Fever and Pulmonary Embolism

Motivation: Clinical lore has it that pulmonary embolism (PE) causes low grade fevers and should not cause a fever as high as 103F.  While deciding on the often pondered question of whether or not a person has PE, I have seen the degree of fever sway the decision one way or the other.  But, is this true?

Paper: Stein, PD, Afzal, A, Henry, J, et. al. "Fever in Acute Pulmonary Embolism" Chest (2000); 117:39-42.

Methods: In the PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) study, retrospective analysis was made of presence of fever in patients with angiographically proven pulmonary embolism (PE).

Results:
Cohort: There were 363 patients from PIOPED study analyzed for this study.  Fever was present in 95 patients (26%; 95% CI: 22-31%).  Of the 95 patients with fever, 43 (45.3%) did not have other causes of fever - solely attributed to PE.  There were 46 (48.4%) patients who had an alternative possible etiology of fever - 15 with malignancy, 10 with infection, 6 with recent operation (top three causes).   Six did not have further investigation (so indeterminate cause).  Fever was not more frequent in patients with pulmonary hemorrhage or infarction than in those without.

Maximum Temperature: Of the 43 patients with available information on temperature, the maximum temperature was 100 to 100.9F in 24, 101 to 101.9F in 14, 102-102.9 in 3.  One patient each had maximum temperature between 103-103.9 and greater than 104F.

Discussion: The clinical lore turns out to be mostly true - majority of patients with PE associated fever have maximum temperature less than 102F.  What I thought was most cautionary, however, is that fever is an infrequent finding in PE (present in only about a fourth).  Even among those with fever, they were just as likely to have an alternate explanation as pulmonary embolism.  What I took away from this paper is that if patients with PE have fever, they still need a thoughtful workup.

Taking a Chance on Chantix

Motivation: Last month, I met a man in clinic who said that his life had changed after his stroke.  Now, after years of fruitless contemplation, he was going to quit smoking.  He asked me about Chantix (generic varenicline).  Is it safe?

My instinct was to say yes.  But, the partial nicotinic agonist effects also make varenicline a sympathomimetic agent.  In patients with cardiovascular disease, are there excess side effects?  Turns out that the issue has been tested in a randomized fashion in 2010.

Paper: Rigotti, N.A., Pipe, A.L., Benowitz, N.L., et. al. "Efficacy and Safety of Varenicline for Smoking Cessation in Patients with Cardiovascular Disease." Circulation (2010); 121: 221-229.

Methods: Multi-center randomized placebo-controlled blinded trial testing varenicline (1 mg daily; quit day eight days after start of therapy) versus placebo in adult (35 to 75 years) smokers with cardiovascular disease (coronary artery disease, peripheral vascular disease, or cerebrovascular disease) existing for more than two months.  Patients with depression, severe neurological deficits from stroke, or severe renal and hepatic diseases were excluded.  Treatment group received 12 weeks of therapy.  Primary outcome was carbon monoxide confirmed abstinence between weeks 9 to 12 after start of therapy.  Patients were followed for 52 weeks.

Results:
Subjects: In total, 714 subjects were randomized to varenicline (355) or to placebo (359).  Study completion rate was 82.8% in varenicline group and 85.1% in placebo group.  Baseline characteristics were comparable between groups.  In the varenicline group, average age was 57 with 75% male and 80% white.  Average smoking history was for forty years.  For CVD, majority had CAD.  Only 4.5% had suffered a stroke.

Efficacy: The abstinence rate at weeks 9 through 12 was 47% in the varenicline group versus 13.9% in placebo (p<0.0001).  The rate of abstinence from week 9 to end of follow-up at week 52 was 19.2% for varenicline versus 7.2% for placebo (p<0.0001).

Adverse Effect: Patients on varenicline suffered more adverse effects than placebo (81.6 vs. 64.9%, CI for difference: 10.3-23.2%) resulting in more participants who stopped drug in varenicline group (9.6%) versus placebo (4.3%).  There were no differences in mortality.  The most common side effect was nausea (29.5% in varenicline vs. 8.6%).  Sleep disorder consisting of abnormal dreams, insomnia, and nightmare was significantly more frequent in treatment group (22.1%) vs placebo (9.7%).  There was a trend towards higher frequency of cardiovascular events in varenicline group (7.1% vs 5.7%) which did not reach significance.

Discussion: In summary, varenicline does not appear to increase risk of cardiovascular events significantly within the power of the study.  It was sobering to see though that after a year, only 19% will be abstinent even after being motivated enough to enroll in a trial and take a drug for twelve weeks.  Varenicline is certainly not free of adverse effects with nausea (30%) and sleep disorder (22%).  Prior to prescribing, patients need to be warned of these potentially bothersome side effects.  Also, of note, the trial was conducted in patients with stable CVD (defined as no events within the past two months).  So, I would likely wait for two to three months before prescribing varenicline to the patient seeking to stop smoking.