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Statin Intolerance Pathway Person at high CVD risk reports potential intolerance to recommended high intensity statin treatment This resource relates to NICE guidance: CG181, CG71, TA385, TA393/394, TA694, TA733, QS100 Consider other potential side effects for statins No New onset or worsening of muscle symptoms • Be aware of Statin Reluctance and Nocebo Effect since starting statins? (pain, tenderness or weakness) • See ‘Person Centred Care’ box at page 2 YES Muscular symptoms not related to statins No Symptoms typical for Statin Related Muscle toxicity (SRM)*? *Symmetrical pain and/or weakness in large proximal muscle groups, worsened by exercise Non SRM: Consider other causes e.g. PMR, Vit D deficiency. YES **Consider other causes if new onset of muscle symptoms Check bone profile, Vit D, CRP. of >2 weeks duration in a person previously tolerant Measure Creatine Kinase (CK) Assess severity of symptoms of statin therapy for > 3months Tolerable symptoms No clinical concern +/- repeat baseline assessment** CK < 4x ULN Intolerable symptoms CK > 10x and < 50x ULN CK > 50x ULN and/or clinical concern and/or CK > 4x and < 10x ULN Improvement within 2 weeks Resolved within 6 weeks No Stop statin for 4-6 weeks Yes Renal function No Stop statin and consider Patient happy to continue Document time to symptom onset and time to resolution stable/normal eGFR Rhabdomyolysis Has CK normalised? No Consider Statin induced necrotizing autoimmune myopathy (SINAM) YES No Non-SRM. Consider other causes Have symptoms resolved? Seek specialist advice Urgently No YES and consider PCSK9i seek specialist advice and Wait for 2 weeks before rechallenge Has the patient been symptom free for at least 2 weeks? (NICE TA 393, 394) inpatient assessment YES Reassess and restart with lower dose / alternative statin (see page 2 - ‘Statin-based Approaches’) Offer low or moderate dose of a higher intensity statin (Atorvastatin 10 or 20 mg OD, or Rosuvastatin 5 or 10mg OD) Abbreviations CK = Creatine Kinase CRP = C-Reactive protein Recurrence of muscle symptoms eGFR = Estimated glomerular filtration rate No recurrence of muscle symptoms Short time to onset PMR = Polymyalgia rheumatica Titrate at 8 weeks intervals to achieve appropriate targets Symptoms intolerable SINAM = Statin induced necrotizing autoimmune myopathy SRM = Statin related muscle toxicity Consider further options ULN = Upper Limit of Normal Range Symptoms tolerable For example commence ezetimibe, or ezetimibe with Vit D = Vitamin D Treatment effective, goals achieved No bempedoic acid or inclisiran or PCSK9i as required, depending on eligibility (TA694, TA733, TA 393, TA394) If not Patient happy to continue see page 2 - ‘Statin-based Approaches’ effective Please refer to page 2 for more details Introduction Classification of statin related muscle toxicity (SRM) Person-centred approach to address statin intolerance • Statins are the cornerstone for prevention and treatment of cardiovascular (CV) Alfirevic A. et. al. Clin Pharm Ther. 2014; 96:470-476 Initial Consultation Follow up disease with a substantial evidence of reduction of morbidity and mortality. SRM Phenotype Incidence Definition 1 • Be aware of “nocebo effect” and • Follow up on agreed plan and Refer to Lipid Management Pathway and related NICE guidelines (CG181, SRM 0 CK elevation <4x ULN 1.5-26% No muscle symptoms “statin reluctance”2 address any issues/concern. CG71) for guidance on initiation, titration and monitoring of statin therapy. • Advise patients to contact you if SRM 1 Myalgia, tolerable 190/100,000 Muscle symptoms without • Reinforce healthy lifestyle habits • In clinical trials, statins were found to be largely well tolerated (often with a Patient-years; CK elevation (e.g. exercise, reducing weight) they experience muscle symptoms similar adverse effect (AE) profile to placebo), however this is not reflected • Listen to the concerns of each patient. • Ongoing patient education and regular in clinical practice where up to 75% of people started on a statin will 0.3-33% SRM 2 Myalgia, intolerable 0.2-2/1,000 Muscle symptoms, CK <4x ULN, • Explain LDL-C targets and strategies review helps addressing concerns discontinue treatment within 2 years. complete resolution to lower LDL-C/non-HDL-C around medicine safety and underline the importance of adherence. • Stopping statin therapy is associated with an increased risk of major CV on dechallenge • Discuss options to reduce LDL-C/ events and there is growing concern that clinicians are labelling patients as SRM 3 Myopathy 5/100,000 CK elevation >4x ULN <10x ULN non-HDL-C with pros and cons ‘statin intolerant’ too quickly. Indeed statin discontinuation is significantly Patient-years ± muscle symptoms, complete (1) Nocebo effect is negative expectations of • Explain the benefits of statins the patient regarding a treatment leading to associated with negative media coverage. resolution on dechallenge • Evaluate and identify any risk factors reporting more negative effects even if they SRM 4 Severe myopathy 0.11% CK elevation >10x ULN <50x are prescribed a placebo. Definition of Statin Intolerance ULN, muscle symptoms, complete and address (e.g. drug interactions) • Intolerance to initial statin therapy is defined by NICE as the presence of • Work with patients to identify and (2) Statin reluctance is an attitudinal state of resolution on dechallenge aversion to taking statins (often without prior clinically significant adverse effects that represent an unacceptable risk to SRM 5 Rhabdomyolysis 0.1-8.4/100,000 CK elevation >10x ULN with agree best options and next steps exposure). the patient or that may reduce compliance with therapy. evidence of renal impairment + Statin-based approaches to manage muscle symptoms • Other definition: any adverse event (AEs) considered unacceptable by muscle symptoms or the patient, and/or some laboratory abnormalities, both attributed to statin CK >50x ULN • Adopt person-centred approach as described above. treatment and leading to its discontinuation. SRM 6 Autoimmune-mediated ~2/million per Detection of HMGCR antibodies, • Therapy with a lower dose statin is preferred to no statin Statin-associated muscle symptoms (SAMS) necrotizing myositis year HMGCR expression in muscle • Apply a repetitive “De-Challenge” - “Re-Challenge” approach to establish if (SINAM) biopsy showing autoimmune symptoms are caused by a statin(s) and the best statin regimen for each patient. • SAMS are one of the principal reasons for statin non-adherence and/or myositis, incomplete resolution discontinuation. However, not all such symptoms should lead to a label of on dechallenge • Switch to a different statin or re-challenge with the same statin using a lower dose or frequency (intermittent dosages) ‘statin intolerance’ as they may not be truly statin related muscle toxicity HMGCR = 3-hydroxy-3-methylglutaryl coenzyme A reductase ULN = upper limit of normal (SRM) as demonstrated by resolution on de-challenge and recurrence with • Patients who do not tolerate statins on a daily basis, alternate day or twice-weekly re-challenge. • SRM is a spectrum from myalgia to severe myopathy dosing is a good option. Non-Statin related musculoskeletal symptoms (Non SRM) • SRM 0 - does not preclude statin therapy, consider reducing starting dose • Rosuvastatin and atorvastatin have longer half-lives, permitting their use on a • SRM 1-3 manage according to pathway non-daily regime. • If patients report symptoms that are not typical of SRM (e.g. asymmetric • Adding ezetimibe to a lower dose statin may be better tolerated with robust distribution, failure to resolve with de-challenge despite normal CK) consider • When SRM4 is suspected, without evidence of impaired renal function, other musculoskeletal disorders, metabolic, degenerative or inflammatory e.g. reduction of LDL-C / non-HDL-C. discontinue statin therapy immediately and refer for outpatient assessment. • Once a new regime is tolerated, dose / frequency can be up-titrated slowly to Vitamin D deficiency, polymyalgia rheumatica. Check Bone profile, Vit D, CRP. Assess and treat possible contributory factors and re-assess the need for a statin. Intensify lifestyle modifications and consider alternative lipid lowering regimens. achieve LDL-C / non-HDL-C goals with minimal or no muscle complaints. Considerations when starting a statin to reduce risk of SRM It is important to note that cardiovascular benefits have not been proven for all the • If rhabdomyolysis (SRM5) is suspected, immediately stop statins, urgently refer • Check baseline thyroid, liver and renal function, any potential drug interactions, to inpatient assessment and management including intravenous rehydration above approaches but any reduction of LDL-C / non-HDL-C is beneficial. and avoid the highest doses in at risk groups (See “Risk Factors” below). as required to preserve renal function. Do not wait for measurement of urinary LDL-C lowering options for patients with genuine statin intolerance • Ask the person if they have had persistent generalised unexplained muscle myoglobin. Post recovery, manage as for SRM4. pain, whether associated or not with previous lipid-lowering therapy. If • Refer to the AAC Lipid Management Algorithm. (click here) • Statin induced necrotizing autoimmune myositis (SINAM) (SRM6) should be they have, measure CK. If CK levels are > 4x ULN do not start statin - suspected in patients with progressive muscle weakness and ongoing CK • Consider ezetimibe, (NICE TA 385) therapy as per algorithm investigation required. • Consider ezetimibe combined with bempedoic acid (NICE TA 694) as per algorithm Do not measure CK if person is asymptomatic. elevation despite statin withdrawal. Requires immunosuppressive treatment and avoidance of re-exposure to statins. Re-assess the need for lipid lowering • Consider inclisiran if eligible for treatment according to NICE TA 733 • Warn patients about AEs, specifically muscle symptoms. Advise people therapy - may be eligible for treatment with PCSK9 inhibitor (NICE TA 393, 394). who are being treated with a statin to seek medical advice if they develop • Consider PCSK9i if eligible for treatment according to NICE TA 393, 394 muscle symptoms (pain, tenderness or weakness). If this occurs, measure Non-muscle related statin side effects CK (see page 1). May vary between different statins. In clinical trials some side effects often associated with statins are not statistically different from placebo. Risk factors for SRM and statin intolerance Most commonly reported: gastrointestinal disturbance and asymptomatic increases in hepatic transaminases (ALT or AST). May affect up to 1 in 10 statin users. Endogenous factors Exogenous Factors Rarer side effects include: Hepatotoxicity, new onset Type 2 Diabetes (benefits outweigh risk, do not stop statin), Renal insufficiency, proteinuria, Neurocognitive and neurological impairments (no apparent link from RCTs), Intracranial haemorrhage (conflicting evidence, benefit outweigh possible harm), Interstitial lung disease, • Female gender • Excessive alcohol intake Pancreatitis, Skin disorders including alopecia, Lupus-like reaction, Sleep disturbance, headache, dizziness, fatigue, depression, sexual dysfunction. • Advanced age (> 75 yrs) • High intensity exercise Management: If symptoms appear statin related, consider de-challenge and re-challenge or change to a different statin (e.g. hydrophilic instead of lipophilic). • Frailty (reduced lean body mass) • Dehydration Liver enzyme abnormalities - minor increases in liver enzymes (<2x ULN) may be seen within the first three months of statin therapy; temporary discontinuation and further • History of muscle disorder or high CK • Drug interactions with statins assessment is warranted if levels exceed 3x ULN. Several studies have confirmed that the cardiovascular benefits of statin treatment in high-risk populations outweigh the • Impaired renal or hepatic function (including herbal medicines) rare adverse effects, such as rhabdomyolysis. • Personal or family history of intolerance • Vitamin D deficiency to lipid-lowering therapies. Authors: Dr Rani Khatib & Dr Dermot Neely on behalf of the AAC Clinical Subgroup. Jan 2022. Review date: Jan 2023. Pathway endorsed by NICE Dec 2021. Please refer to the Lipid Management Pathway and Full List of References (click here). • Hypothyroidism