This document summarizes a clinical trial that studied the safety and efficacy of the antidepressant sertraline for treating major depression in patients who recently had a myocardial infarction or unstable angina. The trial involved 369 patients across 40 centers in 7 countries who were randomized to receive either sertraline or placebo for 24 weeks. The primary outcome was change in left ventricular ejection fraction, and secondary outcomes included cardiovascular events and measures of depression. The trial found no significant differences in ejection fraction or cardiovascular safety measures between the sertraline and placebo groups. Sertraline was found to be significantly more effective than placebo at reducing depressive symptoms.

1. Journal Club
Chair:Dr Arun B Nair
Presenter:Dr Arif Iqbal

2. Sertraline Treatment of Major
Depression in Patients with
Acute MI or Unstable Angina
Alexander H Glassman 1, Christopher M O'Connor, Robert M Califf, Karl Swedberg, Peter
Schwartz, J Thomas Bigger Jr, K Ranga Rama Krishnan, Louis T van Zyl, J Robert Swenson,
Mitchell S Finkel, Charles Landau, Peter A Shapiro, Carl J Pepine, Jack Mardekian, Wilma M
Harrison, David Barton, Michael Mclvor; Sertraline Antidepressant Heart Attack Randomized Trial
(SADHEART) Group

4. INTRODUCTION
● Well-controlled studies, in which initially healthy subjects were followed up
prospectively,have identified depression as a significant independent risk
factor for both first myocardial infarction (MI) and cardiovascular mortality,
●Among individuals with established ischemic heart disease, depression has
been found to be associated with an approximately 3- to 4-fold increase in
the risk of subsequent cardiovascular morbidity and mortality
●The prevalence of major depression (major depressive disorder [MDD]) in
individuals with coronary artery disease is estimated to range from 15% to
23%

5. •It is important to determine whether treating depression can reduce the associated
morbidity and mortality risk.
•However,there was no published evidence that antidepressant drugs are either safe or
efficacious in patients with unstable ischemic heart disease.
•In fact, there is considerable evidence that tricyclic antidepressants are potentially
dangerous

6. METHODS
Overview
•The study was conducted in 40 Cardiology centers and psychiatry clinics in 7
countries.
•Hospitalized patients were identified by chart review or physician referral.
• Those who met preliminary screening criteria and provided written informed
consent were administered :
- structured Diagnostic Interview Schedule (DIS)24 for major depression by a
trained interviewer and completed the self-rated Beck Depression Inventory (BDI)

7. Inclusion Criteria
Male or female adults were required
1.Either to have had an acute MI or to have been hospitalized for unstable angina in
the past 30 days
2. And to be experiencing a current episode of MDD based on DSM-IV criteria
●Acute MI
●Unstable angina

8. Exclusion Criteria
Cardiovascular
(a) uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure
> 100 mm Hg)
(b) cardiac surgery anticipated during the next 6 months
(c) index MI or unstable angina developed less than 3 months after coronary artery bypass graft
procedure
(d) resting heart rate of less than 40/min (or 50/min if symptomatic or daytime sinus pauses of -
3.5 seconds)
(e) MI or unstable angina of non-atherosclerotic etiology (eg, anemia, cocaine use,
periprocedural)
(f) Killip class III or IV status.

9. ● Other Medical.
● (a) persistent clinically significant laboratory abnormalities
● (b) significant renal dysfunc- tion, hepatic dysfunction, or other sig-
nificant noncardiac disease
● (c) women of childbearing potential not using adequate contraception.

10. Concomitant Treatment Exclusions.
(a) current use of class I antiarrhythmic medications
(b) use of reserpine, guanethidine, clonidine, or methyldopa; anticonvulsants or
neuroleptics; antidepressants; or regular benzodiazepine
(c) initiation of psychotherapy in the 3 months prior to study entry.
Psychiatric Exclusions
(a) alcohol or substance abuse or dependence in past 6 months;
(b) psychotic symptoms, history of psychosis, bipolar disorder, organic brain
syndrome, dementia (or a Mini-Mental State Examination score 23)
(c) significant suicide risk.

11. Study Design
● Patients who met the study criteria enumerated above
started receiving single-blind placebo for 14 days
● Prior to randomization, a psychiatrist repeated the DIS to
verify that the patient met full criteria for MDD including 2
week duration and impairment.

13. ●Randomization was stratified by
-percentage of left ventricular ejection fraction (LVEF)(<30% or ≥30%) and
- by the presence of 2 depression severity criteria (≥2 prior episodes of depression
and a current Hamilton Depression [HAM- D] scale score ≥18).
●Consequently, individuals meeting the higher depression severity (HAM-D score
≥18) and 2 previous epi- sodes of MDD were defined a priority, as the group in
whom efficacy would be evaluated.

14. ●Patients received 50 mg/d of sertra- line or matching placebo for the first 6
weeks of treatment.
● Based on clinical response and tolerability, the dosage could be increased to 2
tablets (100 mg/d or matching placebo) at the end of week 6, to 3 tablets (150
mg/d or matching placebo) at week 10, and
● to the maximum dosage of 4 tablets (200 mg/d or matching placebo) at week
12.

15. Outcome Variables
Primary Outcome: LVEF
-Baseline MUGA scans using a standardized protocol were performed prior
to randomization and at the end of week 16 of treatment.
Secondary safety variables
- Heart rate, blood pressure,standard ECG, presence of ventricular
premature complexes,the occurrence of cardiovascular events, MI, stroke,
severe angina, congestive heart failure, and death.

16. Measures of depression severity
● The BDI obtained at screening
● The 17-item HAM-D,obtained at baseline and weeks 6, 10, and 16
● The Clinical Global Impression, Severity (CGI-S) and Improvement
(CGI-I) scales obtained at baseline and at weeks 2, 6, 10, 16, and 24.

17. Statistical Analysis
●Comparability of the treatment groups at baseline was assessed using 2-way analyses
of variance
-including effects for treatment group, study center, and treatment by center interaction
for continuous measures and
- Cochran-Mantel- Haenszel tests for categorical measures.
●A mixed-model repeated-measures analysis of covariance was used to assess the
changes in the CGI-I score and the Hamilton Total Score over the treatment period.
●Statistical analyses were performed using SAS v6.12 (SAS Institute Inc, Cary, NC).

18. RESULTS
Baseline Clinical and Demographic Characteristics

19. Primary Outcome: Cardiovascular Safety

20. ●There was no statistically significant difference in LVEF between patients
receiving sertraline or placebo
●Nor were between- group differences observed in secondary ECG parameters,
heart rate, blood pressure and SDNN (standard deviation of all normal R-R
intervals in a 24-hour ECG recording)
●Serial Holter recordings did not reveal any significant treatment- emergent
between-group difference in the number of runs of ventricular tachycardia.
●Both nausea and diarrhea were significantly more common in patients taking
sertraline

21. Cardiovascular events were not significantly different although
severe cardiovascular events were numerically less frequent with
sertraline (14.5% vs 22.4%).
The incidence of major adverse cardiovascular events involving
death or requiring hospitalization any time during the 24-weeks
course of study treatment (table 5) : 73 of the 369 individuals (20%)
in the study had such events (44% allocated to sertraline vs 56%
allocated to placebo)

22. Efficacy Outcome: Depression

23. ● Analysis found sertraline to be significantly superior to placebo on the CGI-I
scale measured over 24 weeks, but not on the HAM-Dcale, which was obtained
over 16 weeks.
●In the 2 recurrent depression groups, sertraline was significantly superior to
placebo on both the CGI and HAM-D measures.
●In all 3 groups, responder status using the standard criteria of CGI-I score of 1 or
2 (very much or much improved) was achieved at end point by significantly more
patients treated with sertraline than with placebo.

24. COMMENT
● We found no evidence of harm: sertraline was indistinguishable from placebo
across all surrogate measures of cardio- vascular safety.
●Treatment was not associated with any change in LVEF, blood pressure, heart rate,
arrhythmias, or SDNN on 24-hour ambulatory ECGs, with QTc prolongation, or with
any other ECG parameters (Table 3).
● Furthermore, though not statistically significant, the incidence of severe cardiac
events, the gold standard for cardiac safety, was numerically lower among patients
receiving sertraline than among those receiving placebo.

25. ●Study was conducted across 7 countries
●Anticipating thie possibility of patients having lesser severity and shorter duration
of depression as compared to typical antidepressant efficacy trials , a priori “more
severe sample” was defined.
●By requiring a minimum HAM-D score of 18, the subgroup more closely resembled
the severity level of a more typical antidepressant trial.
●To compensate for the very short episode duration in this post-MI sample, 2 prior
episodes of depression were required.
-Despite the limited number of these “more severe” patients, sertraline was found to be
robustly superior to placebo using either CGI-I or HAM- D measures.
STRENGTHS

26. ●The sample size was well short of the numbers needed to identify rare adverse events or
drug- drug interactions.
●In addition, a large number of patients were excluded from this trial either because they
had a second medical condition or because of another psychiatric condition .
- The results cannot be generalized beyond the populations that were actually examined.
●Patients in this study received much more “medical attention” than do the usual post-MI
patients.
-It is unclear if that level of support influenced response rates, and it is possible that in the
usual care setting lower spontaneous remission rates would result and higher drug-
placebo treatment differences would emerge
LIMITATIONS

27. REFERENCES
1. Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry. 1998;155:4-11.
2. Anda R, Williamson D, Jones D, et al. Depressed affect, hopelessness, and the risk of ischemic heart dis- ease in a cohort of US adults.
Epidemiology. 1993;4: 285-294.
3. Ferketich AK, Schwartzbaum JA, Frid DJ, Moesch- berger ML, for the National Health and Nutrition Ex- amination Survey. Depression as an
antecedent to heart disease among women and men in the NHANES I study. Arch Intern Med. 2000;160:1261-1268.
4.Ariyo AA, Haan M, Tangen CM, et al, for the Car- diovascular Health Study Collaborative Research Group. Depressive symptoms and risks of
coronary heart dis- ease and mortality in elderly Americans. Circulation. 2000;102:1773-1779.
5.Schulz R, Beach SR, Ives DG, Martire LM, Ariyo AA, Kop WJ. Association between depression and mor- tality in older adults: the Cardiovascular
Health Study. Arch Intern Med. 2000;160:1761-1768.
6.Glassman AH, Roose SP, Bigger JT Jr. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA. 1993;269:2673-
2675.
7. Glassman AH, O'Connor CM, Califf RM, Swedberg K, Schwartz P, Bigger JT Jr, Krishnan KR, van Zyl LT, Swenson JR, Finkel MS, Landau C,
Shapiro PA, Pepine CJ, Mardekian J, Harrison WM, Barton D, Mclvor M; Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART)
Group. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002 Aug 14;288(6):701-9. doi:
10.1001/jama.288.6.701. Erratum in: JAMA 2002 Oct 9;288(14):1720. PMID: 12169073.

28. THANK
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