Syllabi - General Practice - Harm Scenario

A 50 year old man asked for a repeat prescription of sotalol which he had been taking for several years for his extrasystoles. I had not previously seen him, and was cautious because of the number of antiarrhythmics which had proarrhythmic properties. I formulated the question, in patients with extrasystoles does sotalol increase the risk of sudden cardiac death?

Searching terms and evidence source: sotalol AND (mortality OR death*) - search done in the Cochrane Controlled Trials Registry

Read the article and decide:

• Is the evidence from this study valid?
• If valid, is this evidence important?
• If valid and important, can you apply this evidence in caring for your patient?

Completed Harm Worksheet for Evidence-Based General Practice

Citation

Pratt CM et al. Mortality in the Survival With ORal D-sotalol (SWORD) trial: why did patients die? Am-J-Cardiol 1998: 81:869-76.
AND
Waldo AL et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol.
Lancet 1996; 348:7-12.

Are the results of this harm study valid?

Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause?

Yes - This was a randomised placebo controlled trial.

Were treatment exposures and clinical outcomes measured the same ways in both groups (e.g., was the assessment of outcomes either objective (e.g., death) or blinded to exposure)?

Yes - the major outcome was death.

Was the follow-up of study patients complete and long enough?

The trial was stopped before recruitment had completed because of the clear harm.

Do the results satisfy some "diagnostic tests for causation"?

Is it clear that the exposure preceded the onset of the outcome?

Yes - this was a randomised trial.

Is there a dose-response gradient?

Not tested; a single dose was used in the trial.

Is there positive evidence from a "dechallenge-rechallenge" study?

As the adverse outcome is death, this is not possible.

Is the association consistent from study to study?

Only one study has been powered to look at mortality

Does the association make biological sense?

Yes - it is consistent with findings for other antiarrhythmics.

Are the valid results from this harm study important?

		Adverse Outcome		Totals
		Present (case)	Absent (control)
Exposed to the Treatment	Yes (Cohort)	78 a	1471 b	a + b
	No (Cohort)	48 c	1524 d	c + d
Totals		a + c	b + d	a + b + c + d

In a randomised trial or cohort study:

Relative Risk (RR) = [a/(a+b)]/[c/(c+d)]

In a case-control study:

Odds Ratio (OR) (or Relative Odds) = ad/bc

In this study:

RR = (78/1549)/(48/1572)
= 1.65 (95% CI 1.15 - 2.36), p = 0.006

Should these valid, potentially important results of a critical appraisal about a harmful treatment change the treatment of your patient?

Can the study results be extrapolated to your patient?

Probably - though the patients in SWORD had recent myocardial infraction and a reduced ejection fraction, though is no reason to believe it was the underlying disease rather than the adverse effects of the d-sotalol which caused the increased mortality.

What are your patient's risks of the adverse outcome?

To calculate the NNH (the Number of patients you Need to treat to Harm one of them) for any Odds Ratio (OR) and your Patient's Expected Event Rate for this adverse event if they were NOT exposed to this treatment (PEER):

NNH = (PEER(OR-1)+1)/(PEER(OR-1)x(1-PEER))

What are your patient's preferences, concerns and expectations from this treatment?

He finds the extrasystoles disturbing, and would like them suppressed. However, he is also aware of the risks, and is weighing the risks and benefits.

What alternative treatments are available?

Other potential anti-arrhythmic treatment has either proved dangerous or is untested. Reframing of the extrasystoles seems the most appropriate and safe treatment.

Additional Notes

The SWORD study used d-sotalol, an isomer of sotatol. There is no evidence either way on the safety of sotalol.

D-sotalol increases the risk of sudden cardiac death in patients with recent myocardial infarction and a reduced ejection fraction.

Clinical Bottom Line

d-sotalol increases mortality in patients with previous myocardial infarction.

Citation

Pratt CM et al. Mortality in the Survival With ORal D-sotalol (SWORD) trial: why did patients die? Am-J-Cardiol 1998: 81:869-76. AND Waldo AL et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996; 348:7-12.

Clinical Question

Does sotalol increase the risk of sudden cardiac death?

Search Terms

sotalol AND (mortality OR death*) - search done in the Cochrane Controlled Trials Registry

The Study

The study randomised 3121 patients with a recent myocardial infarction (6-42 days) and an ejection fraction of 40% or less to placebo or 100mg of d-sotalol (increasing to 200mg if tolerated).

The Evidence

There were 78 deaths (5%) among 1549 patients on sotalol compared to 48 deaths (3.1%) among 1572 patients on placebo.

`Relative Risk of 1.65 (95% CI 1.15 to 2.36). Relative Risk for presumed arrhythmic deaths was 1.77. Absolute Risk Difference was 1.9%, giving a Number Needed to Kill of about 50.`

Outcome	Time to Outcome	CER	EER	RRR	ARR	NNH
death		0.031	0.05	65%	0.019	53
	95% Confidence Intervals			15% to 136%	0.006 to 0.034	29 to 167

Comments

D-sotalol is an isomer of sotalol, but there is no equivalent data for sotalol nor for patients who have not had a myocardial infarction. However, prudence would suggest avoided its use unless adequate safety data did appear.

Appraised By

Paul Glasziou