396 - BP and CKD, Psilocybin and Depression, F/U Gonococcal Treatment

From the Guidelines and the KDIGO

1) Managing Blood Pressure with Chronic Kidney Disease (CKD)

According to the latest National Health and Nutrition Examination Survey (NHANES) performed from 2011 – 2014, the overall CKD prevalence among US adults was 14.8% with the prevalence of CKD Stage 3 or greater (eGFR <60) of 7.2%. There is a large body of evidence that patients with CKD have a substantial increase in cardiovascular (CV) risk that can be in part explained by an increase in traditional risk factors such as HTN, T2D, and the metabolic syndrome. However, CKD alone is also an independent risk factor for CVD.

In March of 2021, the Kidney Disease: Improving Global Outcomes (KDIGO) updated their 2012 guideline on managing BP for patients with CKD. The KDIGO definition for CKD is: “Abnormalities of kidney structure or function, present for >3 months, with implications for health" and requires one of two criteria. Either:

• GFR <60 ml/min/1.73 m2

or

• Markers of kidney damage, including albuminuria (albumin-creatinine ratio/ACR > 30) regardless of GFR.

With each recommendation, the strength of recommendation was indicated as Level 1 (strong = “recommend”) or Level 2 (weak = “suggest”), and the quality of the supporting evidence is shown as A (high), B (moderate), C (low), or D (very low). Recommendations include:

Blood Pressure Measurement:

• Recommend standardized office BP measurement in preference to routine office BP measurement for the management of high BP in adults (1B)
  • Practice Point: An oscillometric BP device may be preferable to a manual BP device for standardized office BP measurement; however, standardization emphasizes adequate preparations for measurement, not equipment type.
  • Practice Point: Automated office BP (AOBP), either attended or unattended, may be the preferred method of standardized office BP measurement
• Suggest that out-of-office measurements with ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) be used to complement standardized office blood pressure readings (2A)

Lifestyle Changes for Lowering BP with CKD not on dialysis

• Suggest targeting sodium intake of < 2 gm/day (2C)
• Suggest moderate-intensity physical activity >150 minutes/week or compatible with cardiovascular or physical tolerance (2C)

BP Management with CKD with or without DM not on dialysis

• Suggest target systolic BP <120 when tolerated, using standardized office BP measurement (2C)
  • Practice Point: It is potentially hazardous to apply the recommended SBP target of < 120 to BP measurements obtained in a non-standardized manner.
• Recommend ACEi or ARB for HTN, CKD, and severely increase albuminuria (ACR > 300) without DM (1B)
• Suggest ACEi or ARB for HTN, CKD, and moderately increased albuminuria (ACR 30-300) without DM (2C)
• Recommend ACEi or ARB for HTN, CKD, and moderate-severe (ACR > 30) increased albuminuria with DM (1B)
• Practice Points include:
  • It may be reasonable to treat people with high BP, CKD, and no albuminuria, with or without diabetes, with ACEi or ARB
  • ACEi or ARB should be administered using the highest approved dose that is tolerated to achieve the benefits described because the proven benefits were achieved in trials using these doses
  • Changes in BP, serum creatinine, and serum potassium should be checked within 2-4 weeks of initiation or increase in the dose of ACEi or ARB, depending on the current GFR and serum potassium
  • Hyperkalemia associated with use of ACEi or ARB can often be managed by measures to reduce the serum potassium levels rather than decreasing the dose or stopping them
  • Continue ACEi or ARB therapy unless serum creatinine rises by more than 30% within 4 weeks following initiation of treatment or an increase in dose
  • Consider reducing the dose/discontinuing ACEi or ARB in the setting of either symptomatic hypotension or uncontrolled hyperkalemia despite treatment
  • Mineralocorticoid receptor antagonists are effective for management of refractory hypertension but may cause hyperkalemia or a reversible decline in kidney function, particularly among patients with low eGFR
• Recommend avoiding combination of ACEi, ARB, and direct renin inhibitor (DRI: aliskirin) for CKD with our without DM (1B)

Mark’s Comments:

The prevalence of CKD in the US is significant, and I believe it is too often “monitored” rather than actively managed. This guideline helps provide us some direction in terms of more active management.

Please note that the distinction between “standardized” and “routine” office blood pressure measurement is an important one. A standardized blook pressure measurement is defined in the guideline as one that follows all guideline-recommended preparations as outlined in the guideline (figure 2 and 2^nd reference below). The device used is not part of the definition. “Routine” office blood pressure is BP measured in the office without guideline-recommended preparation before measurement. The values from such measurement (as we well know) are often inconsistent and do not correlate with standardized measurement. Most of what we do in the office would be more consistent with the “routine” measurement, deviating with standardized measurement starting with instruction #1: “Have the patient relax, sitting in a chair (feet on floor, back supported) for > 5 min.”

The guideline shows preference for the oscillometric BP device and automated activation for multiple readings. For some of our readers who are hanging on to the belief that manual readings are “better,” the time has likely arrived to let this belief go. Note as well that the systolic target of <120 assumes the standardized measurement approach. The guideline suggests 1 week of daily HBPM prior to each office visit may be useful to complement standardized office BP for clinical management decisions. However, given that I am not comfortable that most office readings are truly following the standardized process, it becomes uncertain how to determine the value of home readings vs. “routine” office readings. Despite the lack of randomized trials, I continue to encourage use of home BP measurements to help guide therapy, and this is consistent with both the American College of Cardiology and USPSTF guidelines.

References:

• Cheung J, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney International. March 2021. 99(3S): S1-87. Executive Summary Full Guideline
• Munter P, et al. Measurement of Blood Pressure in Humans: A Scientific Statement from the American Heart Association. Hypertension May 2019. 73(5):e35-66. Link

From the Literature

2) Magic Mushrooms (Psilocybin) for Depression?

Antidepressant medications are commonly prescribed for depression (and other indications) but are certainly not universally effective. Psilocybin – the principal psychoactive chemical in psychedelic mushrooms – was at one time investigated for its therapeutic properties but was shelved in the 1960s and is currently listed as a Schedule 1 controlled substance – one with no valid therapeutic use. Recently, there has been interest in revisiting this drug for its psychotherapeutic effects.

A randomized controlled trial of psilocybin vs escitalopram was reported in a recent issue of the New England Journal of Medicine. In addition to the usual validity issues (randomization, withdrawals, power, etc.), there are several validity issues to be wary of in comparison trials like this: Was the dose of both the intervention of interest and the comparison reasonable for treatment of the condition? Were valid outcome measures used? Was the treatment of the subjects otherwise the same in both groups? Can the participants be meaningfully blinded to the treatments?

The investigators studied subjects in the UK with long-standing, moderate to severe depression. There was a list of appropriate exclusions. The blinding of this study was interesting: Those randomized to the psilocybin group got 25 mg of psilocybin on day 1, and another 25 mg after three weeks. They also had to take 1 placebo pill a day for 3 weeks, then increase to 2 placebo pills per day until the end of the study. Those randomized to escitalopram were told they were also taking psilocybin, but only received 1 mg doses (which are presumed to have no significant effect), and took 10 mg of escitalopram for 3 weeks, increasing to 2 10mg tablets daily for the remainder of the study. The subjects all got counseling by mental health professionals and had the same number of study visits.

The subjects were similar except for a large baseline differences in alcohol use between the psilocybin (~37g/week) and escitalopram (~68g/week) groups and mean duration of depression (22 years in psilocybin group, 15 years in escitalopram group). The subjects filled out an impressive number of depression, anxiety, and other scales for outcome assessment. In the end, the difference in the primary outcome – the change from baseline in the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16) score – was not statistically significant. There were no serious adverse events in either group, and no significant differences in other adverse events between the groups. Adjustment for the baseline differences in alcohol use between groups did not change the results. Even though each drug resulted in a reduction of symptoms, the true effectiveness of either drug vs. placebo cannot be assumed because there was no placebo group. Most of the measurements seemed to trend in favor of psilocybin over escitalopram, but there was no adjustment for multiple comparisons, which also limits these conclusions. Finally, the authors note that escitalopram was given only for six weeks – three weeks at each dose step – so it may not have had time to be fully effective and between-group differences may have been smaller with longer follow up.

John’s Comments:

It is odd to me that his study was published in the NEJM. There are so many limitations and missed opportunities in this study, its main value appears to be as a cautionary tale about how a trial like this can fall short of expectations. I agree with the authors that there is at least a suggestion of signal here, and psilocybin probably does deserve to undergo well-done research, since there is an accumulation of low-quality studies that suggest an effect. Maybe this study will justify a larger grant to study this drug.

The authors note that several subjects were prevented from getting their second dose of psilocybin because of a COVID-19 lockdown (in the UK). It will be interesting to watch this sort of routine documentation of the pandemic’s effect for years to come.

Reference:

• Carhart-Harris R, et al. Trial of Psilocybin versus Escitalopram for Depression. N Engl J Med. 2021 Apr 15;384(15):1402–11. Link

3) Follow-up April 19 Take 3 – Treatment of Gonococcal STIs

Randi Earls, PharmD and residency faculty colleague, provided the following very helpful information: For Expedited Partner Therapy (EPT), most pharmacies do not stock the Cefixime 800mg so the patient may be turned away or there may be a delay in care if the pharmacy chooses to order it for the patient (which is unlikely for a single dose). So, the Rx should be written for 400mg x 2. This strength is more widely found in the inventory. Additionally, Doxycycline XL 200mg x 7 days is often prescribed but it is not commonly available either. We should stick with the IR 100mg capsules. The GoodRx pricing for the Cefixime is ~$20. For the Doxy is ~$10. 

Additionally, a clarification. The new recommendation indicates that chlamydial infection should be tested for in addition to the gonococcal infection. If chlamydial infection is ruled out, don’t treat for it.

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Mark and John

Carilion Clinic Department of Family and Community Medicine

Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.

Email: mhgreenawald@carilionclinic.org