Clinical trials studying the efficacy of n-3 polyunsaturated fatty acids (PUFA) in reducing adverse events after acute myocardial infarction (AMI) have yielded conflicting results, and data regarding the influence of n-3 PUFA treatment after AMI in routine clinical practice are scarce. We conducted a retrospective observational cohort study including patients from 5 Italian Local Health Units who were discharged from the hospital with a primary diagnosis of AMI from January 1, 2010, to December 31, 2011. Using unique patient identifiers, patients were linked across governmental hospital discharge, medication prescription, and mortality databases and followed for 12-months post-index discharge. Patient characteristics and risk of all-cause mortality and repeat AMI were compared by n-3 PUFA prescription after discharge (for outcome analyses, defined as ≥2 prescriptions) at a presumed dose of 1 g/day. Overall, 11,269 patients met inclusion criteria, of which 2,425 patients (21.5%) were prescribed n-3 PUFA during follow-up. Patients treated with n-3 PUFA tended to be younger, men, and carry a diagnosis of diabetes and were more likely to be receiving guideline-recommended post-AMI medical therapy, including β blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, statins, and antiplatelet therapy (all p <0.001). After adjusting for patient characteristics and concurrent therapies, n-3 PUFA treatment was associated with reduced all-cause mortality (hazard ratio 0.76, 95% CI 0.59 to 0.97) and recurrent AMI (hazard ratio 0.65, 95% CI 0.49 to 0.87) through 12-month follow-up. In conclusion, in this large, contemporary, observational study of “real-world” Italian patients hospitalized for AMI, the use of n-3 PUFA was independently associated with a robust reduction in all-cause mortality and recurrent AMI. These data support further randomized controlled trials with n-3 PUFA therapy in the post-AMI setting.
Conflicting data exist regarding the protective role of n-3 polyunsaturated fatty acids (PUFA) after acute myocardial infarction (AMI). The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione trial showed that oral administration of 1 g of n-3 PUFA daily decreased the risk of death, nonfatal AMI, and stroke in patients surviving recent AMI. Subsequent randomized trials failed to demonstrate clinical benefit with post-AMI n-3 PUFA use. Nevertheless, the neutral results of n-3 PUFA outcome trials published after GISSI-Prevenzione may not be generalizable to “real-world” practice where uptake of guideline-recommended practices is generally lower than in clinical trials. For example, a sizable proportion of patients with AMI, particularly those with non–ST-segment elevation myocardial infarction (NSTEMI) and who are elderly or with co-morbidities such as renal dysfunction may not undergo PCI. Additionally, adherence with postdischarge medications after AMI may be low and can negatively impact clinical outcomes. Furthermore, existing outcome trial data must now be viewed in the context of the recently presented Effect of Purified Omega-3 Fatty Acids on Reducing Left Ventricular Remodeling after Acute Myocardial Infarction (OMEGA-REMODEL) study, where administration of high-dose n-3 PUFA early after AMI demonstrated significant improvements in left ventricular remodeling and systemic inflammation, compared with placebo. In this context, a reappraisal of n-3 PUFA efficacy is warranted. The goal of the present study was to determine the influence of n-3 PUFA prescription on postdischarge outcomes in a large, “real-world,” contemporary cohort of patients with AMI.
Methods
This was a retrospective cohort-based integrated analysis of administrative databases maintained by 5 Italian Local Health Units (LHUs) located in the regions of Lombardy, Friuli-Venezia Giulia, Lazio, Campania, and Sicily with a combined population of approximately 4.3 million. Each LHU Ethics Committee approved the present study. Using the hospital discharge database, which includes dates of hospital admission and discharge and discharge diagnoses codes according to the International Classification of Diseases Ninth Revision (ICD-9) classification, patients discharged from the hospital from January 1, 2010, to December 31, 2011, with primary diagnosis of AMI (ICD-9 410) were identified. The date of the index hospital discharge was defined as baseline. The follow-up period extended to 12 months after discharge. Patients who moved to other LHUs during follow-up were excluded. The hospital discharge database was used to assess the history of previous cardiovascular hospitalization, location of the index AMI (i.e., anterior/anterolateral or not), receipt of percutaneous coronary intervention (PCI) during index hospitalization (ICD-9 codes 36.0x, excluding 36.04), and subsequent rehospitalization during follow-up.
Using the numeric code released to each citizen by the LHUs as a unique patient identifier, the hospital discharge database was linked to the following databases: (1) Medications Prescription Database, from which data (according to anatomical-therapeutic-chemical [ATC] codes) regarding postdischarge use of n-3 PUFA, β blockers, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs), antiplatelet agents, statins, diabetic medications, and hypertension medications were collected. Data regarding the use of medications for diabetes and hypertension were collected as surrogates for a history of diabetes and hypertension, respectively, (2) mortality database, from which data on mortality, but not cause of death, were collected, and (3) beneficiaries’ database, from which data regarding date of birth, gender, and place of residence were collected.
The prespecified coprimary end points were the rates of all-cause mortality (ACM) and repeat AMI at 12-month follow-up. Cosecondary end points included the rates of ACM and repeat AMI at 6-month follow-up. Repeat AMI was defined as the first subsequent hospital admission with discharge diagnosis of AMI.
For descriptive purposes, patients were counted as treated with n-3 PUFA, β blockers, ACEIs/ARBs, antiplatelet agents, or statins if they were given ≥1 prescription of the medication during the 12-month follow-up and as receiving medication for diabetes or hypertension if they were given ≥2 prescriptions of the respective medication during follow-up. For purposes of survival models and outcome analyses, patients were counted as treated with n-3 PUFA and all other medications if they received ≥2 prescriptions of the drug during the 12-month follow-up. With regard to n-3 PUFA dosing, in Italy, only name brand n-3 PUFA is routinely available and reimbursed by the national health system. Thus, the daily dose of n-3 PUFA presumed in this study is 1 g/day (containing 850 to 882 mg of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl esters in an average ratio of 1:2), the same dosage studied in GISSI-Prevenzione.
Medications for hypertension were defined as antihypertensives (ATC C02), diuretics (ATC C03), or calcium channel blockers (ATC C08). A previous history of cardiovascular hospitalization was defined as hospitalization during the 12 months prior to baseline for ischemic heart disease (ICD-9 410 to 414), peripheral arterial disease (ICD-9 443), heart failure (ICD-9 428), heart dysfunction (ICD-9 429), and chronic kidney failure (ICD-9 585). Heart disease was defined as receipt of ≥2 prescriptions for cardiac drugs (ATC C01) during follow-up, including vasodilators, cardiac glycosides, antiarrhythmics, or other.
All data were summarized as mean ± SD for continuous variables and numbers (percentages) for categorical variables. The primary predictor of the present study was treatment with n-3 PUFA. For descriptive purposes, patient characteristics of those receiving and not receiving n-3 PUFA were compared using Pearson’s chi-squared tests.
Using the medications prescriptions database, exploratory analyses to estimate postdischarge adherence to n-3 PUFA treatment were performed by determining the percentage of days from baseline to 12 months (or death) for which the patient had tablets available, that is, total number of days’ supply of medication dispensed during follow-up divided by total number of follow-up days. Adherence rates were stratified as ≤40%, >40% and ≤80%, and >80%.
Cox proportional hazards models were constructed to estimate the association between follow-up n-3 PUFA treatment and the primary and secondary end points. All models were adjusted for prespecified covariates including age, gender, previous cardiovascular hospitalization, medication for diabetes, medication for hypertension, heart disease, the presence of anterior/anterolateral AMI, PCI during index hospitalization, and follow-up treatment with ACEIs/ARBs, β blockers, statins, and antiplatelet agents (single therapy, dual therapy, ≥3 antiplatelets). Effect sizes were reported as hazard ratios (HRs) and 95% CIs. Subgroup analyses were conducted using interaction tests to assess statistical evidence of heterogeneity in HR across select patient characteristics. Kaplan–Meier curves were constructed for primary end points and times to first events were compared using log-rank tests. All data used in this study were validated internally by the CliCon S.r.l. Health, Economics, and Outcomes Research organization (Ravenna, Italy) by assessing consistency of records across periods and among LHUs and validated externally by LHUs themselves. All analyses were performed using STATA (StataCorp LP, College Station, Texas) and a 2-tailed p <0.05 was considered statistically significant.
Results
A total of 11,269 patients met study inclusion criteria, of whom 2,425 patients (21.5%) received ≥1 prescription for n-3 PUFA during follow-up ( Table 1 ). Patients treated with n-3 PUFA tended to be younger, men, and less likely to have baseline chronic kidney disease or heart failure. They were more likely to be prescribed medications for diabetes and to receive guideline-recommended post-AMI medical therapy, including β blockers, ACEI/ARB, statin, and antiplatelet therapy. Overall, regardless of n-3 PUFA treatment, <25% of patients received PCI during index hospitalization. Approximately, half of the patients (47.8%) treated with n-3 PUFA during follow-up had an adherence rate of >80% ( Table 2 ).
| Variable | n-3 PUFA Treatment | P value | |
|---|---|---|---|
| Yes (n = 2,425) | No (n = 8,844) | ||
| Age (mean ±SD) (years) | 63.1 ±12.4 | 71.0 ±13.3 | <0.001 |
| Men | 1,884 (77.7%) | 5,639 (63.8%) | <0.001 |
| Angioplasty during index hospitalization | 557 (23.0%) | 2,041 (23.1%) | NS |
| Anterior/anterolateral AMI during index hospitalization | 671 (27.7%) | 1,984 (22.4%) | <0.001 |
| Treatment with n-3 PUFA prior to index hospitalization | 473 (19.5%) | 321 (3.6%) | <0.001 |
| Previous hospitalization for ischemic heart disease | 221 (9.1%) | 934 (10.6%) | <0.05 |
| Heart failure | 45 (1.9%) | 453 (5.1%) | <0.001 |
| Peripheral arterial disease | 5 (0.2%) | 22 (0.2%) | NS |
| Chronic kidney disease | 47 (1.9%) | 300 (3.4%) | <0.001 |
| Medications prescribed during follow-up ∗ | |||
| Medication for diabetes | 653 (26.9%) | 1,984 (22.4%) | <0.001 |
| Medication for hypertension † | 1,159 (47.8%) | 4,042 (45.7%) | NS |
| Beta-blocker | 2,093 (86.3%) | 5,814 (65.7%) | <0.001 |
| ACEI/ARB | 2,155 (88.9%) | 6,292 (71.1%) | <0.001 |
| Statin | 2,372 (97.8%) | 6,757 (76.4%) | <0.001 |
| Antiplatelet | 2,338 (96.4%) | 7,095 (80.2%) | <0.001 |
| Single antiplatelet therapy | 620 (25.6%) | 2,618 (29.6%) | <0.001 |
| Dual antiplatelet therapy | 1,645 (67.8%) | 4,342 (49.1%) | <0.001 |
| ≥3 antiplatelets | 73 (3.0%) | 135 (1.5%) | <0.001 |
∗ Patients were defined as treated with n-3 PUFA, β blockers, ACEI/ARB, antiplatelet agents, or statins if they were prescribed ≥1 prescription of the medication during the 12-month follow-up period. Patients were counted as receiving diabetic or hypertension medication if they were prescribed ≥2 prescription of the medication during follow-up.
† Medications for hypertension were defined as antihypertensives (ATC C02), diuretics (ATC C03), or calcium channel blockers (ATC C08).
| Age Group (years) | Adherence Rate ∗ | ||
|---|---|---|---|
| 0-40% | 41-80% | 81-100% | |
| <45 | 36 (22.8%) | 42 (26.6%) | 80 (50.6%) |
| 45-64 | 258 (22.3%) | 302 (26.1%) | 597 (51.6%) |
| 65-74 | 181 (29.2%) | 162 (26.2%) | 276 (44.6%) |
| 75-84 | 125 (30.1%) | 109 (26.3%) | 181 (43.6%) |
| ≥85 | 27 (35.5%) | 24 (31.6%) | 25 (32.9%) |
| Total | 627 (25.9%) | 639 (26.4%) | 1159 (47.8%) |
∗ Adherence rate calculated as total number of days’ supply of medication dispensed during follow-up divided by total postdischarge days from baseline to 12 months or death (whichever occurred first).
There were a total of 1,198 deaths (10.6%) and 494 repeat AMIs (4.4%) during follow-up. After adjustment for patient characteristics and concurrent medical therapy, n-3 PUFA treatment was independently associated with decreased risk of 12-month ACM (HR 0.76, 95% CI 0.59 to 0.97; Table 3 ) and recurrent AMI (HR 0.65, 95% CI 0.49 to 0.87; Table 4 ). Similarly, n-3 PUFA treatment was independently associated with reduced risk of ACM (HR 0.65, 95% CI 0.44 to 0.95) and recurrent AMI (HR 0.68, 95% CI 0.47 to 0.98) at 6 months. Times to first event were significantly different by the Kaplan–Meier method for primary end points ( Figure 1 ).
| Variable | Hazard Ratio (95% CI) | P value |
|---|---|---|
| n-3 PUFA treatment | 0.755 (0.587-0.972) | 0.029 |
| Age (per year) | 1.026 (1.018-1.034) | <0.001 |
| Male | 1.276 (1.132-1.438) | <0.001 |
| Previous cardiovascular hospitalization | 1.386 (1.194-1.610) | <0.001 |
| Heart disease | 1.205 (0.931-1.560) | 0.157 |
| Angioplasty during index hospitalization | 0.797 (0.653-0.973) | 0.026 |
| Anterior/anterolateral MI | 1.000 (0.872-1.147) | 0.998 |
| Prescribed anti-diabetes medication | 0.700 (0.510-0.961) | 0.027 |
| Prescribed anti-hypertension medication | 1.099 (0.832-1.451) | 0.508 |
| ACEI/ARB treatment | 0.295 (0.222-0.393) | <0.001 |
| Statin treatment | 0.533 (0.444-0.639) | <0.001 |
| Beta-blocker treatment | 0.367 (0.275-0.488) | <0.001 |
| Antiplatelet treatment | ||
| Single | 0.164 (0.114-0.237) | <0.001 |
| Dual | 0.194 (0.138-0.273) | <0.001 |
| Variable | Hazard Ratio (95% CI) | P value |
|---|---|---|
| n-3 PUFA treatment | 0.653 (0.488-0.873) | 0.004 |
| Age (per year) | 0.976 (0.964-0.989) | <0.001 |
| Male | 0.965 (0.796-1.170) | 0.715 |
| Previous cardiovascular hospitalization | 1.608 (1.267-2.041) | <0.001 |
| Heart disease | 1.704 (1.384-2.097) | <0.001 |
| Angioplasty during index hospitalization | 1.683 (1.131-2.503) | 0.010 |
| Anterior/anterolateral MI | 0.785 (0.624-0.988) | 0.039 |
| Prescribed anti-diabetes medication | 1.237 (1.000-1.529) | 0.050 |
| Prescribed anti-hypertension medication | 0.541 (0.366-0.799) | 0.002 |
| ACEI/ARB treatment | 0.868 (0.689-1.094) | 0.232 |
| Statin treatment | 0.627 (0.482-0.816) | 0.001 |
| Beta-blocker treatment | 0.775 (0.627-0.958) | 0.018 |
| Antiplatelet treatment | ||
| Single | 0.204 (0.121-0.344) | <0.001 |
| Dual | 0.210 (0.133-0.331) | <0.001 |
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