Clinical Snippets July 2023

The New Zealand General Practice Podcast

Dr Dave Maplesden and Dr Jo Scott-Jones

Shownotes

Clinical Snippets – July 2023 

1.  Superficial venous thrombosis (thrombophlebitis) 

(i)  After reviewing a recent case of death from pulmonary embolus in a patient seen a few days previously with an apparent lower limb SVT, I have reviewed HealthPathways guidance as follows.  Superficial venous thrombosis is usually a benign self-limiting condition, when it involves the smaller tributary veins in the lower limb or in the site of an existing varicose vein.  However, when the larger veins are involved (e.g. great and small saphenous veins) or when adjacent to the sapheno-femoral junction, there is risk of a DVT. A DVT may coexist at the time of diagnosis or the clot may extend to the deep veins within 10 days. 

(ii)   The risk for VTE is the highest immediately following a diagnosis of SVT but persists over time particularly in the first three months and decreasing but still significantly higher after five years.  Diagnosis is made by clinical findings, e.g. tenderness, induration, pain, or erythema along the course of a superficial vein.  D-dimer is not considered sensitive or specific enough to predict DVT in superficial venous thrombosis. 

(iii)  Arrange an ultrasound to exclude DVT if any of: 

• There is an involved segment of vein of 5 cm or more. 
• Either the great or the small saphenous vein is involved. 
• There is asymmetrical leg swelling. 

D-dimer is not considered sensitive or specific enough to predict DVT in superficial venous thrombosis. 

(iv)  Consider full oral anticoagulation for 3 months 3 if:   

• superficial venous thrombosis is within 3 cm of the sapheno-femoral junction and/or if the length of the superficial venous thrombosis is more than 5 cm. Also seek vascular surgery advice as ligation at the sapheno-femoral junction may be recommended. 
• other risk factors for DVT (e.g. an inpatient). Also seek haematology advice. 

(v)  If no risk factors, provide local symptom relief and prevent progression to a DVT: 

• Use pain relief, e.g. NSAIDs, for 8 to 12 days if not contraindicated. 
• Treat with elevation of the leg and compression stockings for comfort and to reduce swelling. 
• Only use antibiotics if signs of infection. 
• Encourage the patient to remain ambulatory. 
• Arrange follow-up at 7 to 10 days or earlier if there is deterioration. 

• If symptoms do not resolve, arrange or repeat the ultrasound. 

2.  ACE inhibitors and angio-oedema  

(i)  The Centre for Adverse Reactions Monitoring (CARM) recently received a report of fatal angioedema with an ACE inhibitor. The patient had experienced minor tongue swelling with an ACE inhibitor previously. A different ACE inhibitor was started at a later date, and the patient developed angioedema with a fatal outcome. 

(ii)   Before prescribing an ACE inhibitor, ask patients if they have taken these medicines before and if they had any adverse reactions. Specifically ask about swelling.  Inform patients who are starting ACE inhibitors about the symptoms of angioedema and advise them to seek urgent medical attention if these occur. 

(iii)  Visceral angioedema due to ACE inhibitors has been described in a handful of case reports and reviews. Most commonly, this presents as diffuse abdominal pain and diarrhoea. In more than one-half of the case reports of visceral angioedema, symptoms began within 72 hours of starting ACE inhibitor therapy, although in other reports, angioedema developed after weeks or years of therapy.  Diagnosis is often delayed. 

(iv)  ACE inhibitors should not be prescribed to patients with a history of ACE inhibitor-induced angioedema. Educate patients who have experienced ACE inhibitor-induced angioedema about the need to avoid all ACE inhibitors in the future.  NZF also advises against use of sacubitril-valsartan (Entresto) in these patients.   Most patients can be cautiously switched to an ARB.  A proportion of patients will have recurrence of angio-oedema after stopping the culprit ACE – most commonly within the first month.    

(v)  Angioedema is thought to occur in around 0.1% to 0.7% of patients who take an ACE inhibitor. Onset is usually during the first weeks or months of therapy, but it can occur years into treatment. Angioedema has also been reported with angiotensin II receptor blockers (ARBs; eg, candesartan, losartan), but the risk is thought to be lower than with ACE inhibitors. 

3.  Ivermectin Special Authority criteria amended 

The Special Authority criteria for ivermectin were recently amended (June, 2023). Any relevant practitioner can now complete the Special Authority form for ivermectin in patients with scabies and close contacts who meet Special Authority criteria. Discussion with a dermatologist, infectious diseases specialist or clinical microbiologist is no longer required. 

For information on the management of scabies, including the role of ivermectin, there is an excellent 2022 BPAC update on the topic.   

4. Allopurinol and variable adherence 

A recent NZ Doctor article on allopurinol  prescribing for the non-adherent included some timely reminders: 

• In a person who has become non-adherent to allopurinol (even for one month), do not automatically restart at a previous dose – re-titration is required.  Titration is dependent on renal function (see 2021 BPAC article for details).  Extra caution must be made with repeat prescribing of allopurinol and assuming a person is administering the last prescribed dose when they may not be. 

• The important point around dosing is to commence allopurinol according to renal function using clinical pathways or 1.5mg of allopurinol per eGFR unit as a guide. Note that renal function is used to guide starting doses, but once a person is stabilised on a dose of allopurinol, the dose should not be routinely decreased if renal function deteriorates. 

• Remember anti-inflammatory prophylaxis (and remember to stop this when stable).  This may be low dose NSAID or colchicine (or prednisone if alternatives not tolerated) 

• To mitigate treatment failure, people must be forewarned of the increased risk of flares when initiating allopurinol. It is also necessary to plan for the eventual cessation of anti-inflammatory prophylaxis. Usually, only three to six months is required, although this may be much longer in people with a high urate burden with tophi. 

• For patients with gout and hypertension, losartan or calcium channel blockers are the antihypertensive medicines of choice as they reportedly have mild uricosuric (urate-excreting) properties. Patients who are taking diuretics for hypertension, for reasons other than heart failure, should be switched to an alternative antihypertensive, if possible. 

• Always advise people that if a rash (especially extensive) occurs, they must cease allopurinol and seek medical assistance promptly.  Rash affects around 2% of people taking allopurinol but could be a symptom of allopurinol hypersensitivity syndrome (includes DRESS, Steven-Johnson syndrome and toxic epidermal necrolysis – affects about 1-4:1000 patients prescribed allopurinol and has a mortality rate of up to 27%). Risk factors for AHS include: higher starting dose of allopurinol and rapid titration; recent commencement (6-8 weeks) of allopurinol; coadministration of diuretics (especially thiazide) and amoxicillin; comorbidities of CKD and cardiovascular disease; risk of AHS is nearly 100-fold higher in carriers of the HLA-B*58:01 allele than in noncarriers. Populations with high allele frequency include people of Han Chinese (6%–8%), Korean (12%) and Thai (6%–8%) descent and NZF recommends genetic testing in these high-risk patients and avoiding allopurinol in confirmed carriers unless there is no suitable alternative.  See SaferRx for more details.   

• Māori and Pacific peoples are inequitably burdened by gout. There is also evidence demonstrating Māori and Pacific peoples are less likely to receive regular allopurinol prescriptions.  You can analyse your gout prescribing on the Epic dashboard in He Ako Hiringa including percentage of patients being prescribed urate lowering therapy irregularly, and there are tips for improving gout prescribing equity.    

5.  Topical anaesthesia for chronic painful leg ulcers 

Prilocaine-lidocaine (EMLA) cream has a listed indication of topical anaesthesia of leg ulcers to facilitate mechanical cleansing or debridement with instruction to apply under an occlusive dressing 30–60 minutes before procedure.  Cost:  Around $45 for the Numit brand (30g) from the Chemist warehouse.  The cream has also been studied as a primary dressing for painful leg ulcers and has proved effective.   

 The NZ Palliative Care Handbook also notes use of topical morphine as local pain relief for palliative patients with fungating wounds or ulcers with instructions:   morphine injection added to a gel in a clean environment and used topically may help (0.05 to 0.1% morphine [i.e. 0.5 to 1 mg/mL] in IntrasiteTM gel, metronidazole gel or KY JellyTM).  More detailed instructions including precautions are available as NHS guidance and note this is off-label use of morphine.   Some systemic absorption will occur, and it is most effective for superficial ulcers.  Some studies have shown reduced healing rates in wounds treated with topical morphine.   

6.  Dense breasts 

GP Research Review Issue 216  summarised a 2023 meta-analysis of MRI imaging in screening women at high risk of breast cancer which showed that  MRI alone increased the detection rate of breast cancer versus mammography alone by 8 per 1000 women screened while MRI plus mammography had a better detection rate versus MRI alone by 1 per 1000 women screened.  The article reviewer noted there is conflicting evidence of the impact of ionising radiation from repeated mammography related to repeated mammographic breast screening in women at high risk of malignancy and taking this into account MRI alone may be considered as best choice in such high-risk women. 

This raises the issues of informed choice and equity, particularly if private screening is the only way MRI imaging can be accessed in this situation.  The issue of reporting of breast density and management of women with extremely dense breasts within the Breast Screen Aotearoa (BSA) national screening programme is ongoing with formal reporting of breast density not currently part of BSA reporting requirements (see BSA information sheet) or planned as part of a recent quality improvement review of clinical quality and safety of the programme.  Discussion was stimulated following publication of European Society of Breast Imaging (EUSOBI) recommendations last year which included that women should be informed of their individual breast density and the diagnostic and prognostic implications of having dense breasts, and that supplemental or standalone MRI screening is offered to women with extremely dense breasts, from age 50-70, preferably every 2-3 years.    

7.  On a lighter note… 

Two more fascinating studies summarised in GP Research Review Issue 216 

1.  A randomized controlled trial on the effects of light music played by piano on satisfaction, anxiety, and pain in patients undergoing colonoscopy showed, in the group with piano music, significantly lower anxiety scores and higher overall satisfaction scores, including satisfaction with pain management, following the procedure than the group with no music.  The reviewer notes the results appear to be perfectly tailored to a GP’s waiting room – less anxiety, more satisfaction and less pain. And at no cost! Probably worth swapping the blaring radio ads/music in the waiting room for something soothing like Mozart. 

2.  A randomized trial on the effects of a topical hop extract gel versus topical oestradiol cream for treatment of postmenopausal sexual dysfunction showed no significant differences in the total Female Sexual Function Index (FSFI) or sub-scores (sexual desire, sexual arousal, vaginal lubrication, satisfaction, orgasm, sexual pain) between the two groups. There were no adverse events. Humulus lupulus L. (hop) has been recognised as having antioxidant, anti-inflammatory, anticancer, and oestrogenic properties.  I could not find any vaginal hop creams currently commercially available on line, and the hopeful sounding Tired Hands Hop Cream turned out to be a beer! 

Clinical Snippets June 2023

Shownotes

Clinical Snippets June 2023

1.  Stopping antidepressants

A recent BPAC bulletin reviewed a 2023 British Journal of General Practice article on appropriate withdrawal of SSRIs.  Key points included:

• A proportionate dose taper should be used where the dose is reduced by a proportion of the previous dose e.g. 50% of previous dose, depending on certain factors such as the patients symptoms and whether the available formulations of the SSRI allow the preferred reduction in dose.  Smaller dose reductions, e.g. 25% of previous dose, might be considered when low doses are reached and this might require alternate day dosing.

• Dose tapering should occur slowly over months to years depending on individual circumstances. Higher doses of SSRIs, longer durations of use and SSRIs with shorter half-lives, e.g. paroxetine, are generally associated with more severe symptoms of withdrawal and patients may require tapering of the dose at a slower rate.

• Monitor patients for symptoms of withdrawal and differentiate between withdrawal and relapse:  Symptoms of withdrawal include irritability, sleep disturbance, hallucination, suicidal ideation dizziness, headaches, sweating and are reported by more than half of patients when discontinuing SSRIs. Reinforce the use of coping strategies, e.g. exercise, mindfulness-based techniques, sleep hygiene and be prepared to slow the taper if withdrawal symptoms occur.  Symptoms of withdrawal are more likely to begin within days of discontinuation or reduction of the SSRI. In contrast, symptoms of relapse typically occur weeks to months after cessation of the SSRI.

• Discuss the possibility of withdrawal symptoms, including the importance of following the tapering protocol to minimise any symptoms. Advise that they should not abruptly stop taking the SSRI. A patient information sheet developed by Medsafe is available here.

Additional resources: 

• For further information on antidepressants, including switching or discontinuing, see: https://nzf.org.nz/nzf_2225
• A guide to what medications can be crushed or dissolved is available from SafeRx. 

2.   Miconazole gel and warfarin

• Miconazole oral gel inhibits the metabolism of warfarin via inhibition of CYP2C9.
• Healthcare professionals are advised to avoid miconazole oral gel in patients taking warfarin.
• If concomitant use of miconazole oral gel and warfarin is necessary, the patient’s INR should be carefully monitored.
• See the 2013 Prescriber Update on this topic. 
• The manufacturer data sheets for miconazole oral gel (and associated consumer information sheets) state it is contraindicated in children less than six months of age while NZFC  notes it is  not approved for use in children under 6 months of age (ie use in this age group is ‘off label’).  However, dosing instructions for neonates and infants under six months of age are provided in NZCF and:  For infants and young children, give oral gel in small amounts at the front of the mouth, or smear around the inside of the mouth. Do not place gel in the back of the mouth as this may cause choking. 

3.  Goodfellow Gem on lung cancer

A recent Goodfellow Gem refers to a Goodfellow Unit webinar on early detection and advances in management of lung cancer including a current study on low dose CT screening for lung cancer in high-risk Māori patients.  Lung cancer is the single biggest contributor to the difference in life expectancy between Māori and non-Māori, with lung cancer the leading cause of death for Māori women and the second leading cause of death for Māori men after cardiovascular disease. Māori women’s rates are more than four times higher and Māori men’s rates nearly three times higher than those of non-Māori.

The Gem looked at eight symptoms to consider for rapid diagnosis of lung cancer:

The persisting cough in the patient with COPD ± smoker is a common presenting symptom. The eight symptoms are:

•          Cough >3 weeks

•          Haemoptysis

•          Chest or shoulder pain

•          Dyspnoea

•          Hoarseness

•          Weight loss >10%

•          Unresolving chest infection

•          Symptoms suggestive of metastasis (liver, bone, brain, skin). In some parts of the country, if the CXR is suggestive of a curable lesion the chest CT can be bypassed but refer them to the respiratory team (refer local pathways). The e-referral should state “high suspicion of cancer”.  In those cases, the team may arrange a PET-CT scan. 

A 2021 systematic review and meta-analysis on performance of plain chest X-ray for diagnosing lung cancer in symptomatic primary care patients showed a sensitivity of around 80% with the comment: A negative chest radiograph does not exclude lung cancer, and physicians should maintain a low threshold to consider specialist referral or cross-sectional imaging.  BPAC has a comprehensive 2021 article on early detection of lung cancer in primary care. 

4.  Can PPIs help crying babies? 

A recent Tools for Practice looked at the clinical question:    In infants (≤1year) with crying/irritability attributed to feeds, do proton pump inhibitors (PPIs) improve symptoms over placebo without additional harms?  The context:

• Frequent effortless regurgitation of feeds is common in early infancy (affecting ≥40%).

• Regurgitation accompanied by distress symptoms (e.g., crying, back arching, irritability) have traditionally been attributed to gastroesophageal reflux disease. While PPIs improve oesophageal pH in infant RCTs, they do not improve symptoms.

• Guidelines recommend against empiric trials of acid-suppressing drugs for crying/distress or regurgitation.  Parents can be reassured that frequent regurgitation can be normal and frequently settles (90% have resolution at age ≤1 year).

The conclusion:  PPIs do not improve crying, fussiness, irritability, or regurgitation attributed to feeds. However, PPIs may increase the risk of serious adverse effects (e.g., respiratory tract infections) from 2.5% on placebo to 12% at 4 weeks.  Local HealthPathways state:  Use of omeprazole in infancy is not indicated in primary care as there is a lack of evidence for its effectiveness, and concerns about its safety. Evidence for the use and safety of alginates (e.g. Gaviscon Infant) is inconsistent. They may have a role in treating infants with GORD but only for an on-demand use rather than regular or long-term use.

5.  Aspirin and primary prevention of CVD

A recent issue of GP Research Review commented on a recently published literature review and meta-analysis on use of aspirin with or without statin across all risk groups in patients without confirmed atherosclerotic cardiovascular disease (ASCVD).  The investigators concluded that in patients without ASVCD the risk of major bleeding associated with aspirin is greater than the reduction in MI risk across all ASCVD risk levels. Concurrent use of a statin reduces the cardiovascular benefits of aspirin without influencing bleeding risk. Therefore, in patients without ASCVD who are already taking a statin, the addition of aspirin is unlikely to achieve a meaningful CV benefit but would increase the risk of major bleeding.

Current HealthPathways recommendations are, for primary cardiovascular disease (CVD) prevention: 

• Consider aspirin only for high-risk patients younger than 70 years, taking into account the benefits and harms.
• If not high risk, aspirin and other antiplatelet agents for primary prevention alone are generally not recommended.
• If older than 70 years, the balance of benefits and harms of aspirin is not clear, so is not recommended for primary prevention alone.

6.  Winter virus action plans

As part of its ongoing commitment to antibiotic stewardship, He Ako Hiringa has developed virus action plans for adults and children which cover rationale for avoiding antibiotics and extensive modifiable management and safety netting advice.  The plans can be edited on-line and then printed and/or downloaded for electronic transmission and retention.   

7.  Sodium valproate in males

A recent Medsafe Prescriber Alert comments on the risk of neurodevelopmental disorders in children fathered by patients using valproate at the time of conception.  Information for healthcare professionals includes: 

• The Epilim data sheet and CMI have been updated to include new safety information relating to use in males of reproductive potential.
• Use of sodium valproate at the time of conception by people who are able to father children has been linked to a potential increased risk of neurodevelopmental disorders in children compared to those who took lamotrigine/levetiracetam.
• Inform patients of this potential risk and consider alternative treatment options for those wishing to father a child.
• Discuss the need for effective contraception when starting sodium valproate and periodically throughout treatment.
• The company has produced a guide which should be provided to all male patients of reproductive potential using sodium valproate.