SADHART

Published

Glassman AH, et al. "Sertraline treatment of major depression in patients with acute MI or unstable angina". Journal of the American Medical Association. 2002. 288(6):701-709.
PubMed • Full text • PDF

Clinical Question

In patients who had been recently hospitalized for ACS, what is the safety and efficacy of sertraline treatment for recurrent depression?

Bottom Line

Sertraline is a safe treatment for recurrent depression among patients recently hospitalized for ACS.

Major Points

Most post-ACS patients who experience symptoms of depression are not administered antidepressants because 50% of episodes spontaneously remit, and there is little evidence regarding the safety and efficacy of antidepressants in post-ACS patients. TCAs can treat depression, but their use has been associated with orthostatic hypotension, QT prolongation, and arrhythmic deaths, and thus their use in post-ACS depression is controversial. This study therefore sought to investigate the role of a different class of antidepressents, namely SSRIs.

The Sertraline Antidepressant Heart-Attack Randomized Trial (SADHART) randomized 369 patients with depression who had been recently hospitalized for ACS to 24 weeks of treatment with sertraline or placebo. SADHART demonstrated that sertraline had no significant effect on cardiac safety measures, including LVEF, HR, BP, arrhythmias, and QT prolongation. The study was not powered to detect differences in depression scores; thus unsurprisingly there were no significant differences in the study's secondary outcome measures, namely the Hamilton Depression and Clinical Global Impression ratings. A subgroup analysis, however, identified improvements in depression ratings among the subgroup of patients who had experienced an episode of major depression prior to their ACS.

Guidelines

Modern ACS guidelines from the ACC/AHA do not make recommendations about use of an SSRI.

Design

• Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
• N=369 depressed patients hospitalized for ACS randomized to:
  • Sertraline (n=186)
  • Placebo (n=183)
• Primary outcome: ≥5% decrease in LVEF at 16 weeks
• Setting: 40 outpatient cardiology centers and psychiatry clinics in 7 countries in the US, Europe, Canada, and Australia
• Enrollment: 1997-2001
• Analysis: Intention-to-treat

Population

Inclusion Criteria

• Adults
• Experiencing a current episode of MDD based on DSM-IV criteria
• Hospitalized within 30 days for ACS

Exclusion Criteria

• Cardiovascular:
  • Uncontrolled HTN (SBP >180mmHg or DBP >100mmHg)
  • Cardiac surgery anticipated during next 6 mos
  • ACS <3 mos after CABG
  • Bradycardia (resting HR <40 bpm, HR <50 bpm if symptomatic or daytime sinus pauses >3.5s)
  • ACS of non-atherosclerotic etiology (anemia, cocaine use, periprocedural)
  • Killip class III or IV
• Other medical:
  • Persistent clinically significant laboratory abnormalities
  • Significant renal, hepatic, non-cardiac disease
  • Women of childbearing potential not using adequate contraception
• Concomitant treatment:
  • Class I antiarrhythmics
  • Reserpine, guanethidine, clonidine, methlydopa
  • Anticonvulsants or neuroleptics
  • Antidepressants
  • Benzodiazepines
  • Psychotherapy within prior 3 months
• Psychiatric:
  • Alcohol or substance abuse or dependence within prior 6 mos
  • Psychotic symptoms, history of psychosis
  • Bipolar disorder
  • Organic brain syndrome
  • Dementia or MMSE <23
  • Significant suicide risk

Baseline Characteristics

Comparisons are sertraline vs. placebo.

• Age: 58 years
• Female: 37%
• BMI: 30
• Race:
  • White: 77%
  • Black: 13%
  • Hispanic: 14% vs. 7%
• Current smoker: 28%
• HTN: 65%
• DM: 31%
• HL: 69%
• Obesity: 33%
• CHF: 14%
• Mean LVEF: 53%
• Killip class II or higher: 7.1%
• Prior CABG, PTCA: 43%
• Prior MI: 42%
• Cardiac event leading to hospitalization:
  • MI: 80%
  • UA: 20%
• Prior episodes of major depression: 0 (50%), 1 (20%), ≥2 (30%)
• Prior psychotropic treatment: 35%
• Mean HAM-D score: 20

Medications

• Calcium channel blockers: 33% vs. 36%
• Nitrates: 65%
• Digoxin 13%
• ß-blockers: 78% vs. 85%
• ACE-inhibitors: 53% vs. 56%
• Statins: 86%
• Aspirin: 91% vs. 86%
• Antiplatelet drugs: 19% vs. 14%
• Anticoagulants: 29%
• Diuretics: 35% vs. 45%

Interventions

• Randomized to 24 weeks of double-blind treatment with sertraline 50-200mg/d or placebo
• Stratified by LVEF (<30% or ≥30%) and by severity (high-severity: ≥2 prior episodes of depression and HAM-D score ≥18)
• Dose began at 50mg/d and titrated based on clinical response at week 6 (max 100mg), week 10 (max 150mg), week 12 (max 200mg)
• Concomitant medications with clinically relevant psychotropic properties were not permitted
• At week 24, study was completed and patients were tapered off study medication at rate of 50mg/day/wk
• Safety monitoring:
  • Vitals, EKG, baseline MUGA scans, and 24hr Holter recordings were performed prior to randomization and 16 weeks of treatment
  • CV events recorded included angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF, MI, tachycardia, bradycardia, changes in BP
• Depression monitoring:
  • Beck Depression Inventory (BDI) at screening
  • 17-item HAM-D at baseline and weeks 6, 10, 16
  • Clinical Global Impression, Severity (CGI-S) and Improvement (CGI-I) at baseline, weeks 2, 6, 10, 16, 24
  • "Responder" if CGI-I score of 1 or 2 by study end
• Mean time from ACS hospitalization to start of medications: 34 days
• Mean duration of treatment: 150 vs. 154 days
• Mean final daily dose: 69 vs. 71 mg

Outcomes

Comparisons are sertraline vs. placebo.

Primary Outcome

≥5% decrease in LVEF by MUGA at 16 weeks

6% vs. 5% (P value not stated)

Secondary Outcomes

Vitals and EKG changes

No differences in HR, BP, PR interval, QRS duration, QTc interval, R-R interval variability, 24h Holter EKG, or PVCs

Mean CGI-score

2.57 vs. 2.75 (P=0.049)

Mean HAM-D change score

-8.4 vs. -7.6 (P=0.14)

CGI-I responder

67% vs. 53% (P=0.01)

Adverse Events

Total CV events

52.7% vs. 59.0%

Nausea

19.9% vs. 10.9%

Diarrhea

18.8% vs. 7.7%

Fatigue

14.5% vs. 13.7%

HA

20.4% vs. 16.4%

Dizziness

15.6% vs. 12.0

Dyspnea

13.4% vs. 19.7%

Pain

10.2% vs. 11.5%

Death

1.1% vs. 2.7% (RR 0.39; 95% CI 0.08-1.39)

MI

2.7% vs. 3.8% (RR 0.70; 95% CI 0.23-2.16)

CHF

2.7% vs. 3.8% (RR 0.70; 95% CI 0.23-2.16)

Stroke

1.1% vs. 1.1% (RR 0.98; 95% CI 0.14-6.93)

Angina

14.0% vs. 16.4% (RR 0.85; 95% CI 0.53-1.38)

Composite

17.2% vs. 22.4% (RR 0.77; 95% CI 0.51-1.16)

Subgroup Analysis

Any recurrent MDD subgroup vs. placebo

Mean CGI-I score

2.49 vs. 2.80 (P=0.02)

Mean HAM-D change score

-9.8 vs. -7.6 (P=0.009)

CGI-I responder

72% vs. 51% (P=0.003)

High-severity subgroup (2 prior episodes of MDD plus HAM-D score ≥18; n=50) vs. placebo (n=40)

Mean CGI-I score

2.41 vs. 2.98 (P=0.002)

Mean HAM-D change score

-12.3 vs. -8.9 (P=0.01)

CGI-I responder

78% vs. 45% (P=0.001)

Total CV events

14.5% vs. 22.4%

Funding

Funding from Pfizer, the Suzanne C. Murphy Foundation, Thomas and Caroline Royster Research Fund, and the Perry and Martin Granoff Family Foundation, with an employee of Pfizer involved in all parts of the study.