Steroids for Dizziness Too

Motivation:  During my final rotation in the ED, I met surprisingly many patients with sudden onset of severe unrelenting dizziness - chalked up to vestibular neuritis after clean MRI.  Besides sympathetic listening and symptomatic control with meclizine, is there anything else to do?  I had thought not.  I recently found out, however, that steroids can help vestibular neuritis too.  How good is the data?

For background, the cause of vestibular neuritis is not definitely known but based on associational data, appears related to viral infection or reactivation of latent HSV1.  Symptoms of dizziness usually last three to seven days but recovery is often incomplete with many patients having persistent vestibular deficits on exam.

Paper: Strupp, M., Zingler, V.C., Arbusow, V. et. al.  "Methylprednisolone, Valacyclovir, or the Combination for Vestibular Neuritis" N. Engl. J. Med. (2004) 351: 354-61.

Methods: A prospective, randomized, double-blind, 2x2 factorial trial testing methylprednisolone and valacyclovir in patients with acute vestibular neuritis.  Adult patients were recruited through ED in academic hospitals in Munich and Mainz, Germany.  Diagnosis of vestibular neuritis was based on history of acute onset of severe prolonged vertigo with exam showing unidirectional horizontal nystagmus with a rotational component.  Patients were primarily excluded if they had additional cochlear symptoms (tinnitus or hearing loss), other brainstem deficits, central lesions on MRI, or contraindications to steroids or valacyclovir (peptic ulcer disease, osteoporosis, renal failure, liver injury, etc.).  Methylprednisolone was dosed at 100 mg on first three days with a prolonged taper ending at 10 mg on day 22.  Valacyclovir was dosed at 1000 mg three times daily for seven days.  Primary outcome was vestibular paresis at 12 months.

Results:
Cohort: In total, 141 patients were randomized - 38 to placebo, 35 to methylprednisolone, 33 to valacyclovir, and 35 to steroid plus valacyclovir.  Baseline characteristics were balanced, and average age was in late 40s for most groups.  Treatment was started on average 1.6 to 1.8 days after onset of symptoms.  Follow-up data present for 30/38 in placebo, 29/35 in steroids, 27/33 for valacyclovir, and 28/35 for steroid plus valacycolvir group.  Most common reason for withdrawing was unwillingness to follow-up or non-compliance.

Efficacy Measurement: Change in vestibular function over time was measured by assessing nystagmus in response to caloric stimulation (warm water) in the ears.  Intact vestibular response leads to appropriate nystagmus while damaged vestibular system leads to relative paresis.  Analysis was by as treated and not by intention to treat population.

Steroid: At 12 months, patients receiving methylprednisolone had 62.4% improvement in vestibular function compared to 39.6% improvement with placebo (p<0.001).

Valacyclovir: At 12 months, patient receiving valacyclovir had 36% improvement in vestibular function compared to 39.6% improvement with placebo (not significant).  Combination of steroid and valacyclovir resulted in 59.2% improvement in vestibular function, but the improvement was not significantly different from that achieved by steroids alone.

Discussion:  This trial demonstrates that acute treatment of vestibular neuritis with corticosteroids may help prevent long-term vestibular damage.  Interestingly, the authors did not track resolution of vertigo - the primary symptom that brought the patients in.  The authors intentionally did not track vertigo because they assumed that the brain would compensate centrally for the imbalanced input from the two ears after a few days.  Symptom improvement would not correlate with actual recovery of the vestibular system, but it would have been nice to have the data to compare.  The trial also shows that valacyclovir treatment really did not affect the long-term outcome.  The reason could either be that vestibular neuritis is usually not HSV mediated or that the actual reactivation and replication occurred prior to symptoms and initiation of treatment with valacyclovir.  While convincing, this trial has some serious limitations including small number of subjects, no intention to treat analysis, and significant number of patients lost to follow-up in each group (17% dropout rate in steroid group).  This data needs to be backed up with a larger trial.  For now, though, for patients with acute vestibular neuritis with no contraindications to steroids, starting treatment early may likely have long-term beneficial effects.

Renal Artery Stenosis - Ultrasound or MRI?

Motivation: During this year, I have presumed renal artery stenosis in many people, tested some of them, and found none.  Among so many with vascular disease just about everywhere, I have not discovered a single new case of renal artery stenosis.  After the last patient in whom I was very sure of finding renal artery stenosis and found myself fooled once more when reading the radiology report, I wondered whether I am using the right test.  The first-line test used - at least as far as I can tell from my experience - has been renal ultrasound with doppler.  I wondered whether other imaging ways such as MRI might be better.

Paper: Solar, M., Zizka, J., Krajina, A., et. al. "Comparison of Duplex Ultrasonography and Magnetic Resonance Imaging in the Detection of Significant Renal Artery Stenosis." Acta Medica (2011) 54: 9-12.

Methods: In an academic hospital in Prague, 94 patients with high clinical suspicion of renovascular hypertension were examined by duplex ultrasound, MRA with contrast, and angiography.  Angiography was performed last.  The gold standard was angiography.  For ultrasound, significant renal artery stenosis was defined by peak systolic velocity above or equal to 180 cm/sec (usual standard).  For MRA and angiography, a cutoff of 60% stenosis was used.

Results:
Cohort: Of the 94 patients, 41 were women.  Average age was 60 years with patients taking on average 3.8 anti-hypertensives.  The mean systolic pressure was 153 mmHg (standard deviation of 31).  About a third had diabetes.  Based on angiography, renal artery stenosis was found in 61 kidneys among 186 kidneys examined (atherosclerosis in 58 and additional four had fibromuscular dysplasia - unexplained whether one case of fibromuscular dysplasia was overlap with atherosclerosis or did not cause significant stenosis).

Duplex Ultrasonography: Ultrasonography could be performed successfully in 81 patients (86%).  The most common reason for inability was poor imaging quality.  For ultrasound (among imaged kidneys), sensitivity: 85%, specificity: 84%.  Positive predictive value: 70%, negative predictive value: 92%.

MRA: By MRA, adequate images could be obtained in 93 of 94 patients.  Sensitivity: 93%, specificity: 93%.  Positive predictive value: 86%, negative predictive value: 97%.

Discussion:  Based on this direct comparison of ultrasound and MRA, testing for someone with high pre-test probability of renal artery stenosis should probably proceed by MRA given higher sensitivities.  In cases with low to moderate pre-test probability, renal ultrasound may sufficiently decrease the probability.  Neither method is, of course, perfect.  While this study was done in Prague, it is likely that a regular American population might be more obese and have higher BMI - particularly in patients with sustained hypertension.  The adequacy of an ultrasound examination may be further decreased in this group.  A misconception that I had was that if an ultrasound examination could be performed well, it is just as good as MRA.  But, even among kidneys that could be examined well, the sensitivity of ultrasound was lower than MRA.  Some caveats of this study are that this was a single center study and that there is no verification that radiologists examining the MRA were blinded to the results of the ultrasound (although with MRA, more lesions were detected compared to US).  So, from now, if I am really suspicious of renal artery stenosis, I will go ahead with the MRA.  Maybe, I will find someone with renal artery stenosis.

Aspirin After Stenting

Motivation: Reviewing a patient's home medication list yesterday, I found my favorite offender on the list - aspirin at 325 mg dosage.  The man had a drug eluting stent placed two years ago.  I grumbled out loud something about unnecessary risks to patients.  One of the seniors sitting within earshot struck back that in fact every patient is kept on a full dose aspirin plus clopidogrel after drug eluting stent placement.  Turns out that this fact had escaped me nine months into internship.  But, is there data to support the practice?

Paper: Mehta, S.R., Tanguay, J.-F., Eikelbloom, J.W., et. al. "Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS7): a randomized factorial trial." Lancet (2010) 376: 1233-43.

Methods: Multinational randomized factorial trial.  Inclusion criteria were symptoms of acute coronary syndrome and either EKG evidence or raised biomarkers.  All patients underwent coronary angiography with intent to undergo PCI within 72 hours.  Exclusion criteria was increased risk of bleeding or active bleeding.  All patients initially got full dose aspirin.  From day two, patients were randomized to either high dose (300-325 mg) or low dose (75-100 mg) aspirin.  In the clopidogrel arm, patients either received 600 mg loading dose followed by 150 mg from days 2-7 or received 300 mg loading dosed followed by 75 mg on days 2-7.  With the factorial design, there were four groups receiving varying combinations of clopidogrel and aspirin.  Primary outcome was composite of CV death, MI, or stroke within 30 days.

Results:
When the trial was first released, the clopidogrel trial results attracted much attention and controversy.  Multiple editorials comment on the analysis of the clopidogrel piece of the trial.  I will just describe the aspirin portion of the trial.

Cohort: There were 8624 patients randomized to high dose aspirin and 8639 randomized to low dose aspirin. The two treatment arms were very similar in baseline characteristics.  Average age was about 61 years with 25% female.  About 63% of the patients had NSTEMI/UA while the remaining patients presented with STEMI.  About 37% of patients took regular aspirin, and another 20% took regular clopidogrel prior to randomization.

Angiography: After initial angiography, 8160 of the 8624 (94.6%) in the high dose ASA group received a stent (58% BMS and 42% DES).    In the low dose ASA group, 8163 of the 8639 (94.5%) received a stent (58% BMS and 42% DES).  Patient did not undergo PCI because of (1) no coronary disease - most common, (2) no suitable area for revascularization, or (3) CABG was better alternative.

Follow-up: Primary outcome of cardiovascular death, stroke, or MI did not differ between the high dose and low dose group (HR: 0.98, 95% CI 0.84-1.13, p = 0.76).  Between high and low dose aspirin, there was no difference in definite or probable stent thrombosis (0.9% vs 1.0%, CI: 0.68-1.26).  In secondary analysis, recurrent ischemia was slightly higher in low dose aspirin (0.4%) compared to high dose aspirin (0.2%) though event numbers were small to make meaningful post-hoc secondary comparisons.  In the overall trial analysis (including those who got PCI and those who did not), high dose aspirin resulted in significant increase in minor bleeding (5.0% vs 4.2%, p = 0.04).

Discussion: This trial shows that even in the acute post-PCI setting, use of a lower dose aspirin does not increase likelihood of stent thrombosis.  Some of the strengths of this trial are the randomized trial design with very large number of subjects (over 8,000 in both groups).  While this trial looks only at initial 30 day events, low dose aspirin is expected to be adequate in long-term setting as well given its equivalence to high dose aspirin in the high-risk post-procedure period.  There are no randomized trials in the long-term setting, but there have been retrospective observational studies which show that there is no increased risk of stent thrombosis with low dose aspirin.  On the other hand, there is more definite evidence showing increased risk of bleeding with high dose aspirin compared to low dose aspirin.  Current practice guidelines, however, continue to recommend prolonged administration of high dose aspirin after stenting!

Diuresis on steroids

Motivation: Ever been stuck with diuresis?  Every morning you are drawing even with fluid balance, and metolazone plus bumex is making no progress on the crackly lungs.  Short of sending the patient to the ICU for ionotropes, is there anything else?  Recently one of my fellow interns pointed out that prednisone may actually help with diuresis.  I was at first skeptical.  After all, with the mineralocorticoid activity of prednisone, I would expect prednisone to worsen diuresis.  But, turns out that there is more to steroids.  Prednisone also has renal vasodilatory effects and increases renal plasma flow and GFR.  So, some data?

Paper: Zhang, H., Liu, C., Ji, Z. et. al.  Prednisone Adding to Usual Care Treatment for Refractory Decompensated Congestive Heart Failure.  Int. Heart J. (2008) 49: 587-95

Methods: The authors conducted an observational study in which patients were recruited who had been been hospitalized for at least one week for decompensated heart failure and had failed to respond to IV diuretics.  Exclusion criteria included infection, cardiogenic shock, SBP<80 or >140, HFpEF, or myocarditis.  Patients could receive IV ionotropes so long as they were maintaining blood pressure.  Prednisone (1 mg/kg/day with max dose of 60 mg) was added to therapy for nine days.  Primary end-points were urine volume, patient assessed dyspnea, changes in renal function, and physician assessed clinical status.

Results:
Cohort: The authors recruited 35 patients with median age of 52.3 years and gender distribution of 48.6% male.  All patients were in class IV heart failure with all patients having LVEF less than 30%.  Besides IV diuretics, 74% of patients (26/35) were also receiving IV ionotropes with the majority also getting IV nitroglycerine (91.4%, 32/35) and digoxin (82.9%, 29/35).

Outcomes: After nine days of prednisone therapy, mean urine output increased from 1400 mL/day to 2400 mL/day (statistically significant).  Interestingly, the main jump in urine output occurred at day 3 when urine output jumped to about 2100 ml/day.  Patient assessed dyspnea improved in 80% of patients (p<0.01).  All but one patient were transitioned entirely to PO medications (off IV diuretics, ionotropes, or nitroglycerin) by day nine.  GFR increased from baseline of 63.4 mL/min to 74.1 mL/min (p<0.05).  Average weight loss was 3.17 kg. 

Safety: There were no deaths.  Prednisone therapy increased fasting glucose levels in diabetic patients but did not affect fasting levels in non-diabetic patients.  There were no new infections noted in the cohort.

Discussion:  This study could really benefit from a control group!  The patients improved remarkably with prednisone administration, but one could also argue that if you stick with diuresis long enough, you will eventually make some headway.  The argument made by the authors is that the patients had received conventional therapy for the week prior without improvement in clinical status.  A concurrent control group or even a historical control group in the second week of therapy for CHF would make the case more convincing.  On the flip side, 34 out of 35 patients progressed from decompensated CHF dependant on IV therapy to PO therapy.  The progress was quite dramatic and may suggest benefit from prednisone.  So, how does this change therapy?  I would still not add prednisone to usual therapy for CHF, but if a patient presents with dyspnea along with the usual CHF/COPD combination, I would be less hesitant to add on the steroids.  Also, this topic is a great mini research project for a retrospective outcomes analysis for CHF patients who got steroids (likely for COPD) compared to CHF patients who did not get steroids.