Adderall and cardiovascular risks: A therapeutic dilemma

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Adderall (Shire Pharmaceuticals, Canada) is a preparation of mixed amphetamine salts made up of dextro-amphetamine saccharate, dextroamphetamine sulfate, (racemic dextro/levoamphetamine) aspartate monohydrate and (racemic dextro/levoamphetamine) sulfate in equimolar concentrations. The aut

Adderall and cardiovascular risks: A therapeutic dilemma

Adderall (Shire Pharmaceuticals, Canada) is a preparation of mixed amphetamine salts made up of dextro-amphetamine saccharate, dextroamphetamine sulfate, (racemic dextro/levoamphetamine) aspartate monohydrate and (racemic dextro/levoamphetamine) sulfate in equimolar concentrations. The authors used Adderall in this manuscript even though generic names are usually preferred.

CASE PRESENTATION

A boy of eight years old is diagnosed with ADHD. His mother expresses concern when discussing the therapeutic options. Her father died from 'an abnormal rhythm of the heart'. She has also heard that children with a history of heart disease should not take sustained-release ADHD medication.

Is it safe to give children ADHD sustained-release salts of amphetamine?

The safety of prescription stimulants is a controversial issue. This article will outline the current controversies regarding the prescription of stimulants. It will also summarize the guidelines for prescribing inspirations to children with ADHD.

 

ADDERALL: CONCERNS RAISED ABOUT ADDERALL

Adderall is an amphetamine-salt mixture indicated to treat ADHD.

Health Canada approved Adderall XR for use in Canada on January 4, 2004. Health Canada suspended Adderall XR's notice of conformity in February 2005 due to 20 global/international reports of cardiac deaths and strokes among individuals treated with Adderall. These reports were submitted to the United States Food and Drug Administration's (FDA's) adverse event reporting system. 14 of these people were children ( 1). Some patients in the FDA adverse events reports had toxic levels of mixed amphetamines. They also had a history of ventricular arrhythmia in their family, participated in strenuous exercise, and were dehydrated. Other patients had structural cardiac abnormalities. The abnormalities that were described included aberrant origins of coronary arteries and idiopathic subaortic hypertrophic stenosis. These anomalies may be affected negatively by stimulant drugs.

In Canada, in 2005, the Adderall XR New Drug Committee, formed under the Food and Drug Act to assess the evidence of these serious adverse effects, concluded that the analyses provided by Shire Pharmaceuticals and Health Canada used different groups of data and were methodologically weak <http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/ndca_rep_cnma_rap_2005-08-25-eng.pdf>. The Committee also stated that all stimulants could theoretically increase the risk for stroke or sudden cardiac death. The Committee did not specify whether this risk was dependent on the inspiration whether the person used strenuous exercises or had cardiac risk factors.

Adderall returned to the Canadian marketplace in August 2005 with recommendations that the labelling be changed to indicate that stimulants should only be prescribed cautiously to patients who engage in strenuous activity, take other stimulants, or have a history of sudden death in the family ( 1).

The FDA's Drug Safety and Risk Management Advisory Committee recommended a black box warning on February 9, 2006, describing the cardiovascular risk of stimulants used for ADHD treatment ( 1).

Is the drug effective?

Adderall is effective in treating ADHD when compared to placebo. It is also as practical or even more effective than other stimulants (3 - 6) used to treat ADHD.

Adderall side effects are not always dose-related. The overall incidence is comparable to other stimulants ( 4). In both short and long-term trials, the most common adverse cardiovascular effects reported were elevated blood pressure or heart rate. This increase is considered statistically but not to be clinically significant. ( 7). A chronically elevated heart rate and blood pressure could lead to cardiovascular morbidity. It may be prudent to monitor children's blood pressure and heart rates on stimulants (8 or 9).

The risk of sudden death from cardiac arrest in children on stimulants may be higher than the rate in the general population. However, adverse event reporting is voluntary in Canada and the United States. A formal monitoring system is not available, making it difficult to estimate such death rates ( 10). Adderall was safe for patients with essential high blood pressure in adult studies ( 2). In otherwise healthy adults (n=223), 3% of patients experienced adverse cardiovascular effects such as hypertension, palpitation, or tachycardia. This adverse event rate aligns with most cardiovascular medications' expected negative event rate ( 2). It is estimated that the incidence of cardiac abnormalities in children with ADHD approximates that of the general public. There is therefore no reason to believe that these children are at a higher risk of having their anomalies affected by stimulant therapy.

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SUGGESTED PLAN TO PRESCRIBE ADDERALL

These recommendations are based on the fact that untreated ADHD ( 11) is associated with significant morbidity, as well as the benefits and side effects of Adderall. These measures are meant to be used by primary and community child health care providers. They are an addition to the current recommendations on prescribing stimulant medication in children.

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Considerations for Pre-treatment

Only after a confirmed diagnosis of ADHD using either the International Classification of Diseases, Tenth Edition or the Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition, should treatment be considered. Only patients with moderate to severe impairments in two settings should begin treatment.

WORKUP BEFORE STARTING ADDERALL (RECOMMENDATIONS FROM THE AMERICAN HEART ASSOCIATION STATEMENT [12])

The past medical history: Important facts

  • Dizziness or fainting, especially during exercise.
  • Exercise tolerance or chest pain with exercise;
  • Seizures; Rheumatic fever;
  • Palpitations or rapid heartbeats are two examples of pulses.
  • History of heart murmurs other than the innocent (functional) murmur or other heart problems.
  • A viral infection that causes chest pain and palpitations.
  • Hypertension in history
  • Medication (prescription, over-the-counter and alternative);
  • Health Supplements (nonprescription)

Family history: Important facts

  • Death that occurs suddenly or without explanation in a young person
  • Heart attack or sudden cardiac death in members under 35 years old;
  • Sudden death during exercise; Cardiac arrhythmias;
  • Hypertrophic cardiomyopathy is a term used to describe a variety of cardiomyopathies, including right ventricular cardiomyopathy and dilated cardiomyopathy.
  • Long QT syndrome, short QT syndrome or Brugada syndrome;
  • Wolff-Parkinson-White syndrome or similar abnormal rhythm conditions;
  • Syncope, or any other event requiring resuscitation that occurs in a young member (under 35 years old);
  • Marfan's syndrome.

Physical Examination

  • A pathological murmur is present.
  • Heart rate irregularity
  • Tachycardia, Hypertension and
  • Physical findings that suggest Marfan's Syndrome

Baseline Investigations

The American Academy of Pediatrics released a supplementary statement in August 2008 ( 13 ) that did not recommend an electrocardiogram to screen for cardiac problems before prescribing stimulants. If the patient is suspected of having cardiac disease, including arrhythmia or syncope, then an ECG must be performed. The ECG must be read by either a paediatric cardiologist, a cardiologist who has experience with paediatric ECGs, or any other physician with paediatric ECG reading experience. Before prescribing stimulants, the initial assessment should reveal any symptoms that raise concerns about cardiovascular disease.

MONITORING WHEN TREATMENT IS UNDERWAY

  • Each time you visit, perform a cardiovascular exam. Before starting Adderall, record your baseline heart rate and blood pressure. Repeat readings should be taken during annual follow-up visits. Consider reducing or stopping the medication if you get three consecutive readings higher than the 95th percentile of your age. You can also consult a doctor who is an expert in evaluating children with hypertension.
  • Ask about side effects and cardiovascular symptoms during follow-up appointments, such as shortness of breath, chest pain, palpitations and syncope. Also, ask about dizziness, headaches and social withdrawal.
  • If there are any new family histories, ask.

In our case, we would need to know the exact circumstances of the death of the father, including his age, whether it was unexpected, the diagnosis made regarding the arrhythmia and if there was any other family member with heart disease.

A full cardiovascular assessment may be required for this patient. If an arrhythmia is suspected, this would include an ECG baseline (e.g. if it was a sudden unaccounted death due to the possibility of inherited arrhythmia). If this assessment revealed a cardiac concern, stimulants should be used cautiously, pending a referral to cardiology.

A MedLine search was conducted in OVID (1966-2007) with the following keywords: Adderall, Adderall XR ADHD, children treatment, stimulants sudden death, side effects.

Guidelines for stimulant use were reviewed from the following organization/association Web sites: the Canadian Paediatric Society, the American Academy of Pediatrics, the Royal College of Paediatrics and Child Health, and the American Academy of Child & Adolescent Psychiatry.

Acknowledgements

Children's Health Research Institute, Children's Optimal Therapeutics Program and the Canadian Institutes of Health Research – GlaxoSmithKline Paediatric Clinical Pharmacology Chair supported the present research.

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