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

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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

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Outline

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

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

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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

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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
• Non – smoker
• Drinks 1 – 2 glasses of scotch per

day (last drink 10-12 days ago)

• Annual flu vaccine

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Review of Systems

Oct 1, 2016 Oct 3, 2016 Vitals T 37, BP 199/80, HR 72, RR ___, O2sat 94% RA T __, BP 185/91, HR 62, RR ___, O2sat __% 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, Bili T/C 15/5, Alb 41 Alb 36 GU/ RENAL BUN 13.6, SCr 190, eGFR 24 (Baseline SCr 170-198 GFR 26-30 Jul – Sep 2016) SCr 191, eGFR 27 ENDO TSH 14.1, fT4 17.3, fT3 3.1 FBG 5.8, A1c 5.4 TSH 18.7, fT4 16.8, fT3 2.9 HEME WBC 7.3, Hgb 120, CRP 8.7 FLUIDS/ LYTES Na+ 141, K+ 3.5 Na+ 139, K+ 3.1

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Other investigations

• Micro

– Urine Culture: 80 mil mixed enteric – Urinalysis: + protein, trace ketones

• CXR: no consolidation
• Head CT: nil acute

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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

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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

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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

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Hypertensive crisis

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Hypertensive urgency

Treatment1,2

• 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

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Hypertension

Potential combinations Diltiazem 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 ??

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Calcium Channel Blockers

• Dihydropyridines: amlodipine, felodipine,

nifedipine, nicardipine3

– Act on L-type calcium channels in peripheral smooth muscles à peripheral vasodilation

• Non-dihydropyridines3

– Act on L-type calcium channels in cardiac muscles à negative inotropic effect (SA & AV node) and vasodilation – Phenylalkylamines: verapamil (more potent) – Benzothiazepines: diltiazem

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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

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Clinical Question

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

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Search strategy

Databases Pubmed, MEDLINE, EMBASE Search Terms (Non-Dihydropyridine Calcium Channel Blockers OR 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

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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

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Alviar et al 2013

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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)

Alviar et al 2013

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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)

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)

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Alviar et al 2013

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• 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

formulating conclusions?

No

• 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

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

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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”

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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.

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S

Saseen 1996 Frishman 1988

P

N=16 Baseline DBP 95 – 115 mmHg N=24 Chronic stable angina > 3m, CAD/hx MI Excluded mod-severe HTN

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Verapamil 180mg or diltiazem 180mg + nifedipine 30mg Diltiazem 360 mg + nifedipine 120mg

C

nifedipine 30mg Diltiazem 360 mg or nifedipine 120mg

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• SBP, DBP, HR
• Max: DIL/NIF: SBP 20.2 +/- 6.3%;

DBP 27.9 +/- 5%

• SS at 6 and 24 hr post dose vs. NIF

alone SBP, DBP, HR

• Combination had greater

reduction in standing DBP/DBP at rest

Applying this to PG

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

Goals of Therapy

• 1. Prevent any major cardiovascular events

(stroke, MI, heart failure)

• 2. Slow the progression of chronic kidney

disease

• 3. Target goal BP < 140/90
• 4. Promote adherence to therapy
• 5. Prevent any adverse drug effects

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Recommendations

• 1. d/c diltiazem
• 2. Titrate amlodipine 2.5mg daily up to 10

mg daily q2-3d

• 3. Consider adding low dose ramipril 2.5 mg

PO daily once renal function stabilizes

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Monitoring Plan

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Efficacy Outcome Frequency

Major cardiovascular event (stroke, MI, heart failure) Absence Daily Blood pressure Target <140/90 mmHg Daily

Safety Outcome Frequency

Amlodipine ADRs (peripheral edema, flushing, dizziness, hypotension) Absence Daily Ramipril ADRs (cough, angioedema, hypotension) Absence Daily Hyperkalemia K+ 3.5 – 5 mmol/L Q2-3d Renal function SCr (<170) and GFR (>30 ml/ min) return to baseline Q2-3d

Follow up

• Oct 6:

– Diltiazem d/c’d, increase to amlodipine 5mg – BP 166/84 – 185/94 – Urine microalbuminemia 172 mmol/L – Alb/Cr: 12.3

• Oct 8:

– Increased to amlodipine 7.5mg

• Oct 11:

– BP 165/100 – 190/90 – SCr 213, eGFR 23 – d/w nephrologist & hospitalist to start perindopril 4mg PO daily and increase amlodipine 10mg PO daily

• Oct 12:

– BP 0820: 112/59, 1245: 136/69, 2005: 152/72, 2400: 132/68 – SCr 223, 245 eGFR 22, 20 K 5.5, 4.1 – Started perindopril 4mg and amlodipine 10mg

• Oct 13

– BP 0400: 169/77, 0800: 163/77 – Held perindopril 32

References

1. Varon JElliot W. Hypertensive Urgency [Internet]. Uptodate. 2014 [cited 13 October 2016]. Available from: https://www.uptodate.com/contents/management-of-severe-asymptomatic- hypertension-hypertensive-urgencies-in-adults?source=search_result&search=hypertensive %20urgency&selectedTitle=1~43#H1 2. Pollack CRees C. Hypertensive Emergencies: Acute Care Evaluation and Management. EMCREG International. 2008;3:1-11. 3. Goodman L, Gilman A, Brunton L. Goodman & Gilman's manual of pharmacology and

• therapeutics. New York: McGraw-Hill Medical; 2008.

4. Sica D. Combination Calcium Channel Blocker Therapy in the Treatment of Hypertension. The Journal of Clinical Hypertension. 2001;3(5):322-327 5. Alviar C, Devarapally S, Nadkarni G, Romero J, Benjo A, Javed F et al. Efficacy and Safety of Dual Calcium Channel Blockade for the Treatment of Hypertension: A Meta-Analysis. American Journal of Hypertension. 2012;26(2):287-297 6. Saseen J. Comparison of nifedipine alone and in combination with diltiazem and verapamil in

• hypertension. American Journal of Hypertension. 1996;9(4):150A

7. Frishman W, Charlap S, Kimmel B, Teicher M, Cinnamon J, Allen L et al. Diltiazem, nifedipine, and their combination in patients with stable angina pectoris: effects on angina, exercise tolerance, and the ambulatory electrocardiographic ST segment. Circulation. 1988;77(4):774-786. 33