BASIC/CLINICAL SCIENCE
Risk of Myocardial Infarction in Canadian Patients with Psoriasis: A Retrospective Cohort Study Annie Levesque, Jean Lachaine, and Robert Bissonnette Background: Studies have shown that psoriatic patients are at increased risk for myocardial infarction (MI) and stroke. There is a lack of data on MI risk in Canadian psoriatic patients. Objective: To compare MI risk in Canadian psoriatic patients to that in control patients. Methods: This was a retrospective cohort study using Quebec’s health insurance database (2005–2010) comparing MI risk in psoriatic patients to that in matched controls. Severe psoriasis was defined as any diagnosed psoriatic patient who used phototherapy or oral or injectable psoriasis treatments. Adjustments were made for several MI risk factors. Results: There were 31,421 patients in the psoriasis population, of which 5,159 had severe psoriasis. The unadjusted MI incidence rate per 1,000 person-years was 4.88 (95% confidence interval [95% CI] 4.50–5.20), 5.58 (95% CI 5.10–6.10), and 5.32 (95% CI 4.40–6.40) for the control and mild and severe psoriasis groups, respectively. After adjustments, the hazard ratio of MI was significantly higher for psoriatic patients than for controls (1.17; 95% CI 1.04–1.31). The hazard ratio was also significantly higher than for controls in the mild psoriasis group (1.18; 95% CI 1.05–1.33) but not in the severe psoriasis group (1.16; 95% CI 0.94–1.42). Conclusion: The relative MI risk is higher for Canadian psoriatic patients than for controls. Contexte: D’apre`s des e´tudes, les personnes souffrant de psoriasis connaissent un risque accru d’infarctus du myocarde (IM) et d’accident vasculaire ce´re´bral. Toutefois, il y a insuffisance de donne´es sur le risque d’IM chez ces personnes au Canada. Objectif: L’e´tude visait a` comparer le risque d’IM chez des personnes souffrant de psoriasis au Canada avec celui de te´moins. Me´thode: Il s’agit d’une e´tude de cohorte, re´trospective, reposant sur la base de donne´es du re´gime d’assurance maladie du Que´bec (2005–2010) et comparant le risque d’IM chez des personnes atteintes de psoriasis avec celui de te´moins apparie´s. Le psoriasis grave e´tait de´fini comme tout cas ave´re´ de la maladie, devant eˆtre traite´ par la photothe´rapie ou par un produit antipsoriasique oral ou injectable. Des rajustements ont e´te´ faits pour tenir compte de plusieurs facteurs de risque d’IM. Re´sultats: Le nombre de personnes atteintes de psoriasis s’e´levait a` 31 421, dont 5159 souffraient de psoriasis grave. Le taux d’incidence non rajuste´ d’IM e´tait respectivement de 4.88 (intervalle de confiance a` 95% [IC a` 95%]: 4.50–5.20), de 5.58 (IC a` 95%: 5.10–6.10) et de 5.32 (IC a` 95%: 4.40–6.40), pour 1000 personnes-anne´es, chez les te´moins, chez les patients atteints de psoriasis le´ger et chez les patients atteints de psoriasis grave. Apre`s rajustements, le rapport des risques instantane´s (RRI) d’IM e´tait sensiblement plus e´leve´ chez les personnes atteintes de psoriasis que chez les te´moins (1.17; IC a` 95%: 1.04–1.31). Quant au RRI, il e´tait significativement plus e´leve´ dans le groupe de psoriasis le´ger que dans le groupe te´moin (1.18; IC a` 95%: 1.05–1.33) mais pas dans le groupe de psoriasis grave (1.16; IC a` 95%: 0.94–1.42). Conclusion: Le risque relatif d’IM est plus e´leve´ chez les personnes souffrant de psoriasis que chez les te´moins, au Canada.
SORIASIS is a frequent disease with a reported prevalence as high as 3% in white populations.1 A number of studies have suggested that patients with psoriasis are at increased risk for myocardial infarction
P
From Innovaderm Research Inc., and PeriPharm Inc., Montreal, QC. Address reprint requests to: Robert Bissonnette, MD, FRCPC, 1851 Sherbrooke Street East, Suite 502, Montreal, QC H2K 4L5; e-mail: [email protected].
DOI 10.2310/7750.2013.13052 # 2013 Canadian Dermatology Association
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(MI) and stroke.2–6 Unfortunately, there is a lack of data on the risks of MI in Canadian patients with psoriasis. The objective of the current study was to compare the risk of MI for Canadian patients with psoriasis to that of Canadian patients without psoriasis.
Methods Study Design and Study Groups This was a retrospective cohort study conducted using the Re´gie de l’Assurance Maladie du Que´bec (RAMQ)
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database, the public health plan for the province of Quebec in Canada. Patients 20 years and older who were seen at least once for a diagnosis of psoriasis (International Classification of Diseases, Ninth Revision [ICD-9] codes 6961, 6968, and 6969) between 2005 and 2010 were analyzed in this study. A control group of patients matched (1:1) for age, sex, and period of data availability was created from a random list of 120,000 RAMQ patients, excluding patients with a diagnostic code of psoriasis. The follow-up period started at the first diagnosis of psoriasis for the psoriasis group and at the first visit regardless of the reason of the visit for the control group. The follow-up period ended when patients died, had an MI, or were no longer covered by the RAMQ plan (estimated on cessation of all services for at least 12 months), whichever came first. The severe psoriasis population was defined as any patient with a diagnosis of psoriasis who used one of the following treatments at any time during the period from 2005 to 2010: ultraviolet B (UVB) phototherapy, psoralen plus ultraviolet A (PUVA) therapy, methotrexate, cyclosporine, acitretin, alefacept, efalizumab, adalimumab, etanercept, infliximab, or ustekinumab. The mild psoriasis population was defined as any patient with a diagnosis of psoriasis who did not use the treatments previously stated.
Measurement of Covariates Patient exact age and date of birth are not recorded in the database to preserve patient anonymity. It is recorded using 19 categories (, 1, 1–4, 5–9, 10–14, …, 80–84, $ 85 yr). The age category for a given patient represents the patient’s age during the first year of the study (2005 in this case). The middle age of a category was used to calculate the mean age for a given population (eg, the age of every patient in the age category 20 to 24 years was set at 22 years). Patients were categorized as having diabetes (ICD-9 codes 2500 to 2509), hyperlipidemia (ICD-9 codes 2720 to 2729), and hypertension (ICD-9 codes 4010 to 4019) if they received an ICD-9 code consistent with these diagnoses between 2005 and 2010. Patients were classified to have a history of MI if they received a code of an old MI (ICD-9 codes 4120 to 4129) between 2005 and 2010, unless the old MI occurred after a new acute MI was experienced after the start date. The following systemic corticosteroids were considered: dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone. Patients who received corticosteroids were considered corticosteroid users if they used it for more than 21 days.
Outcome Patients were identified as having an acute MI if they received an ICD-9 code consistent with this diagnosis (from 4100 to 4109) after the start date and before the end date.
Statistical Analysis Demographic and clinical characteristics of study groups are presented as frequency and percentage for categorical values and as mean, median, and interquartile range for continuous values. Two-sided Fisher exact and Student ttests were used to test the association between the presence of psoriasis and various categorical and continuous covariates, respectively. The significance level was .05. The incidence rate of MI for patients with mild and severe psoriasis and for control patients per 1,000 patient-years was calculated and compared using 95% confidence intervals (95% CIs). The Cox proportional multivariate hazard model was used to compare the rate of MI in patients with psoriasis to that in patients without psoriasis. The model was adjusted for the MI risk factors (age, sex, history of MI, presence of diabetes, hypertension, and hyperlipidemia) and the use of systemic corticosteroids. All statistical analyses were performed using SPSS statistics version 19.0 (IBM Corp.).
Results A total of 31,421 patients with psoriasis were identified, with 5,159 classified as having severe psoriasis based on their use of systemic treatment (Table 1). The majority (62.3%) of severe psoriasis patients received phototherapy (Table 2). A control group of 31,421 matching patients with similar age, sex, and period of data availability was randomly created from the database. There was no significant difference in sex and age between control patients and patients with mild or severe psoriasis. The proportion of patients who had a previous MI was significantly higher for patients with mild and severe psoriasis compared to control patients (see Table 1). The proportion of patients with hyperlipidemia was significantly higher in patients with mild psoriasis compared to control patients, and a similar trend was observed in severe psoriasis patients (see Table 1). There were significantly more patients with diabetes in the severe psoriasis group than in the control group. Finally, the proportion of patients with hypertension was significantly lower in the mild psoriasis group than in the control group, and no
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Table 1. Characteristics of the Study Groups* Study Group Control (n 5 31,421)
Characteristic Sex, male, n (%) Age, yr Mean Median (IQR) Diabetes, yes (%) History of MI, yes (%) Hyperlipidemia, yes (%) Hypertension, yes (%)
14,638 (46.6) 52.83 52 (37–67) 5,083 (16.2) 137 (0.4) 4,153 (13.2) 11,337 (36.1)
p Value
Mild Psoriasis (n 5 26,262)
Severe Psoriasis (n 5 5,159)
12,167 (46.3)
2,471 (47.9)
.541
.081
52.65 52 (37–67) 973 (18.9) 37 (0.7) 729 (14.1) 1,891 (36.7)
.830
.537
.068 .001 .001 .001
, .001 .010 .077 .435
52.86 52 (37–67) 4,101 (15.6) 169 (0.6) 3,731 (14.2) 9,113 (34.7)
Mild Psoriasis vs Control
Severe Psoriasis vs Control
IQR 5 interquartile range; MI 5 myocardial infarction. *Data are presented as number (percentage) unless otherwise indicated.
significant difference was observed between the severe psoriasis and control groups. After adjustment for the various MI risk factors and the use of corticosteroids, patients with psoriasis had an increased relative risk of MI compared to control patients without psoriasis (1.17; 95% CI 1.04–1.31) (Table 3). The same analysis performed in patients with mild and severe psoriasis showed that the risk of MI was significantly increased in patients with mild psoriasis but not in patients with severe psoriasis, although the hazard ratio (1.16) for patients with severe psoriasis was close to the hazard ratio for patients with mild psoriasis (1.18). Multivariate analysis confirmed the previously known higher risk of MI in patients with diabetes, patients with hypertension, and those taking systemic corticosteroids (see Table 3). When the unadjusted incidence rate of MI was compared between groups, patients with mild or severe psoriasis had a numerically higher incidence of MI compared to control patients, but the difference did not reach statistical significance (Table 4). We performed a number of sensitivity analyses to validate our results (data not shown). Similar hazard ratios
of MI in patients with mild or severe psoriasis compared to control patients were also obtained when both the diagnosis and medication codes were used for the definition of the comorbidities, when only the last 4.5 years of data were used, when patients on methotrexate or biologics were excluded, when patients on acitretin or cyclosporine were excluded, or when the last visit or last prescription (latest of the two) was used to define the end of the follow-up period. All sensitivity analyses confirmed the higher risk of MI in patients with psoriasis.
Discussion The results from the current study show that the previously reported higher risk of MI in patients with psoriasis also applies to Canadian patients. The hazard ratio of having MI was significantly higher in patients with psoriasis than in those without psoriasis (1.17; 95% CI 1.04–1.31). A number of different groups reported on the risk of MI or occlusive cardiovascular events in nonCanadian patients using various methodologies. Although it is not possible to make direct comparisons between
Table 2. Systemic Therapies Received by Patients with Severe Psoriasis Systemic Therapy, n (%) Phototherapy (UVB phototherapy and PUVA therapy) Methotrexate Cyclosporine Acitretin Biologics
Severe Psoriasis (N 5 5,159) 3,213 1,603 233 834 506
(62.3) (31.1) (4.5) (16.2) (9.8)
PUVA 5 psoralen plus ultraviolet A; UVB 5 ultraviolet B. The number of patients and percentages do not add up to 5,159 and 100, respectively, because patients could have received more than one systemic therapy. For corticosteroids and biologics, the number of patients includes patients who received at least one corticosteroid or at least one biologic.
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Table 3. Multivariable Cox Proportional Hazard Regression Models of the Risk of MI in Patients with Mild and Severe Psoriasis Compared to Control Patients Model Hazard Ratio (95% CI) Covariate Age Diabetes History of MI Hyperlipidemia Hypertension Male sex Use of corticosteroids Psoriasis
Psoriasis (n 5 31,421) 1.57 1.71 2.32 0.81 1.24 1.81 1.32 1.17
Mild Psoriasis (n 5 26,262)
(1.51–1.63) (1.52–1.91) (1.66–3.25) (0.70–0.95) (1.11–1.40) (1.62–2.02) (1.02–1.69) (1.04–1.31)
1.56 1.66 2.40 0.80 1.28 1.83 1.47 1.18
(1.49–1.62) (1.48–1.87) (1.70–3.40) (0.68–0.94) (1.13–1.45) (1.64–2.05) (1.22–1.77) (1.05–1.33)
Severe Psoriasis (n 5 5,159) 1.52 1.66 2.36 0.82 1.22 1.80 1.38 1.16
(1.45–1.60) (1.44–1.91) (1.51–3.68) (0.68–1.00) (1.06–1.41) (1.57–2.06) (1.11–1.72) (0.94–1.42)
CI 5 confidence interval; MI 5 myocardial infarction.
studies, most publications reported hazard ratios that were in the same order of magnitude.2–5,7 MaraditKremers and colleagues reported that the hazard ratio for MI in patients with psoriasis compared to controls was 1.26 (95% CI 1.01–1.58).7 Ahlehoff and colleagues showed that the hazard ratio of recurrent MI, stroke, and cardiovascular death after a first event was 1.26 (95% CI 1.06–1.54) in patients with psoriasis compared to controls.2 Prodanovich and colleagues measured a hazard ratio of 1.91 (95% CI 1.64–2.24) of having ischemic heart disease, peripheral arterial disease, or cerebrovascular disease in patients with psoriasis compared to control
patients.4 Gelfand and colleagues observed a relative risk of MI of 1.54 (95% CI 1.24–1.91) in patients with mild psoriasis.3 The hazard ratio of MI observed for patients with severe psoriasis in this study (1.16; 95% CI 0.94– 1.42) is lower than what Gelfand and colleagues reported (7.08; 95% CI 3.06–16.36) and more in the range of what was observed by Mehta and colleagues (1.57; 95% CI 1.26–1.96).3,5 However, the hazard ratios reported by Gelfand and colleagues are not directly interpretable as the effect was age dependent. The incidence rate of MI for patients with mild psoriasis was numerically higher than that for control
Table 4. Incidence of MI in Patients with Psoriasis Compared to Control Patients Study Group Variable Follow-up time, yr Mean (SD) Median (IQR) Number of person-years Number of new MI cases (%) Incidence of MI per 1,000 personyears (95% CI), unadjusted Incidence of MI per 1,000 personyears, according to age (95% CI), unadjusted 20–29 yr 30–39 yr 40–49 yr 50–59 yr 60–69 yr 70–79 yr 80+ yr
Control (n 5 31,421) 5.20 5.78 163,254.62 796 4.88
0.09 0.76 3.02 4.15 7.69 8.71 12.24
(1.36) (5.21–5.94) (2.5) (4.50–5.20)
(0.00–0.30) (0.50–1.20) (2.40–3.80) (3.50–4.90) (6.60–8.90) (7.70–9.80) (10.40–14.40)
Mild Psoriasis (n 5 26,262) 3.19 3.32 83,904.12 468 5.58
0.08 0.45 2.97 4.68 8.14 10.26 20.48
(1.78) (1.67–4.76) (1.8) (5.10–6.10)
(0.00–0.40) (0.20–1.00) (2.20–4.10) (3.70–5.80) (6.60–10.10) (8.80–12.00) (17.00–24.60)
Severe Psoriasis (n 5 5,159) 4.01 4.49 20,682.29 110 5.32
0.00 0.00 3.19 5.25 7.53 12.62 14.34
(1.79) (2.67–5.66) (2.1) (4.40–6.40)
(0.00–0.00) (0.00–0.00) (1.80–5.60) (3.60–7.70) (4.90–11.60) (9.30–17.10) (8.00–25.50)
CI 5 confidence interval; IQR 5 interquartile range; MI 5 myocardial infarction.
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patients, but this difference was not statistically significant based on overlapping confidence intervals. The difference in the incidence rate of MI for mild psoriasis (5.58; 95% CI 5.10–6.10) and control (4.88; 95% CI 4.50–5.20) patients is the same order of magnitude as what was previously reported by Gelfand and colleagues (mild psoriasis: 4.04 [95% CI 3.88-4.21]; control: 3.58 [95% CI 3.52–3.65]), who observed a statistically significant difference between patients with mild psoriasis and controls.3 The absence of a statistically significant difference between the two groups in the current study may be related to larger 95% CIs due to identification of one control for each psoriasis patient as opposed to up to five controls by Gelfand and colleagues and the smaller number of patients with mild psoriasis identified in the current publication. The incidence rate of MI for patients with mild and severe psoriasis was in the same order of magnitude and not statistically different. In contrast, Gelfand and colleagues found that patients with severe psoriasis had a higher incidence rate of MI.3 In the current study, severe psoriasis was defined as patients with a diagnosis of psoriasis who used either a systemic agent or phototherapy. We performed a sensitivity analysis with patients with a diagnosis of psoriasis and use of systemic therapy (excluding phototherapy) to define severe patients, and the same conclusion was reached (data no shown). Interestingly, a recent study showed that patients using systemic treatments for psoriasis were at decreased risk for MI compared to patients treated with a topical agent.8 Abuabara and colleagues compared the risk of MI in patients receiving systemic therapy or phototherapy to patients receiving topical treatments and did not find a difference in the risk of MI between the two groups.9 Possible reasons to explain the difference between our results and the results from Wu and colleagues and what Gelfand and colleagues observed may include differences in the systemic treatments used. Some of our patients were on biologics, which were not used for psoriasis between 1987 and 2002, the time period analyzed by Gelfand and colleagues.3 In addition, a number of patients from Gelfand and colleagues’ study were on azathioprine, hydroxyurea, and PUVA, which are seldom used nowadays to treat psoriasis. The dose of systemic treatments used, especially if they have a positive or negative impact on the risk of MI, is also important, and this information is usually lacking from databases. In the current study, about 73% of patients on systemic medications (excluding phototherapy) were on methotrexate and/or tumor necrosis factor (TNF)-a 402
antagonists compared to only 59% who were on methotrexate in the Gelfand and colleagues study.3 Both TNF-a antagonists and methotrexate have been associated with a lower risk of MI in patients with rheumatoid arthritis and/or psoriasis.8,10–12 The high use (and possibly difference in dose used) of methotrexate and/or TNF-a antagonist in the current study and the study performed by Wu and colleagues8 may explain the absence of a higher risk of MI in patients treated with systemic therapies. The limitations of our study include the fact that the analysis was limited to Quebec patients and the absence of information in RAMQ database on some other wellknown risk factors for psoriasis, such as smoking and body mass index. The definition of psoriasis severity based on the treatment used instead of actual measurement is also a limitation, but other larger studies performed with a health care database also suffer from the same limitation. In addition, the relatively small sample size, with only 5,159 patients in the severe psoriasis group, is a limitation that could explain the absence of significant difference in hypertension and hyperlipidemia between patients with severe psoriasis and controls. Other similar studies should be conducted in other Canadian provinces to see if our findings are also applicable to patients living outside the province of Quebec.
Conclusion Canadian patients with psoriasis are at increased risk for MI. Additional studies are needed on the generalizability of our results to the entire Canadian population and on the effect of methotrexate and TNF-a antagonists on the risks of MI.
Acknowledgments We would like to thank Marie-Eve Lapierre for her assistance with the extensive data analysis. Financial disclosure of authors: This study was funded by an investigator grant from Amgen Canada Inc. Jean Lachaine has received research grants from Abbott Laboratories/ AbbVie, Pfizer, and Novartis. Robert Bissonnette has been an investigator, advisory board member, consultant, and/or speaker and has received grants and/or honoraria from AbbVie, Amgen, Novartis, Janssen, Pfizer, Tribute, Eli Lilly, Merck, Astellas, and/or Incyte. Annie Levesque has no conflicts of interest to declare. Financial disclosure of reviewers: None reported.
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References 1. Schon MP, Boehncke WH. Psoriasis. N Engl J Med 2005;352:1899– 912, doi:10.1056/NEJMra041320. 2. Ahlehoff O, Gislason GH, Lindhardsen J, et al. Prognosis following first-time myocardial infarction in patients with psoriasis: a Danish nationwide cohort study. J Intern Med 2011;270:237–44, doi:10.1111/j.1365-2796.2011.02368.x. 3. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA 2006;296:1735–41, doi:10.1001/jama.296.14.1735. 4. Prodanovich S, Kirsner RS, Kravetz JD, et al. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch Dermatol 2009;145:700–3, doi:10.1001/archdermatol.2009.94. 5. Mehta NN, Azfar RS, Shin DB, et al. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database. Eur Heart J 2010;31:1000– 6, doi:10.1093/eurheartj/ehp567. 6. Gelfand JM, Dommasch ED, Shin DB, et al. The risk of stroke in patients with psoriasis. J Invest Dermatol 2009;129:2411–8, doi:10.1038/jid.2009.112. 7. Maradit-Kremers H, Dierkhising RA, Crowson CS, et al. Risk and predictors of cardiovascular disease in psoriasis: a population-based
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study. Int J Dermatol 2013;52:32–40, doi:10.1111/j.1365-4632. 2011.05430.x. Wu JJ, Poon KY, Channual JC, et al. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol 2012;148:1244–50, doi:10.1001/archdermatol.2012.2502. Abuabara K, Lee H, Kimball AB. The effect of systemic psoriasis therapies on the incidence of myocardial infarction: a cohort study. Br J Dermatol 2011;165:1066–73, doi:10.1111/j.1365-2133.2011. 10525.x. Jacobsson LT, Turesson C, Gulfe A, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol 2005;32:1213–8. Greenberg JD, Kremer JM, Curtis JR, et al. Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis. Ann Rheum Dis 2011;70:576–82, doi:10.1136/ard.2010.129916. Dixon WG, Watson KD, Lunt M, et al. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2007;56:2905–12, doi:10. 1002/art.22809.
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Risk of Myocardial Infarction in Canadian Patients with Psoriasis: A Retrospective Cohort Study Annie Levesque, Jean Lachaine, and Robert Bissonnette Background: Studies have shown that psoriatic patients are at increased risk for myocardial infarction (MI) and stroke. There is a lack of data on MI risk in Canadian psoriatic patients. Objective: To compare MI risk in Canadian psoriatic patients to that in control patients. Methods: This was a retrospective cohort study using Quebec’s health insurance database (2005–2010) comparing MI risk in psoriatic patients to that in matched controls. Severe psoriasis was defined as any diagnosed psoriatic patient who used phototherapy or oral or injectable psoriasis treatments. Adjustments were made for several MI risk factors. Results: There were 31,421 patients in the psoriasis population, of which 5,159 had severe psoriasis. The unadjusted MI incidence rate per 1,000 person-years was 4.88 (95% confidence interval [95% CI] 4.50–5.20), 5.58 (95% CI 5.10–6.10), and 5.32 (95% CI 4.40–6.40) for the control and mild and severe psoriasis groups, respectively. After adjustments, the hazard ratio of MI was significantly higher for psoriatic patients than for controls (1.17; 95% CI 1.04–1.31). The hazard ratio was also significantly higher than for controls in the mild psoriasis group (1.18; 95% CI 1.05–1.33) but not in the severe psoriasis group (1.16; 95% CI 0.94–1.42). Conclusion: The relative MI risk is higher for Canadian psoriatic patients than for controls. Contexte: D’apre`s des e´tudes, les personnes souffrant de psoriasis connaissent un risque accru d’infarctus du myocarde (IM) et d’accident vasculaire ce´re´bral. Toutefois, il y a insuffisance de donne´es sur le risque d’IM chez ces personnes au Canada. Objectif: L’e´tude visait a` comparer le risque d’IM chez des personnes souffrant de psoriasis au Canada avec celui de te´moins. Me´thode: Il s’agit d’une e´tude de cohorte, re´trospective, reposant sur la base de donne´es du re´gime d’assurance maladie du Que´bec (2005–2010) et comparant le risque d’IM chez des personnes atteintes de psoriasis avec celui de te´moins apparie´s. Le psoriasis grave e´tait de´fini comme tout cas ave´re´ de la maladie, devant eˆtre traite´ par la photothe´rapie ou par un produit antipsoriasique oral ou injectable. Des rajustements ont e´te´ faits pour tenir compte de plusieurs facteurs de risque d’IM. Re´sultats: Le nombre de personnes atteintes de psoriasis s’e´levait a` 31 421, dont 5159 souffraient de psoriasis grave. Le taux d’incidence non rajuste´ d’IM e´tait respectivement de 4.88 (intervalle de confiance a` 95% [IC a` 95%]: 4.50–5.20), de 5.58 (IC a` 95%: 5.10–6.10) et de 5.32 (IC a` 95%: 4.40–6.40), pour 1000 personnes-anne´es, chez les te´moins, chez les patients atteints de psoriasis le´ger et chez les patients atteints de psoriasis grave. Apre`s rajustements, le rapport des risques instantane´s (RRI) d’IM e´tait sensiblement plus e´leve´ chez les personnes atteintes de psoriasis que chez les te´moins (1.17; IC a` 95%: 1.04–1.31). Quant au RRI, il e´tait significativement plus e´leve´ dans le groupe de psoriasis le´ger que dans le groupe te´moin (1.18; IC a` 95%: 1.05–1.33) mais pas dans le groupe de psoriasis grave (1.16; IC a` 95%: 0.94–1.42). Conclusion: Le risque relatif d’IM est plus e´leve´ chez les personnes souffrant de psoriasis que chez les te´moins, au Canada.
SORIASIS is a frequent disease with a reported prevalence as high as 3% in white populations.1 A number of studies have suggested that patients with psoriasis are at increased risk for myocardial infarction
P
From Innovaderm Research Inc., and PeriPharm Inc., Montreal, QC. Address reprint requests to: Robert Bissonnette, MD, FRCPC, 1851 Sherbrooke Street East, Suite 502, Montreal, QC H2K 4L5; e-mail: [email protected].
DOI 10.2310/7750.2013.13052 # 2013 Canadian Dermatology Association
398
(MI) and stroke.2–6 Unfortunately, there is a lack of data on the risks of MI in Canadian patients with psoriasis. The objective of the current study was to compare the risk of MI for Canadian patients with psoriasis to that of Canadian patients without psoriasis.
Methods Study Design and Study Groups This was a retrospective cohort study conducted using the Re´gie de l’Assurance Maladie du Que´bec (RAMQ)
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 398–403
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database, the public health plan for the province of Quebec in Canada. Patients 20 years and older who were seen at least once for a diagnosis of psoriasis (International Classification of Diseases, Ninth Revision [ICD-9] codes 6961, 6968, and 6969) between 2005 and 2010 were analyzed in this study. A control group of patients matched (1:1) for age, sex, and period of data availability was created from a random list of 120,000 RAMQ patients, excluding patients with a diagnostic code of psoriasis. The follow-up period started at the first diagnosis of psoriasis for the psoriasis group and at the first visit regardless of the reason of the visit for the control group. The follow-up period ended when patients died, had an MI, or were no longer covered by the RAMQ plan (estimated on cessation of all services for at least 12 months), whichever came first. The severe psoriasis population was defined as any patient with a diagnosis of psoriasis who used one of the following treatments at any time during the period from 2005 to 2010: ultraviolet B (UVB) phototherapy, psoralen plus ultraviolet A (PUVA) therapy, methotrexate, cyclosporine, acitretin, alefacept, efalizumab, adalimumab, etanercept, infliximab, or ustekinumab. The mild psoriasis population was defined as any patient with a diagnosis of psoriasis who did not use the treatments previously stated.
Measurement of Covariates Patient exact age and date of birth are not recorded in the database to preserve patient anonymity. It is recorded using 19 categories (, 1, 1–4, 5–9, 10–14, …, 80–84, $ 85 yr). The age category for a given patient represents the patient’s age during the first year of the study (2005 in this case). The middle age of a category was used to calculate the mean age for a given population (eg, the age of every patient in the age category 20 to 24 years was set at 22 years). Patients were categorized as having diabetes (ICD-9 codes 2500 to 2509), hyperlipidemia (ICD-9 codes 2720 to 2729), and hypertension (ICD-9 codes 4010 to 4019) if they received an ICD-9 code consistent with these diagnoses between 2005 and 2010. Patients were classified to have a history of MI if they received a code of an old MI (ICD-9 codes 4120 to 4129) between 2005 and 2010, unless the old MI occurred after a new acute MI was experienced after the start date. The following systemic corticosteroids were considered: dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone. Patients who received corticosteroids were considered corticosteroid users if they used it for more than 21 days.
Outcome Patients were identified as having an acute MI if they received an ICD-9 code consistent with this diagnosis (from 4100 to 4109) after the start date and before the end date.
Statistical Analysis Demographic and clinical characteristics of study groups are presented as frequency and percentage for categorical values and as mean, median, and interquartile range for continuous values. Two-sided Fisher exact and Student ttests were used to test the association between the presence of psoriasis and various categorical and continuous covariates, respectively. The significance level was .05. The incidence rate of MI for patients with mild and severe psoriasis and for control patients per 1,000 patient-years was calculated and compared using 95% confidence intervals (95% CIs). The Cox proportional multivariate hazard model was used to compare the rate of MI in patients with psoriasis to that in patients without psoriasis. The model was adjusted for the MI risk factors (age, sex, history of MI, presence of diabetes, hypertension, and hyperlipidemia) and the use of systemic corticosteroids. All statistical analyses were performed using SPSS statistics version 19.0 (IBM Corp.).
Results A total of 31,421 patients with psoriasis were identified, with 5,159 classified as having severe psoriasis based on their use of systemic treatment (Table 1). The majority (62.3%) of severe psoriasis patients received phototherapy (Table 2). A control group of 31,421 matching patients with similar age, sex, and period of data availability was randomly created from the database. There was no significant difference in sex and age between control patients and patients with mild or severe psoriasis. The proportion of patients who had a previous MI was significantly higher for patients with mild and severe psoriasis compared to control patients (see Table 1). The proportion of patients with hyperlipidemia was significantly higher in patients with mild psoriasis compared to control patients, and a similar trend was observed in severe psoriasis patients (see Table 1). There were significantly more patients with diabetes in the severe psoriasis group than in the control group. Finally, the proportion of patients with hypertension was significantly lower in the mild psoriasis group than in the control group, and no
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Table 1. Characteristics of the Study Groups* Study Group Control (n 5 31,421)
Characteristic Sex, male, n (%) Age, yr Mean Median (IQR) Diabetes, yes (%) History of MI, yes (%) Hyperlipidemia, yes (%) Hypertension, yes (%)
14,638 (46.6) 52.83 52 (37–67) 5,083 (16.2) 137 (0.4) 4,153 (13.2) 11,337 (36.1)
p Value
Mild Psoriasis (n 5 26,262)
Severe Psoriasis (n 5 5,159)
12,167 (46.3)
2,471 (47.9)
.541
.081
52.65 52 (37–67) 973 (18.9) 37 (0.7) 729 (14.1) 1,891 (36.7)
.830
.537
.068 .001 .001 .001
, .001 .010 .077 .435
52.86 52 (37–67) 4,101 (15.6) 169 (0.6) 3,731 (14.2) 9,113 (34.7)
Mild Psoriasis vs Control
Severe Psoriasis vs Control
IQR 5 interquartile range; MI 5 myocardial infarction. *Data are presented as number (percentage) unless otherwise indicated.
significant difference was observed between the severe psoriasis and control groups. After adjustment for the various MI risk factors and the use of corticosteroids, patients with psoriasis had an increased relative risk of MI compared to control patients without psoriasis (1.17; 95% CI 1.04–1.31) (Table 3). The same analysis performed in patients with mild and severe psoriasis showed that the risk of MI was significantly increased in patients with mild psoriasis but not in patients with severe psoriasis, although the hazard ratio (1.16) for patients with severe psoriasis was close to the hazard ratio for patients with mild psoriasis (1.18). Multivariate analysis confirmed the previously known higher risk of MI in patients with diabetes, patients with hypertension, and those taking systemic corticosteroids (see Table 3). When the unadjusted incidence rate of MI was compared between groups, patients with mild or severe psoriasis had a numerically higher incidence of MI compared to control patients, but the difference did not reach statistical significance (Table 4). We performed a number of sensitivity analyses to validate our results (data not shown). Similar hazard ratios
of MI in patients with mild or severe psoriasis compared to control patients were also obtained when both the diagnosis and medication codes were used for the definition of the comorbidities, when only the last 4.5 years of data were used, when patients on methotrexate or biologics were excluded, when patients on acitretin or cyclosporine were excluded, or when the last visit or last prescription (latest of the two) was used to define the end of the follow-up period. All sensitivity analyses confirmed the higher risk of MI in patients with psoriasis.
Discussion The results from the current study show that the previously reported higher risk of MI in patients with psoriasis also applies to Canadian patients. The hazard ratio of having MI was significantly higher in patients with psoriasis than in those without psoriasis (1.17; 95% CI 1.04–1.31). A number of different groups reported on the risk of MI or occlusive cardiovascular events in nonCanadian patients using various methodologies. Although it is not possible to make direct comparisons between
Table 2. Systemic Therapies Received by Patients with Severe Psoriasis Systemic Therapy, n (%) Phototherapy (UVB phototherapy and PUVA therapy) Methotrexate Cyclosporine Acitretin Biologics
Severe Psoriasis (N 5 5,159) 3,213 1,603 233 834 506
(62.3) (31.1) (4.5) (16.2) (9.8)
PUVA 5 psoralen plus ultraviolet A; UVB 5 ultraviolet B. The number of patients and percentages do not add up to 5,159 and 100, respectively, because patients could have received more than one systemic therapy. For corticosteroids and biologics, the number of patients includes patients who received at least one corticosteroid or at least one biologic.
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Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 398–403
Myocardial Infarction Risk in Psoriatic Patients
Table 3. Multivariable Cox Proportional Hazard Regression Models of the Risk of MI in Patients with Mild and Severe Psoriasis Compared to Control Patients Model Hazard Ratio (95% CI) Covariate Age Diabetes History of MI Hyperlipidemia Hypertension Male sex Use of corticosteroids Psoriasis
Psoriasis (n 5 31,421) 1.57 1.71 2.32 0.81 1.24 1.81 1.32 1.17
Mild Psoriasis (n 5 26,262)
(1.51–1.63) (1.52–1.91) (1.66–3.25) (0.70–0.95) (1.11–1.40) (1.62–2.02) (1.02–1.69) (1.04–1.31)
1.56 1.66 2.40 0.80 1.28 1.83 1.47 1.18
(1.49–1.62) (1.48–1.87) (1.70–3.40) (0.68–0.94) (1.13–1.45) (1.64–2.05) (1.22–1.77) (1.05–1.33)
Severe Psoriasis (n 5 5,159) 1.52 1.66 2.36 0.82 1.22 1.80 1.38 1.16
(1.45–1.60) (1.44–1.91) (1.51–3.68) (0.68–1.00) (1.06–1.41) (1.57–2.06) (1.11–1.72) (0.94–1.42)
CI 5 confidence interval; MI 5 myocardial infarction.
studies, most publications reported hazard ratios that were in the same order of magnitude.2–5,7 MaraditKremers and colleagues reported that the hazard ratio for MI in patients with psoriasis compared to controls was 1.26 (95% CI 1.01–1.58).7 Ahlehoff and colleagues showed that the hazard ratio of recurrent MI, stroke, and cardiovascular death after a first event was 1.26 (95% CI 1.06–1.54) in patients with psoriasis compared to controls.2 Prodanovich and colleagues measured a hazard ratio of 1.91 (95% CI 1.64–2.24) of having ischemic heart disease, peripheral arterial disease, or cerebrovascular disease in patients with psoriasis compared to control
patients.4 Gelfand and colleagues observed a relative risk of MI of 1.54 (95% CI 1.24–1.91) in patients with mild psoriasis.3 The hazard ratio of MI observed for patients with severe psoriasis in this study (1.16; 95% CI 0.94– 1.42) is lower than what Gelfand and colleagues reported (7.08; 95% CI 3.06–16.36) and more in the range of what was observed by Mehta and colleagues (1.57; 95% CI 1.26–1.96).3,5 However, the hazard ratios reported by Gelfand and colleagues are not directly interpretable as the effect was age dependent. The incidence rate of MI for patients with mild psoriasis was numerically higher than that for control
Table 4. Incidence of MI in Patients with Psoriasis Compared to Control Patients Study Group Variable Follow-up time, yr Mean (SD) Median (IQR) Number of person-years Number of new MI cases (%) Incidence of MI per 1,000 personyears (95% CI), unadjusted Incidence of MI per 1,000 personyears, according to age (95% CI), unadjusted 20–29 yr 30–39 yr 40–49 yr 50–59 yr 60–69 yr 70–79 yr 80+ yr
Control (n 5 31,421) 5.20 5.78 163,254.62 796 4.88
0.09 0.76 3.02 4.15 7.69 8.71 12.24
(1.36) (5.21–5.94) (2.5) (4.50–5.20)
(0.00–0.30) (0.50–1.20) (2.40–3.80) (3.50–4.90) (6.60–8.90) (7.70–9.80) (10.40–14.40)
Mild Psoriasis (n 5 26,262) 3.19 3.32 83,904.12 468 5.58
0.08 0.45 2.97 4.68 8.14 10.26 20.48
(1.78) (1.67–4.76) (1.8) (5.10–6.10)
(0.00–0.40) (0.20–1.00) (2.20–4.10) (3.70–5.80) (6.60–10.10) (8.80–12.00) (17.00–24.60)
Severe Psoriasis (n 5 5,159) 4.01 4.49 20,682.29 110 5.32
0.00 0.00 3.19 5.25 7.53 12.62 14.34
(1.79) (2.67–5.66) (2.1) (4.40–6.40)
(0.00–0.00) (0.00–0.00) (1.80–5.60) (3.60–7.70) (4.90–11.60) (9.30–17.10) (8.00–25.50)
CI 5 confidence interval; IQR 5 interquartile range; MI 5 myocardial infarction.
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patients, but this difference was not statistically significant based on overlapping confidence intervals. The difference in the incidence rate of MI for mild psoriasis (5.58; 95% CI 5.10–6.10) and control (4.88; 95% CI 4.50–5.20) patients is the same order of magnitude as what was previously reported by Gelfand and colleagues (mild psoriasis: 4.04 [95% CI 3.88-4.21]; control: 3.58 [95% CI 3.52–3.65]), who observed a statistically significant difference between patients with mild psoriasis and controls.3 The absence of a statistically significant difference between the two groups in the current study may be related to larger 95% CIs due to identification of one control for each psoriasis patient as opposed to up to five controls by Gelfand and colleagues and the smaller number of patients with mild psoriasis identified in the current publication. The incidence rate of MI for patients with mild and severe psoriasis was in the same order of magnitude and not statistically different. In contrast, Gelfand and colleagues found that patients with severe psoriasis had a higher incidence rate of MI.3 In the current study, severe psoriasis was defined as patients with a diagnosis of psoriasis who used either a systemic agent or phototherapy. We performed a sensitivity analysis with patients with a diagnosis of psoriasis and use of systemic therapy (excluding phototherapy) to define severe patients, and the same conclusion was reached (data no shown). Interestingly, a recent study showed that patients using systemic treatments for psoriasis were at decreased risk for MI compared to patients treated with a topical agent.8 Abuabara and colleagues compared the risk of MI in patients receiving systemic therapy or phototherapy to patients receiving topical treatments and did not find a difference in the risk of MI between the two groups.9 Possible reasons to explain the difference between our results and the results from Wu and colleagues and what Gelfand and colleagues observed may include differences in the systemic treatments used. Some of our patients were on biologics, which were not used for psoriasis between 1987 and 2002, the time period analyzed by Gelfand and colleagues.3 In addition, a number of patients from Gelfand and colleagues’ study were on azathioprine, hydroxyurea, and PUVA, which are seldom used nowadays to treat psoriasis. The dose of systemic treatments used, especially if they have a positive or negative impact on the risk of MI, is also important, and this information is usually lacking from databases. In the current study, about 73% of patients on systemic medications (excluding phototherapy) were on methotrexate and/or tumor necrosis factor (TNF)-a 402
antagonists compared to only 59% who were on methotrexate in the Gelfand and colleagues study.3 Both TNF-a antagonists and methotrexate have been associated with a lower risk of MI in patients with rheumatoid arthritis and/or psoriasis.8,10–12 The high use (and possibly difference in dose used) of methotrexate and/or TNF-a antagonist in the current study and the study performed by Wu and colleagues8 may explain the absence of a higher risk of MI in patients treated with systemic therapies. The limitations of our study include the fact that the analysis was limited to Quebec patients and the absence of information in RAMQ database on some other wellknown risk factors for psoriasis, such as smoking and body mass index. The definition of psoriasis severity based on the treatment used instead of actual measurement is also a limitation, but other larger studies performed with a health care database also suffer from the same limitation. In addition, the relatively small sample size, with only 5,159 patients in the severe psoriasis group, is a limitation that could explain the absence of significant difference in hypertension and hyperlipidemia between patients with severe psoriasis and controls. Other similar studies should be conducted in other Canadian provinces to see if our findings are also applicable to patients living outside the province of Quebec.
Conclusion Canadian patients with psoriasis are at increased risk for MI. Additional studies are needed on the generalizability of our results to the entire Canadian population and on the effect of methotrexate and TNF-a antagonists on the risks of MI.
Acknowledgments We would like to thank Marie-Eve Lapierre for her assistance with the extensive data analysis. Financial disclosure of authors: This study was funded by an investigator grant from Amgen Canada Inc. Jean Lachaine has received research grants from Abbott Laboratories/ AbbVie, Pfizer, and Novartis. Robert Bissonnette has been an investigator, advisory board member, consultant, and/or speaker and has received grants and/or honoraria from AbbVie, Amgen, Novartis, Janssen, Pfizer, Tribute, Eli Lilly, Merck, Astellas, and/or Incyte. Annie Levesque has no conflicts of interest to declare. Financial disclosure of reviewers: None reported.
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Myocardial Infarction Risk in Psoriatic Patients
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