalent. La proportion de patients n’atteignant pas la cible recommandée n'a jamais pas été bien documentée dans une population québécoise. Cet article a pour but de déterminer quels sont les facteurs cliniques associés à la non-atteinte des niveaux de lipides recommandés chez des patients ayant subi un infarctus du myocarde dans la région de Québec, Canada.
Pour ce faire, des patients présentant un infarctus du myocarde avec sus-décalage du segment ST (STEMI) et subissant une intervention coronarienne percutanée à l'Institut des maladies du cœur et des poumons de Québec ont été recrutés et suivis prospectivement. Les profils lipidiques à jeun ont été obtenus au départ et à 1 an. Les patients ont été divisés en deux groupes, ceux qui ont atteint le C-LDL cible d'un an et ceux qui ne l'ont pas atteint. Nous avons comparé la proportion et les caractéristiques cliniques des patients atteignant des niveaux de lipides cibles d'un an. Une analyse de régression logistique multivariée a été utilisée pour déterminer les prédicteurs indépendants de l'incapacité à atteindre les niveaux cibles d'un an de C-LDL.
44
Abstract
Background: Current Canadian clinical guidelines support the use of aggressive lipid
lowering therapies to achieve a low-density lipoprotein cholesterol (LDL-C) < 2.0 mmol/L to reduce cardiovascular events in patients with coronary artery disease. Clinical factors associated with failure to achieve the current target lipid levels in real-life has not been well documented in a Canadian population.
Methods: Patients with ST-elevation myocardial infarction (STEMI) and undergoing
percutaneous coronary intervention at the Quebec Heart and Lung Institute were enrolled and followed prospectively. Fasting lipid profiles were obtained at baseline and at 1 year. Patients were divided into two groups, those who achieved 1-year target LDL-C, and those who did not. We compared the proportion and clinical characteristics of patients achieving 1-year target lipid levels. Multivariable logistic regression analysis was used to determine independent predictors of not achieving 1-year LDL-C target levels.
Results: A total of 639 STEMI patients were included. At 1 year, 420 (65.7%) of patients achieved target LDL-C and 219 (34.3%) did not. Those who did not achieve target LDL-C were older (63±12 years vs. 58±10, p<0.008), women (28.8% vs. 18.1%, p=0.002), smokers (47.0% vs. 35.3%, p=0.004), and were more often treated with a moderate-dose statin (76.7% vs. 67.4%, p=0.01), and had less previous coronary disease (p=0.03) and less diabetes (p=0.01). On multivariate analysis, a moderate-dose statin [OR 1.67 (1.13-2.49), p=0.011], age [OR 1.27 (1.08-1.49), p=0.005], and female [OR 1.97 (1.30-2.97), p=0.001] were predictors of failure to achieve LDL-C target at 1 year.
Conclusion: In this observational study, more than one third of patients who suffered a
STEMI did not achieve currently recommended target lipid levels at 1 year. Patients treated with a moderate dose statin were less likely to have classic risk factors. A more aggressive lipid-lowering approach should be encouraged.
45
1. Introduction
Patients with known cardiovascular (CV) disease are at high risk of recurrent CV events and death. Cholesterol-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in such patients has been shown to reduce CV events as well as mortality (1). A meta-analysis of landmark clinical trials conducted over the past decade has shown a 12 percent proportional reduction in all-cause mortality per 1 mmol/L reduction in low-density lipoprotein cholesterol (LDL-C) (2). The Canadian Cardiovascular Society (CCS) 2009 and 2016 guidelines recommend in high risk patients a target LDL-C ≤ 2 mmol/L or a ≥ 50% reduction of LDL-C or apolipoprotein B (apoB) ≤ 0.8 g/L (1,3). The most recent 2016 Guidelines added the target of non-high-density lipoprotein cholesterol (non-HDL-C) ≤ 2.6 mmol/L (1). Despite clear recommendations, there is growing evidence of suboptimal statin treatment in patients with known CV disease (4,5). The Dyslipidemia International Study has shown that up to 45% of high risk patients do not meet LDL-C goal (5). The prevalence of lipid abnormalities in the Quebec City region has never been well documented. The aim of this study is to determine factors associated with failure to achieve target lipid levels in patients with ST-elevation myocardial infarction (STEMI) treated in a tertiary cardiovascular referent center.
2. Methods
This study was a single-center prospective analysis of a retrospective observational study. Six hundred thirty-nine STEMI patients who underwent primary coronary revascularization (PCI) at our institution were included. All patients for whom a fasting lipid profile (total cholesterol (TC), triglyceride (TG), LDL-C, high density lipoprotein cholesterol (HDL-C), and non-HDL-C) was obtained at baseline as part of routine clinical care, and that were discharge from the hospitalization with a statin were included. Exclusion criteria were being part of an active clinical study and the absence of clinical atherosclerosis. The protocol was approved by the scientific and ethics committees of the Quebec Laval University Heart and Lung Institute. Written informed consent was obtained from all patients.
46
Patients were divided into 2 groups; 1) those who achieved 1-year target LDL-C and, 2) those who did not. Baseline clinical characteristics and baseline lipid profiles were obtained by retrospective chart review. Statin type and dosage were prescribed at the discretion of the treating cardiologist and recorded. The high-dose group included patients treated with rosuvastatin 20 mg or 40 mg, atorvastatin 80 mg or simvastatin 80 mg daily whereas the moderate-dose group included all other statin types and dosages. Adherence to statin therapy and pharmacological treatment modifications were assessed by telephone interview at 12 months. Follow-up lipid profile was obtained at 12-months as part of routine clinical care. Interviews were conducted by a research professional. In case of failure to contact the patient, an attempt was made to the patient’s primary care physician.
3. Statistical Analysis
Continuous variables are presented as mean ± standard deviation. Categorical variables are presented as count and percentage. We compared patients who achieved target lipid levels to those who did not. Differences between groups were analyzed by unpaired Student’s t-test for continuous variables and chi-squared test for categorical variables. Multivariable logistic regression analysis was performed to determine independent factors associated with failure to achieve of target lipid levels. Adjusted ORs with 95% CIs were calculated. Differences between baseline and 1-year lipid profile between patients treated with a high-dose compared to a moderate dose statin were analyzed by paired-t test. All statistical analyses were conducted using SPSS version 25 (SPSS, Inc., Chicago, IL, USA), and defined statistical significance at a 2-sided P-value of < 0.05.
47
4. Results
During the study period, 1612 patients presented with STEMI. Six hundred thirty-nine patients with STEMI who underwent primary PCI at our institution were discharged with a statin (Figure 1). Statin types and dosages for both groups are shown in Figure 2. Patients characteristics are reported in Table 1. Patients who did not achieve 1-year target LDL-C were older (p<0.008) and included a greater proportion of women (p<0.002) and were less likely to have been discharged with a high-dose statin (p=0.01). Furthermore, patients who did not achieve 1-year target LDL-C had less previous coronary artery disease (CAD) (p=0.03), less diabetes (p=0.01), and were less often smokers (p=0.004).
After adjusting for confounding factors and assessing for variable interaction, multivariate analysis demonstrated that a moderate-dose statin [OR 1.67 (1.13-2.49), p=0.011], age (for each 10 -years increase) [OR 1.27 (1.08-1.49), p=0.005], and female sex [OR 1.97 (1.30- 2.97), p=0.001] were predictors of failure to achieve 1-year LDL-C target. (Table 3).
At baseline, 188 (29.4%) patients were prescribed a high-dose statin, and 451 (70.6%) patients were discharged with a moderate-dose statin. Compared to the moderate-dose group, patients in the high-dose group were younger (p<0.0001) and had higher body mass index (BMI) (p=0.04). A greater proportion of men (p<0.0001) and previous CAD (p=0.04) was found in the high-dose group. Twenty-seven (4.2%) patients had a reduction in statin intensity therapy during follow-up. At 1-year follow-up, a greater proportion of patients in the high-dose group achieved target LDL-C ≤ 2 mmol/L (72.9% vs. 62.7% patients, p=0.001). There was no significant difference in the number of patients achieving target non-HDL ≤ 2.6 mmol/L at 1 year between those treated with a high-dose statin compared to those treated with a moderate-dose statin (68.1% vs. 61.9%, respectively, p=0.12). At 1-year, all patients had a significant reduction in CT, LDL-C, HDL-C, TG, and non-HDL-C in the high- dose group (all p<0.001), but not for non-HDL-C in the moderate-dose group (p=0.780) (Table 2). In the high-dose group, there was a 1-year decrease in LDL-C level (difference between baseline LDL-C and 1-year LDL-C) of 0.97 ± 0.98 mmol/l whereas in the moderate- dose group, there was a 1-year decrease in LDL-C of 0.58 ± 0.90 mmol/l (p<0.001).
48
5. Discussion
In this retrospective observational study, we demonstrated that more than one third of STEMI patients did not reach the recommended target LDL-C levels at one year, and that women, older patients and patients treated with a moderate-dose statin were less likely to reach 1-year target LDL-C. To our knowledge, this is the first study to assess dyslipidemia under treatment in STEMI patients in a Quebec population.
These data are in line with other published reports suggesting under achievement of target lipid levels in high-risk patients. Goodman et al. demonstrated in a cross-sectional study recruiting 2436 Canadian patients that up to 45% high-risk patients did not achieve LDL-C level recommendations based on the Canadian Cardiovascular Society guidelines (4). Under-treatment of high-risk patients is also a concern in United States (6). The American Heart Association and the American College of Cardiology both recommend reaching LDL- C <1.8 mmol/L or lipid management with an aggressive high-dose statin (7). Guidelines recommendations are based on meta-analyses of large randomized controlled trials concluding that aggressive LDL-C-lowering therapy in CAD patients is associated with a reduction in cardiovascular mortality (8). Many hypotheses can be suggested to explain the gap between target lipid levels and « real-life » findings (9,10). One possible explanation is that Quebec physicians were not aware of guidelines’ recommendations. Another hypothesis could be that physicians were not inclined to prescribe high-dose statins because of fear from side effects and consequently lower patient adherence to therapy (10).
The use of a high-dose statin compared to a moderate-dose statin in patients with acute coronary syndrome (ACS) has been the scope of numerous studies (11-14). In PROVE-IT TIMI 22 trial, an intensive treatment with atorvastatin 80 mg daily was associated with a 16% relative reduction in death or major CV events compared to a treatment with pravastatin 40 mg daily in patients with ACS (12). Similarly, phase Z of the A to Z trial, demonstrated a 11% relative reduction in primary endpoint in patients post-ACS and treated with simvastatin 80 mg daily compared to a treatment with simvastatin 40 mg daily (13). In our study, the 1- year mean LDL-C levels were 1.77 mmol/L and 1.90 mmol/L in the high-dose and moderate-
49
dose groups, respectively. These results demonstrate a 1-year LDL-C level decrease of 36% in the high-dose group and 24% in the moderate-dose group. These values were comparable to those reported in the previously mentioned randomized controlled trials. A large prospective meta-analysis demonstrated that a 1 mmol/l reduction in LDL-C was associated with a 22% (p<0.0001) in major cardiovascular events (14). Among the 5 trials of more intensive vs. less intensive statin therapy, there was an on-treatment LDL-C reduction of 1–2 mmol/L with the more intensive regimens, which was about 0.5 mmol/L lower on average compared with treatment with a moderate-intensity statin therapy. This further LDL-C reduction was associated with a 15% significant reduction in major vascular events compared with moderate therapy, with no increases in the risk for cancer or non- cardiovascular mortality (15). Therefore, patients post-ACS should be considered for a high- dose statin unless specified otherwise, a therapy sufficient to achieved at least 30-40% reduction in LDL-C level at 1 year (16).
We found no significant difference between patients treated with a high-dose statin and a moderate-dose statin in achieving 1-year target non-HDL-C. This result can partly be explained by different effects of different statin type and dosage on plasma ApoA-I kinetics, leading to different impact on HDL-C concentrations (17). Recent studies suggested that non-HDL-C better predicts cardiovascular risk compared than LDL-C levels (18). Thus, the recent CCS guidelines recommends non-HDL-C as an alternative target to LDL-C (1). This result may suggest that a subgroup of patients with lower TC and higher HDL-C levels may well achieve target non-HDL-C with a moderate-dose statin, and therefore benefit from this non-HDL-C reduction. In our study, cardiologists seemed less likely to treat female patients with high dose statin. Patients without classical CAD risk factors were also less likely to get aggressive therapy. These patients were also less likely to reach LDL-C target. As previously reported in Canada and in the United States (4,19), sex disparities in the management of dyslipidemia post-ACS is also present in the Quebec City region. This observation could contribute, among other clinical factors, to a worse prognostic in women compared to men after ACS (19). As an aggressive LDL-C reduction after ACS has shown a survival benefit in both men and women (12,20,21), it is strongly supported by scientific evidence to treat these women with a high intensity statin therapy (7,22). In our study, 219 (34.3%) patients did not achieve the target LDL-C. This failure to achieve target LDL-C level could be explained by other factors than the intensity of statin therapy. At baseline, 118 (18.4%) of
50
patients had LDL-C level > 5 mmol/L. This observation could suggest the presence of undiagnosed familial hypercholesterolemia, an inherited condition highly prevalent in the Quebec province (23). Furthermore, 27 patients had a reduction in statin intensity therapy during follow-up in our cohort. This finding suggests possible statin intolerance which could also be a factor of failure to achieve target LDL-C levels.
Our study suffers limitations, mainly derived by its non-randomized observational design. This is a single center study in which only STEMI patients were prospectively included. Consequently, selection bias and unmeasured cofounders cannot be excluded. We attempted to account for the potential selection bias as much as possible by using multivariable time-dependent covariate adjustment models. Also, we did not collect information of dietary habits and other non-pharmacological treatment of dyslipidemia. Lipid measurements were not performed in a core laboratory and subject to technical variations. Finally, adherence was not assessed by pill count or pharmacy record.
6. Conclusion
In this non-randomized observational study, more than one third of high-risk patients, including women and patients without classic CAD risk factors in the Quebec region did not achieve target C-LDL levels as recommended by the Canadian Cardiovascular Society Guideline. Better understanding of factors leading to under management of dyslipidemia will help promote better strategies, such as promoting higher dose of statins, add-on lipid lowering therapies and aggressive non-pharmacological interventions.
51
Tables and Figures
Table 7. Baseline characteristics of the study groups
Achieved Target LDL-C Not Achieved Target LDL-C p N=420 (65.7%) N=219 (34.3%) Age (mean) 59±12 62±11 0.008 Sex female % 76 (18.1) 63 (28.8) 0.002 Height (cm) 170.6±8.2 169.6±9.0 0.16 Weight (kg) 79.1±16.6 76.9±16.2 0.12
Body mass index (kg/m2) 27.1±4.9 26.8±4.9 0.39
Previous coronary heart disease % 61 (14.6) 19 (8.7) 0.03
Diabetes % 54 (12.9) 14 (6.3) 0.01
Hypertension % 187 (44.5) 93 (42.5) 0.62 Smoking % 148 (35.3) 103 (47.0) 0.004 Creatinine clearance < 30 umol/L % 0 (0) 8 (2.0) 0.06 Baseline high-dose statin % 137 (32.6) 51 (23.3) 0.01 Baseline moderate-dose statin % 283 (67.4) 168 (76.7) 0.01
ASA % 389 (97.7) 203 (97.2) 0.65 Beta-blockers % 281 (71.3) 146 (70.5) 0.84 ACEI % 234 (59.4) 95 (46.1) 0.002 Niacin % 2 (0.6) 1 (0.5) 0.98 Ezetimibe % 10 (2.8) 10 (5.4) 0.13 Fibrate % 1 (0.3) 2 (0.1) 0.23 Baseline CT 4.22±1.06 4.75±1.01 <0.001 Baseline HDL-C 1.14±0.31 1.23±0.34 0.004 Baseline LDL-C 2.35±0.92 2.86±0.92 <0.001 Baseline TG 1.61±1.00 1.48±0.79 0.17 Baseline Non-HDL 1.88±0.47 1.89±0.39 0.70 Means ± SD or N (%) are shown.
52
Table 8. Lipid profiles of the study groups
8.1) High dose group
Baseline 1 year P
Total Cholesterol (mmol/L) 4.63 ± 1.18 3.62 ± 0.79 <0.001 HDL-C (mmol/L) 1.15 ± 0.30 1.19 ± 0.31 0.006 LDL-C (mmol/L) 2.70 ± 1.05 1.77 ± 0.62 <0.001 Triglycerides (mmol/L) 1.79 ± 1.20 1.48 ± 0.96 <0.001 Non-HDL (mmol/L) 1.94 ± 0.47 1.86 ± 0.50 0.009 Means ± SD are shown.
8.2) Moderate dose group
Baseline 1 year P
Total Cholesterol (mmol/L) 4.28 ± 1.01 3.78 ± 0.80 <0.001 HDL-C (mmol/L) 1.19 ± 0.33 1.24 ± 0.36 <0.001 LDL-C (mmol/L) 2.43 ± 0.89 1.90 ± 0.64 <0.001 Triglycerides (mmol/L) 1.48 ± 0.80 1.39 ± 0.70 0.005 Non-HDL (mmol/L) 1.86 ± 0.43 1.88 ± 0.46 0.78 Means ± SD are shown.
Table 9. Independent predictors for failure to achieve target LDL-C
at one year
OR 95% CI P
Moderate-dose statin 1.67 1.13-2.49 0.01 Age (for each 10-years
increase)
1.27 1.08-1.49 0.005
Sex female 1.97 1.30-2.97 0.001
Adjusted for: Sex, previous CAD, diabetes, smoking, age, moderate-dose statin, body mass index.
53
Figure 4. Flow-chart
1612 STEMI patients
639 (39.6%) with 1-year lipid profile
420 (65.7%) achieved 1-year target LDL-C 219 (34.3%) did not achieved 1- year target LDL-C 973 (60.4%) lost in follow-up, death, did not underwent
54
Figure 5. Statin dosage for all patients
Figure 5.1) High Dose Group
Figure 5.2) Moderate Dose Group
Rosuvastatin 20 Rosuvastatin 40 Atorvastatin 80 Simvastatin 80 28 (14.9%) 2 (0.1%) 125 (27.8%) 46 (10.2%) Rosuvastatin 10 Atorvastatin 10 Atorvastatin 20 Atorvastatin 40 Pravastatin 20 Pravastatin 40 Simvastatin 40 Rosuvastatin 5 2 (0.4%) 5 (1.1%) 17 (3.8%) 15 (3.3%)
55
References
1. Anderson TJ, Gregoire J, Pearson GJ et al. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular