Double down on CCBs: The efficacy and safety of dual calcium channel - PowerPoint PPT Presentation

Double down on CCBs: The efficacy and safety of dual calcium channel blocker therapy in the treatment of hypertension Anna Yee LMPS Adult Resident Thursday October 13, 2016 1

Outline • Objectives • Meet PG • Drug Therapy Problems • Goals of Therapy • Hypertension • PICO/Evidence • Recommendations • Monitoring • Follow up 2

Objectives • To describe the efficacy and safety associated with the use of combination calcium channel blockers • To identify the role of combination calcium channel blockers in the treatment of hypertension 3

Meet PG ID: - 86 M (80kg) admitted October 2, 2016 CC: - Decreased mobility HPI: - 2 week history of difficulty ambulating, poor balance & fatigue - Fall ~ 1 week ago - Had stopped all medications x 6m and recently restarted in Sept Allergies: - NKDA 4

Meet PG PMHx MPTA Hypothyroidism Levothyroxine 112 mcg PO daily Hypertension Diltiazem 240mg PO daily Hydrochlorothiazide 12.5 mg PO daily Dyslipidemia Pravastatin 20mg PO daily Depression Paroxetine 20mg PO daily Anxiety Diazepam 5mg PO daily PRN (last dose 10-12 days ago) OTCs/NHPs Vitamin C 500mg PO daily Vitamin B50 complex PO daily Vitamin D 1000U PO daily Social Hx: Immunizations - IL @ Royal Arch Masonic Home - Annual flu vaccine - Non – smoker - Drinks 1 – 2 glasses of scotch per day (last drink 10-12 days ago) 5

Review of Systems Oct 1, 2016 Oct 3, 2016 Vitals T 37, BP 199/80, HR 72, RR ___, O 2sat 94% T __, BP 185/91, HR 62, RR RA ___, O 2sat __% RA CNS GCS 15 (fully awake and orientated) AOx3 CVS S1S2 heart sounds, ECG: NSR RESP Normal breath sounds, Ø cough/wheeze GI Abdomen soft, non tender LIVER GGT 31, AST 14, ALT 20, ALP 111, Alb 36 Bili T/C 15/5, Alb 41 GU/ BUN 13.6, SCr 190, eGFR 24 (Baseline SCr SCr 191, eGFR 27 RENAL 170-198 GFR 26-30 Jul – Sep 2016) ENDO TSH 14.1, fT 4 17.3, fT 3 3.1 FBG 5.8, A1c 5.4 TSH 18.7, fT 4 16.8, fT 3 2.9 HEME WBC 7.3, Hgb 120, CRP 8.7 FLUIDS/ Na + 141, K + 3.5 Na + 139, K + 3.1 LYTES 6

Other investigations • Micro – Urine Culture: 80 mil mixed enteric – Urinalysis: + protein, trace ketones • CXR: no consolidation • Head CT: nil acute 7

Current medications Medical Condition Medications Hypothyroidism Levothyroxine 112 mcg PO daily Hypertension Diltiazem 240mg PO daily Hydrochlorothiazide 12.5mg PO daily – D/C’d Amlodipine 2.5mg PO daily Hydralazine 10mg PO q10min PRN SBP >180 Captopril 12.5 mg PO q1h PRN SBP >180 Dyslipidemia Pravastatin 20mg PO daily – D/C’d Depression Paroxetine 20mg PO daily Anxiety Diazepam 5mg PO daily – D/C’d DVT prophylaxis Dalteparin 5000 units SC daily Constipation Geriatic Bowel Protocol 8

Drug Therapy Problems • PG is experiencing hypertensive urgency and is at risk of acute organ damage (i.e stroke, MI, renal failure) from uncontrolled hypertension and would require reassessment of his drug therapy • PF is currently experiencing asymptomatic hyperkalemia and would benefit from potassium supplementation • PF is at experiencing ongoing hypothyroid symptoms (weakness, mild cold intolerance) from receiving a suboptimal therapy and would benefit from optimizing his drug therapy 9

Hypertensive crisis 1,2 • Hypertensive urgency – Blood pressure >180/>120 mmHg without evidence of end organ damage • Hypertensive emergency – Blood pressure > 180/>120 mmHg with evidence of end organ damage – Neurological, cardiac, vascular, renal symptoms 10

Hypertensive crisis 11

Hypertensive urgency Treatment 1,2 • Reduce blood pressure < 160/100 mmHg – Over hours or days depending on the urgency and risk for imminent CV events – Treat with oral, short-acting agents such as captopril, labetalol, clonidine, then observe • Adjustment/initiation of antihypertensive therapy 12

Hypertension Potential Diltiazem combinations Thiazide Diuretics eGFR 27 ml/min – ineffective ACE inhibitors Acute worsening of renal fxn ARBs Acute worsening of renal fxn Beta Blockers HR 62; neg. inotrope Alpha Blockers Possible choice Others: Hydralazine Possible choice DHP CCBs ?? 13

Calcium Channel Blockers • Dihydropyridines: amlodipine, felodipine, nifedipine, nicardipine 3 – Act on L-type calcium channels in peripheral smooth muscles à peripheral vasodilation • Non-dihydropyridines 3 – Act on L-type calcium channels in cardiac muscles à negative inotropic effect (SA & AV node) and vasodilation – Phenylalkylamines: verapamil (more potent) – Benzothiazepines: diltiazem 14

Dual CCB Therapy • Pharmcokinetics 4 – Diltiazem & Verapamil = CYP3A4 inhibitors – DHP CCBs (amlodipine, felodipine, nifedipine) = CYP3A4 substrates – Exploitation of a PK interaction • Pharmacodynamics – Higher [DHP CCB] = greater hemodynamic effect 15

Clinical Question P Elderly patients with hypertension, eGFR < 30ml/min Diltiazem and Amlodipine (Non-DHP CCB + DHP I CCB) C Non-DHP CCB or DHP CCB monotherapy Major cardiovascular outcomes (Stroke, MI, Heart failure) O Renal function Blood pressure reduction Major adverse events 16

Search strategy Databases Pubmed, MEDLINE, EMBASE Search (Non-Dihydropyridine Calcium Channel Blockers OR Terms Diltiazem OR Verapamil) AND (Dihydropyridine Calcium Channel Blockers OR amlodipine OR felodipine OR nifedipine) AND hypertension AND combination therapy AND dual therapy AND chronic kidney disease Limits English, Humans Results n=18 1 Meta-analysis 6 RCTs 1 Retrospective Trial 3 case series 17

18

Alviar et al 2013 D Meta-analysis P • n = 153 • 6 RCTs (3 diltiazem + nifedipine/felodipide/nitrendipine, 2 verapamil + lacidpine/nitrendipine, 1 both + nifedipine) • At least 1 week follow up • 55.5 y/o, 78% male I Dual calcium channel blocker (Non DHP + DHP) C Calcium channel blocker monotherapy (Non NHP or DHP) O Efficacy: change in SBP and DBP from baseline Safety: adverse effects (edema, HA, constipation, flushing), heart rate 19

Alviar et al 2013 Change of SBP from baseline 2A: Dual CCB vs DHPs • Mean change of 10.9 mmHg more than DHP alone (p <0.01) 2B: Dual CCB vs NDHPs • Mean change of 14 mmHg more than NDHP alone (p = 0.002) 20

Alviar et al 2013 Change of DBP from baseline 2A: Dual CCB vs DHPs • Mean change of 5.5 mmHg more than DHP alone (p <0.001) 2B: Dual CCB vs NDHPs • Mean change of 5.3 mmHg more than NDHP alone (p = 0.03) 21

Alviar et al 2013 • Adverse effects – No statistical difference in edema, HA or flushing between dual CCB and each monotherapy – less constipation in dual CCB vs NDHP (p = 0.01) • Heart rate – Dual CCB reduced HR by 6 beats/min more than DHP alone (p<0.001) – Dual CCB reduced HR by 2 beats/min less than NDHP (nss) 22

Alviar et al 2013 1. Was an ‘a priori’ design provided? No 2. Was there duplicate study selection and data extraction? Yes 3. Was a comprehensive literature search performed? Yes 4. Was the status of publication (i.e. grey literature) used as an inclusion criterion? No 5. Was a list of studies (included and excluded) provided? Yes 6. Were the characteristics of the included studies provided? Yes 7. Was the scientific quality of the included studies assessed and documented? No 8. Was the scientific quality of the included studies used appropriately in No formulating conclusions? 9. Were the methods used to combine the findings of studies appropriate? Yes 10. Was the likelihood of publication bias assessed? No 11. Was the conflict of interest included? No Total Score 5/11 23

Alviar et al 2013 • Limitations – Small RCTs (n=153) – Clinical heterogeneity • Each study looked at different CCBs and different doses – Short term studies (longest was 20 weeks) – Varying degrees of hypertension – Only assessed effect on SBP/DBP – ?? CV outcomes 24

Alviar et al 2013 • Author’s conclusion – “given the lack of outcome data, as well as the short follow-up period and the small of subjects … our results should be interpreted with caution and dual CCB therapy should not be an alternative treatment in patients with resistent hypertension as previously recommended” 25

My conclusion • Difficult to say which combination of NDHP + DHP is effective at reducing BP, and at which dose? • Despite BP lowering effects, suggest cautious use of dual CCB without long term efficacy and safety data, and lack of CV outcomes. 26

S Saseen 1996 Frishman 1988 N=24 N=16 Chronic stable angina > 3m, CAD/hx P Baseline DBP 95 – 115 mmHg MI Excluded mod-severe HTN Verapamil 180mg or diltiazem 180mg + I Diltiazem 360 mg + nifedipine 120mg nifedipine 30mg Diltiazem 360 mg or nifedipine nifedipine 30mg C 120mg • SBP, DBP, HR SBP, DBP, HR • Max: DIL/NIF: SBP 20.2 +/- 6.3%; • Combination had greater O DBP 27.9 +/- 5% reduction in standing DBP/DBP at • SS at 6 and 24 hr post dose vs. NIF rest alone 27

Applying this to PG P Elderly patients with hypertension, eGFR < 30ml/min ✗ Diltiazem and Amlodipine (Non-DHP CCB + DHP I CCB) ✗ C Non-DHP CCB or DHP CCB monotherapy Major cardiovascular outcomes (Stroke, MI, Heart failure) ✗ Renal function ✗ O Blood pressure reduction ✓ Major adverse events ✓ 28