Sandbox:Mitra

Medical Therapy

Antidepressant drugs include selective serotonin reuptake inhibitors, such as escitalopram oxalate (Lexapro), citalopram (Celexa), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft), are the primary medications considered for patients, having fewer side effects than the older monoamine oxidase inhibitors (MAOIs).

The effect size is very small for moderate depression but increased with severity reaching the NICE criteria for 'clinical significance' for very severe depression. This result is consistent with the earlier clinical studies where only patients with severe depression benefited from the treatment with a tricyclic antidepressant imipramine or from psychotherapy more than from the placebo treatment. According to the STAR*D randomized controlled trial, about 50% of patients with major depression have a response and about 30% of have remission of symptoms with usage of citalopram.

Bupropion (Wellbutrin, Zyban), an atypical antidepressant that acts as a norepinephrine and dopamine reuptake inhibitor, is also considered to be effective in the treatment of depression, without sexual dysfunction or sexual side effects and without weight gain. Bupropion has also been shown to be more effective than SSRIs at improving symptoms such as hypersomnia and fatigue in depressed patients.

Measurement-based care, which guides mediation based on serial measurement of psychometric testing, improves outcomes according to randomized controlled trials.

Predictors of a response to treatment

Severity of depression

The effectiveness is antidepressants may or may not depend on the severity of a patient's depression. This relationship may be due to the declining effect of placebo among more severely depressed patients.

The effectiveness of antidepressants depending on severity of depression

American Psychiatric Association classification of severity	Hamilton Depression Rating Scale (HDRS)	Number needed to treat	Clinical significance (NICE)
Mild to moderate	< 19	16	No
Severe	19 - 22	11	No
Very severe	> 22	4	Yes

Genetic variations

Variations in the GRIK4 (glutamate receptor, ionotropic, kainate 4 protein) and HTR2A (5-hydroxytryptamine receptor) genes predict response to citalopram.

Treatment failure

Treatment after monotherapy failure
(VAST-D Study)

Intervention		Outcome
Medication	Mode final dose	Remission %	Quit 2˚ ADRs (%)
Switch medications
Bupropion SR	200 mg twice daily	22.3%	10%
Augment medications
Aripiprazole	10 mg	29%	5%
Bupropion SR	300 mg daily	27%	7%

After starting medications, treatment should be switched if there is no response within one month.

When treated with monotherapy for depression, approximately 30% of patients have remission of symptoms while 50% have a response to medications.

For patients with inadequate response, randomized controlled trials provide guidance.

• The original VAST-D trial, that did not include aripiprazole, confirms that augmenting with bupropion is the most effective of options other than augmentation with aripiprazole. In this trial, either adding sustained-release bupropion ("bupropion was 200 mg per day during weeks 1 and 2, increasing to 300 mg per day by week 4 and to 400 mg per day (the final dose) during week 6") or buspirone (up to 60 mg per day) for augmentation as a second drug can cause remission in approximately 30% of patients (bupropion may be more effective than buspirone), while switching medications can achieve remission in about 25% of patients. Alternatively, "extended-release venlafaxine, the starting daily dose of 37.5 mg for 7 days was increased to 75 mg from day 8 to 14, to 150 mg from day 15 to 27, to 225 mg from day 28 to 41, to 300 mg from day 42 to 62, and to 375 mg from day 63 onward."
• The PReDICT trial found that among patients who initially were treated with either an SSRI or CBT, remission was increased when the opposite treatment (CBT or SSRI) was added to non-remitters.
• The newer VAST-D trial found that augmentation with aripiprazole is effective. The dose of aripiprazole was 2 mg of with titration to 5, 10, or 15 mg daily as guided by measurement-based care using the PHQ-9. However, aripiprazole led to more adverse drug reactions including somnolence, akathisia, and weight gain. The second most effective was augmentation with buproprion starting at 150 mg sustained release to 300 mg or 400 mg daily as guided by measurement-based care using the PHQ-9.

• More recently, mirtazapine, was found not to add to SSRIs.

Treatment after SSRI (citalopram) failure
(STAR*D Studies)

Intervention		Outcome
Medication	Mean final dose	Remission %	Quit 2˚ ADRs (%)
Switch meds (NEJM 2006; PMID: 16554525)
Bupropion SR	283 mg	21%	27%
Sertraline (SSR)	136 mg	18%	21%
Venlafaxine ER (SNRI)	194 mg	25%	21%
Augment meds (NEJM 2006; PMID: 16554526)
Bupropion SR	268 mg	30%	13%
Buspirone	41 mg	30%	21%

The STAR*D trial has reported the frequency of re-emergence of suicidality for different second levels of treatment.

In level 3 of the STAR*D trials, patients who had failed two trials of a second-generation antidepressant, tended to better with nortriptyline than mirtazapine.

Aripiprazole, originally introduced as an atypical antipsychotic agent, is approved as an adjunct to other antidepressants.

Stopping medications

Patients are generally advised not to stop taking an antidepressant suddenly and to continue its use for at least four to months to prevent the chance of recurrence. For patients that have chronic depression, medication may need to be continued for the remainder of their life.

Patients should be treated indefinitely if they have "three or more prior major depressive episodes or who have chronic major depressive disorder should proceed to the maintenance phase of treatment after completing the continuation phase."

Distinguishing the Jugular Venous Pulse frm the Carotid Pulse
Feaure	Internal Jugular Vein	Carotid Artery
Appearance of pulse	Biphasic	Monophasic
Response to inspiration	Inspiration generally decreases the pressure (the height of column decrease and troughs become more prominent)	No respiratory change
Pulpabillity	Not palpable (exception: severe TR)	Palpable
Effect of pressure

Resident Survival Guide

Acute Coronary Syndrome Chapters
Heart Attack Patient Information
Unstable Angina Patient Information
Overview
Classification Unstable Angina Non-ST Elevation Myocardial Infarction ST Elevation Myocardial Infarction
Causes
Differential Diagnosis
Treatment
AHA/ACC Guidelines for Acute Coronary Syndrome
Guideline for Risk Stratification in ACS
Guideline for Pre-Hospital Evaluation and Care
Guidelines for Initial Management of ACS
Guidelines for Patients with Atrial Fibrillation Complicating ACS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]; Tarek Nafee, M.D. [3]; Sabawoon Mirwais, M.B.B.S, M.D.[4]

Synonyms and keywords: ACS

Overview

Acute coronary syndrome (ACS) refers to any group of symptoms attributed to obstruction of the coronary arteries. The most common symptom prompting diagnosis of ACS is chest pain, often radiating to the left arm or angle of the jaw, pressure-like in character, and associated with nausea and sweating. Acute coronary syndrome usually occurs as a result of one of three problems: ST-elevation myocardial infarction (30%), non ST-elevation myocardial infarction (25%), or unstable angina (38%). These types are named according to the appearance of the electrocardiogram. There can be some variation as to which forms of myocardial infarction (MI) are classified under acute coronary syndrome.

ACS should be distinguished from stable angina, which is chest pain which develops during exertion and resolves at rest. New onset angina however should be considered as a part of acute coronary syndrome, since it suggests a new problem in a coronary artery.Though ACS is usually associated with coronary thrombosis, it can also be associated with cocaine use. Cardiac chest pain can also be precipitated by anemia, bradycardias or tachycardias.

Classification

Acute coronary syndrome may be classified as follows:

• Unstable Angina
• Non ST Elevation Myocardial Infarction
• ST Elevation Myocardial Infarction

Symptoms

The signs and symptoms of acute coronary syndrome include:

• Chest pain

• Substernal chest pain
• Occurs at rest or exertion
• Radiation to neck, jaw, left shoulder and left arm
• Aggravated by physical activity and emotional stress
• Relieved by rest, nitroglycerin or both

• Chest discomfort described crushing, squeezing, burning, choking, tightness or aching
• Dyspnea
• Diaphoresis
• Nausea and vomiting
• Fatigue
• Syncope

Pathophysiology

For more information on atherosclerotic plaque, click here.

The pathophysiology of acute coronary syndromes depends on coronary atherosclerotic plaque which includes:

Initiation and Progression of Coronary Atherosclerotic Plaque

• The endothelium of coronary arteries are damaged by the risk factors resulting in endothelial dysfunction, leading to the formation of atherosclerotic plaque.
• The macrophages in the atherosclerotic plaque release matrix metalloproteinases, leading to plaque disruption.
• The balance between smooth muscle cells and macrophages in the plaque plays a major role in plaque vulnerability and the propensity to rupture.

Plaque Vulnerability

The plaque vulnerability depends on the following factors:

• Inflammation (A high density of macrophages and T-lymphocytes are marker of unstable atherosclerotic plaque)
• Large lipid core
• Locally increased matrix metalloproteinases that degrade collagen
• Thin fibrous cap
• Relative paucity of smooth muscle cells
• Increase in plaque neovascularity and plaque hemorrhage
• Eccentric outward remodelling

Pathogenesis

The pathogenesis of acute coronary syndrome depends on:

• Endothelial integrity
• Inflammation
• Thrombogenicity of the blood

Following plaque rupture or endothelial erosion, the subendothelial matrix is exposed to the circulating platelets, which get activated leading to thrombus formation. Two types of thrombi can form:

• White clots: Platelet-rich clots which partially occludes the artery
• Red clots: Fibrin rich clots superimposed on white clots and cause total occlusion of the artery

Risk Factors

Common risk factors in the development of acute coronary syndrome are:

• Age (men >45 and women >55)
• Diabetes mellitus
• Hypercholesterolemia
• Hypertension
• Smoking
• Obesity
• Lack of physical activity
• Family history of heart disease
• History of HTN, DM and pre-eclampsia during pregnancy

Diagnosis

High-sensitivity Cardiac Troponin (hs-cTn)

	99th percentile of a healthy reference population (recommended cut-off)	Turnaround time	Name and manufacturer	FDA Approval?
Troponin T hs-cTnT	14 ng/L	18 minutes	Elecsys (Roche Diagnostics)
Troponin I hs-cTnI	26.2 ng/L		ARCHITECTSTAT (Abbott Laboratories)

Clinical Implications of High-sensitivity Cardiac Troponin Assays

Compared with standard cardiac troponin assays, high-sensitivity assays:
Have higher negative predictive value for acute MI.
Reduce the “troponin-blind” interval leading to earlier detection of acute MI.
Reduce the “troponin-blind” interval leading to earlier detection of acute MI.
Are associated with a 2-fold increase in the detection of type 2 MI.
Levels of high-sensitivity cardiac troponin should be interpreted as quantitative markers of cardiomyocyte damage (i.e. the higher the level, the greater the likelihood of MI):
Elevations beyond 5-fold the upper reference limit have high (>90%) positive predictive value for acute type 1 MI.
Elevations up to 3-fold the upper reference limit have only limited (50–60%) positive predictive value for acute MI and may be associated with a broad spectrum of conditions.
It is common to detect circulating levels of cardiac troponin in healthy individuals.
Rising and/or falling cardiac troponin levels differentiate acute from chronic cardiomyocyte damage (the more pronounced the change, the higher the likelihood of acute MI).
Adapted from European Heart Journal (2016) 37, 267–315

Available high sensitivity troponin assays:

• Troponin T: Elecsys by Roche Diagnostics
• Troponin I: ARCHITECTSTAT by Abbott Laboratories

When both tests have sensitivity of > 99%, cTnT can exclude infarction in more patients with a sensitivity of 90% according to meta-analysis.

The agreement between hscTnT and hscTnI measurements is excellent (Cohen's kappa =0.9).

High sensitivity troponin levels have reduced predictive value when prevalence is low.

Clinical Prediction Rules

Clinical prediction rules can help diagnose:

• HEART risk score (History, EKG, Age, Risk factors, and troponin) is the only one of these three prediction rules designed for use prior to diagnosis
• GRACE risk score incorporates 8 findings
• TIMI risk score

Regarding the comparative performance of the prediction rules:

• In the setting of acute chest pain, the HEART score may best predict complications according to a cohort study.
• In the setting of NSTEMI, the GRACE risk score may best predict complications according to a cohort study. However, the HEART risk score was not assessed in this cohort.

Diagnostic Pathways

Clinical diagnostic pathways may help. The European Society of Cardiology recommends two pathways:

• 0 h/3 h
• 0 h/1 h

The last American Health Association guidelines were prepared prior to approval of hs-cTn tests by the FDA.

More recent strategies include:

• Single cTnT measurement, combined with a non-ischemic EKG, that reports troponin is below the limits of detection.

• Single cTnI measurement, combined with low-risk clinical prediction rule

Differential Diagnosis

Diagnosis of ACS is initiated by a clinical suspicion based on a thorough history of the patient's symptoms. Subsequently, confirmatory tests should be ordered to confirm the diagnosis, identify the specific cause of ACS, or to rule out other possible differentials. In some circumstances, utilizing a clinical prediction tool may be beneficial in guiding the clinician's diagnosis. View the page on diagnosis using the clinical prediction rule for ACS for more detail. Acute Coronary Syndrome (ACS) may be differentiated from other diseases as follows:

Organ System	Diseases	Presentation										Diagnostic Tests						Past Medical History						Other Findings
		Chest Pain					GI Symptoms			Pulmonary	Neck
		On Palpation	On inspiration	Radiating to Extremeties	Radiating to Back	With Movement	Nausea or Vomitting	Epigastric Pain	Odynophagia or Dysphagia	Shortness of Breath	Jugular Distention	Cardiac Biomarkers	CBC Findings	ESR	D-Dimer	EKG Findings	CXR Findings	DM	Hyperlipidemia	Obesity	Trauma	Inxn*	Htn
Cardiovascular	Acute Coronary Syndrome			+	+		+	+		+		+				+		+	+	+			+	•Palpitations •Sweating
	Aortic Dissection			+	+					+		-					+		+	-			+	•Pain maximal upon onset •Pain difficult to treat with opiates •Weak pulse in one arm compared to other •Syncope •Symptoms similar to stroke •Smoking
	Brugada Syndrome	No chest pain														+								•Syncope •Cardiac arrest •ST-segment elevation •F/H of sudden cardiac death
	Takotsubo carditis	Sudden onset of chest pain mimicking myocardial infarction					+	+		+		+				+				-				•Extreme emotional or physical stress•syncope •Women>men •ST segment elevation •Left ventricular apical ballooning on echo •Normal coronary arteries
	Pericarditis		+	+	+	•Relieving factor: Sitting up and leaning forward •Aggravating factor: Lying down and breathing deep				+			+	+		+	+				+	+		•Other causes:Malignancy, autoimmune disorders, chest trauma •Pericardial friction rub
Organ System	Diseases	Presentation										Diagnostic Tests						Past Medical History						Other Findings
		Chest Pain					GI Symptoms			Pulmonary	Neck
		On Palpation	On inspiration	Radiating to Extremeties	Radiating to Back	With Movement	Nausea or Vomitting	Epigastric Pain	Odynophagia or Dysphagia	Shortness of Breath	Jugular Distention	Cardiac Biomarkers	CBC Findings	ESR	D-Dimer	EKG Findings	CXR Findings	DM	Hyperlipidemia	Obesity	Trauma	Inxn*	Htn
Pulmonary	Pleuritis (pleurisy)	+	+	+	+	•Aggravating factor: Deep breathing				+			+	+			+				+	+		•Other causesPulmonary embolism, malignancy, autoimmune diseases
	Pulmonary Embolism		+			•Aggravating factors: Deep breathing, coughing, eating, bending and stooping				+					+		+							•Other causes: Immobility, pregnancy, oral contraceptive pills
	Pneumonia		+							+			+	+			+					+		•Complications: Sepsis, ARDS, Lung abscess
Gastrointestinal	GERD							+	+											+				•Other symptoms: Hoarseness, Dry cough at night, Sensation of lump in throat etc
	Esophageal Spasms			+	+	+			+	+							+						+	• Risk factors: Anxiety or depression and drinking wine, very hot or cold foods
	Esophagitis						+	+	+				+	+				+				+		• Causes: Hiatal hernia, infection, medications, radiation therapy
	Gastritis						+	+	+				+	+			+					+		• Causes: H.pylori infection, bile reflux, alcohol use, alcohol use
Organ System	Diseases	Presentation										Diagnostic Tests						Past Medical History						Other Findings
		Chest Pain					GI Symptoms			Pulmonary	Neck
		On Palpation	On inspiration	Radiating to Extremeties	Radiating to Back	With Movement	Nausea or Vomitting	Epigastric Pain	Odynophagia or Dysphagia	Shortness of Breath	Jugular Distention	Cardiac Biomarkers	CBC Findings	ESR	D-Dimer	EKG Findings	CXR Findings	DM	Hyperlipidemia	Obesity	Trauma	Inxn*	Htn
Musculoskeletal	Muscle sprain/Spasm	+	+			+															+			• Causes: Over use, dehydration, electrolyte abnormalities
	Costochondritis	+	+	+	+	+				+			+	+			+				+	+		• Risk factors: Rheumatoid arthritis, ankylosing spondylitis, Reiter's syndrome
	Rib fracture/Trauma	+	+	+	+	+				+			+	+			+				+			• Complications: Pneumothorax, hemothorax, surgical emphysema
Psychiatry	Anxiety (Panic Attack)	Chest tightness					+			+														• Other symptoms: Palpitations, trembling, sweating, choking, light headed, hot or cold flashes.

The following table summarizes the significant history, and diagnostic test findings that will help differentiate the acute coronary syndromes from one another, as well as from other coronary artery diseases:

Acute Coronary Syndromes	History and Symptoms			Pathology		Diagnostic tests		Treatment		Complications	Prognosis
	Chest pain		Duration of Chest pain	Coronary Artery	Plaque	Cardiac Biomarkers (e.g.CK-MB, Troponins)	EKG Findings	Medical Therapy	Reperfusion (e.g. PCI, CABG, or Medical)
	At Rest	Exertion
Unstable Angina	+	+	<30 minutes	Partial occlusion	Erosion or Rupture (39%)	Normal	•Normal EKG findings (some cases) •Flipped or inverted T waves •ST segment depression •Non-specific ST-T changes	+		•Arrhythmias •Congestive heart failure •Hypotension •New mitral regurgitation •MI •Sudden death	•1 year mortality rate is 1.7%
NSTEMI	+	+	>30 minutes	Partial or complete occlusion	Rupture (56%) or Erosion	Elevated	•No EKG findings (some cases) •Flipped or inverted T waves •ST segment depression •Non-specific ST-T changes •New left bundle branch block	+	+	•Arrhythmias •Congestive heart failure •Hypotension •New mitral regurgitation •Ventricular aneurysms •Sudden death	•1 year mortality rate is 24.4% •30 day mortality rate is about 2%
STEMI	+	+	>30 minutes	Complete occlusion	Rupture (50%-75%) or Erosion	Elevated	•ST elevation in at least 2 contiguous leads in V2-V3 •ST depression in at least two precordial leads V1-V4 •ST depression in several leads plus ST elevation in lead aVR (suggestive of occlusion of the left main or proximal LAD artery)	+	+	•Reinfarction •Arrhythmias •Left ventricular aneurysm •Pseudoaneurysm •rupture of papillary muscle, interventricular septum and LV free wall •Sudden death	•30 day mortality rate is 1.1% in <45 yrs and 20.4% in >75 yrs patients
Other Coronary Artery Diseases
Chronic stable angina	-	+	≤ 5 minutes	Severely narrowed coronary vessels	Stable plaque	Normal	•Normal EKG in 50% of cases •Down sloping, up sloping or horizontal ST segment depression •T wave inversion	+		•Heart failure	•Estimated annual mortality rate is 0.9%-1.4% •Annual incidence of non-fatal MI between 0.5%-2.6% •1 year mortality rate is 1.3%
Prinzmetal's angina	•Occur at rest (Mid night to early morning) •Not associated with exertion		5-30 minutes	Coronary artery vasospasm	-	Normal	•Transient ST segment elevation	+		•Arrhythmias •MI	•5 year survival is excellent (90%-95%)

Differential Diagnoses of Acute Coronary Syndromes in the Setting of Chest Pain

Cardiac	Pulmonary	Vascular	Gastrointestinal	Orthopedic	Other
Myopericarditis Cardiomyopathiesa	Pulmonary embolism	Aortic dissection	Esophagitis, reflex or spasm	Musculoskeletal disorders	Anxiety disorders
Tachyarrhythmias	(Tension)-Pneumothorax	Symptomatic aortic aneurysm	Peptic ulcer, gastritis	Chest trauma	Herpes zoster
Acute heart failure	Bronchitis, pneumonia	Stroke	Pancreatitis	Muscle injury/inflammation	Anemia
Hypertensive emergencies	Pleuritis		Cholecystitis	Costochondritis
Aortic valve stenosis				Cervical spine pathologies
Tako-Tsubo cardiomyopathy
Coronary spasm
Cardiac trauma
Bold = Common and/or important differential diagnoses aDilated, hypertrophic and restrictive cardiomyopathies may cause angina or chest discomfort

Treatment

Coronary Angiography

Coronary angiography within 12 hours likely benefits high risk (elevated cardiac biomarkers at baseline or diabetes or a GRACE score more than 140) patients.

Recommendations for Anti-ischemic Drugs in the Acute Phase of Non-ST-elevation Acute Coronary Syndromes

Recommendations	Class of Recommendations	Level of Evidence
Early initiation of beta-blocker treatment is recommended in patients with ongoing ischemic symptoms and without contraindications.	I	B
It is recommended to continue chronic beta-blocker therapy, unless the patient is in Killip class III or higher.	I	B
Sublingual or i.v. nitrates are recommended to relieve angina;a intravenous treatment is recommended in patients with recurrent angina, uncontrolled hypertension or signs of heart failure.	I	C
In patients with suspected/confirmed vasospastic angina, calcium channel blockers and nitrates should be considered and beta-blockers avoided.	IIa	B
aShould not be administered in patients with recent intake of sildenafil or vardenafil (< 24 h) or tadalafil (< 48 h).

Prevention

Primary Prevention

The primary prevention strategies include:

• Dietary modifications:

• Regular consumption of fruits, vegetables, whole grains and lean meats
• Limit foods high in cholesterol and saturated fats

• Physical exercise

• 30 minutes of moderate exercise

• Weight loss
• Smoking cessation
• Regular blood pressure, blood sugar and cholesterol check

Secondary Prevention

The secondary prevention strategies include:

• Dietary modifications
• Regular blood pressure, blood sugar and cholesterol check
• Compliance with therapy for post acute coronary syndrome event
• Cardiac rehabilitation programs