Effect of Escitalopram vs Placebo Treatment for Depression on Long-Term Cardiac Outcomes in Patients with Acute Coronary Syndrome

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Clinical Question

In patients with recent acute coronary syndrome and depression, does the use of escitalopram as an antidepressant therapy, compared to no additional therapy, reduce the risk of future cardiovascular events and mortality?

Bottom Line

In patients suffering from depression and recent acute coronary syndrome, use of escitalopram to treat depression, compared to placebo, resulted in significantly lower risk of major adverse cardiac events (a composite of all-cause mortality, myocardial infarction, and percutaneous coronary intervention).

Major Points

Patients with cardiovascular disease have increased risk of depression compared to patients without heart disease. Major depressive disorder can be treated with antidepressants or psychotherapy or a combination of both. Antidepressant medications, such as SSRIs, Sertraline and Citalopram have been studied the most, and deemed are safe and effective in patients with heart disease. Long term outcomes however have not been studied extensively and is an area where further research is needed.

Patients with Acute Coronary Syndrome (ACS) often also have depression and have poor outcomes which include increased mortality and nonfatal events. This study looked to answer the question of whether or not antidepressant treatment reduce the risk of future cardiovascular events and decrease adverse effects. Previous research looking into whether or not antidepressant treatment following ACS with long term outcomes has been inconclusive with not significant evidence.

This randomized double blinded, placebo controlled study followed 300 patients with acute coronary syndrome and clinical presentation of depression. They were treated for 24-weeks with escitalopram or placebo and the occurrence of major adverse cardiac outcomes was 40.9% vs 53.6%, with a lower risk of MACE after a median of 8.1 years. This study effectively showed that escitalopram vs placebo in the treatment of acute phase depression in patients with a recent ACS resulted in benefits in longer term cardiac outcomes. Recruitment was carried out from only one site, and all the participants were Korean which will limit the generalizability of the findings. Follow-up study is needed in other ethnic groups to generalize the findings of this study. Additionally doses were randomly assigned, and patients were not followed past one year both these points contribute to reduced generalizability. Similarly myocardial infarction was lowered significantly, whereas all-cause mortality, cardiac death, and percutaneous coronary intervention were not significant findings.

Guidelines

No guidelines have been published that reflect the results of this trial.

Design

➢ Randomized, double blinded, placebo controlled trial

➢ N= 300

    ○ Escitalopram (N=149)
    ○ Placebo (N=151) 

➢ Setting: Chonnam National University Hospital, Gwangju, South Korea

➢ Enrollment: May 2007- March 2013

➢ Mean Follow-up: 8.1 years

➢ Analysis: intention-to-treat

➢ Primary Outcome: Major adverse cardiovascular events (MACE)


Population

Inclusion Criteria

➢ 18-85 years old

➢ ACS diagnosis with coronary angiography within the last two weeks from the start of the trial

➢ Beck Depression Inventory over 10 with Major or Minor Depressive Disorder according to the DSM-IV

➢ Ability to complete questionnaires

➢ Understanding of the study

➢ Providing informed consent


Exclusion Criteria

➢ Acute Coronary Syndrome (ACS) when hospitalized for reasons other than ACS

➢ ACS developed within 3 months of coronary artery bypass graft procedure

➢ Uncontrolled hypertension (systolic > 180 mmHg or diastolic > 100 mmHg)

➢ Heart rate under 40/min (resting)

➢ Severe illness which threatens life or prevents ACS recovery

➢ Persistent abnormal laboratory values

➢ Concurrent use of:

      ○	Class I antiarrhythmic medications
              ■	Reserpine
              ■	Guanethidine
              ■	Clonidine 
              ■	Methyldopa
      ○	Anticonvulsants 
      ○	Neuroleptics

➢ Neuropsychiatric illness history of:

      ○	Dementia
      ○	Parkinson’s Disease
      ○	Brain tumor
      ○	Psychoses
      ○	Alcoholism
      ○	Substance abuse 

➢ Pregnancy


Baseline Characteristics

From the Escitalopram group

➢ Age : 60y/o

➢ Men: 59.1%

➢ Cardiovascular risk factors:

      ○	Hypertension: 60.4%
      ○	Diabetes Mellitus: 29.5%
      ○	Hypercholesterolemia : 49.0%
      ○	Obesity: 39.6%
      ○	Smoker (current): 28.9%
      ○	Previous ACS: 5.4%
      ○	Family history for ACS: 6.0%

➢ Depression:

      ○	Beck Depression Inventory Score: 16
      ○	DSM-IV diagnosis of Major Depressive Disorder: 57.0%
      ○	Previous depression: 4.0% 


Interventions

➢ Patients were randomly assigned to receive either escitalopram doses of 5,10, 15, or 20 mg/dose or placebo to take for 24 weeks

      ○	149 patients were assigned to escitalopram
              ■	108 completed 24-wk treatment
      ○	151 patients were assigned to a placebo
              ■	109 completed 24-wk treatment

➢ All patients had a complete follow-up between 5-11 years after 24 week placebo/escitalopram trial


Outcomes

Primary Outcomes

Occurrence of Major Adverse Cardiovascular Events

      ■	24 week trial
              ●	40.9% vs. 53.6% (HR = 0.69; 95% CI = 0.49-0.96; P = 0.03; NNT = 8)
      ■	1 year follow-up
              ●	40.3% vs. 53.4% (HR = 0.69; 95% CI = 0.48-0.96; P = 0.03; NNT = 8)

Occurrence of Major Adverse Cardiovascular Events in Patients with Left Ventricle Ejection Fraction

      ■	Results were not clinically significant (P = 0.12)


Secondary Outcomes

Incidence of Myocardial Infarction

      ■	8.7% vs. 15.2% (HR = 0.54; 95% CI = 0.27-0.96; P = 0.04; NNT = 16)

All-Cause Mortality

      ■	20.8% vs. 24.5% (HR = 0.82; 95% CI = 0.51-1.33; P = 0.43)

Cardiac Death

      ■	10.7% vs. 13.2% (HR = 0.79; 95% CI = 0.41-1.52; P = 0.48)

Percutaneous Coronary Intervention

      ■	12.8% vs. 19.9% (HR = 0.58; 95% CI = 0.33-1.04; P = 0.07)

Subgroup Analysis

Adverse Events

Criticisms

➢ Recruitment was carried out from only one site, and all the participants were Korean which will limit the generalizability of the findings. Follow-up study is needed in other ethnic groups to generalize the findings of this study.

➢ Not all patients took the same dose, as the dose was randomly assigned between doses of 5, 10, 15, or 20 mg/dose.

➢ After 1 year, they did not track the occurrence of depression or use of antidepressants which could impact the results and limit the generalizability.

➢ In secondary outcomes, only myocardial infarction was lowered significantly, whereas all-cause mortality, cardiac death, and percutaneous coronary intervention were not significant findings.


Funding

This study was funded via a grant from the National Research Foundation of Korea and from funding allocated to Dr. Stewart. The sponsors had no control/influence over the design of the study, collection, management, analysis, and interpretation of the resulting data, nor contribution to the manuscript and decision to publish.

Further Reading