Comparison of Nifedipine Alone and With Diltiazem or Verapamil in Hypertension

Design

Randomized, double-blind, three-period crossover study

N= 16

Objective

To determine blood pressure reductions using nifedipine alone, nifedipine plus diltiazem, and nifedipine plus verapamil

Study Groups

Nifedipine monotherapy (n=16)

Nifedipine with verapamil (n=16)

Nifedipine with diltiazem (n=16)

Inclusion Criteria

Adults with a previous diagnosis of hypertension baseline supine diastolic blood pressure (DBP) between 95 and 115 mm Hg

Exclusion Criteria 

Serious concurrent medical condition (i.e. hepatic or liver disease, malnutrition, immunological disorders, alcohol abuse, heart failure, or other severe forms of heart disease, including unstable angina, conduction abnormalities, myocardial infarction, or coronary artery bypass graft within the past 3 months), smokers, contraindication to CCB therapy, or use of medications other than antihypertensives, blood pressure greater than 200/115 mm Hg for more than 2 weeks after titration off antihypertensives

Methods

All patients received sustained-release nifedipine (Adalat CC) 30 mg PO BID for two weeks. If DBP remained >90 mmHg then patients also received either sustained-release diltiazem (Cardizem CD) 180 mg PO daily or sustained-release verapamil (Verelan) 180 mg PO daily (for weeks 2-4 in addition to nifedipine). Weeks 4-6 consisted of a washout period of nicardipine monotherapy, followed by the last 2 weeks of patients receiving either diltiazem or verapamil (whichever they did not receive during weeks 2-4). All other antihypertensives were discontinued prior to initiation. 

Duration

Total treatment length: 8 weeks

Outcome Measures

Baseline Characteristics

Study cohort (n=16)

Age, years

Men

Black

Mean supine SBP, mm Hg

Mean supine DBP, mm Hg

Mean heart rate, bpm

Results

All three treatments significantly lowered supine SBP (p < 0.001) and DBP (p < 0.02) compared with baseline at all times postdose (i.e. hours 0, 2, 6, and 24). The mean percent maximal reductions each group for SBP includes 16.1% for nifedipine alone, 20.2% for nifedipine with diltiazem, and 18.9% for nifedipine with diltiazem. For DBP the mean percent maximal reductions in each group include 19.8% for nifedipine alone, 27.9% for nifedipine with diltiazem, and 26.5% for nifedipine with diltiazem. No statistically significant reductions in heart rate from baseline were seen in any treatment arm. 

Adverse Events

Common Adverse Events: constipation 50% in nifedipine with verapamil group, mild lower extremity edema 18.8% while taking each dual therapy, headache 37.5% in nifedipine monotherapy, 12.5% in nifedipine with verapamil, and 31.3% in nifedipine with verapamil 

No serious adverse effects were reported and no patients discontinued due to drug tolerability

Study Author Conclusions

The addition of either diltiazem or verapamil to nifedipine results in an additive antihypertensive effect. This additive effect is greater with diltiazem and is most pronounced near the end of the dosing interval. The use of CCB combinations appears to be safe and effective and should be viewed as a potential treatment strategy for hypertension.

InpharmD Researcher Critique

Normal doing of sustained-release verapamil (Verelan) should be titrated every 24 hours starting at 120 mg to 180mg, 240 mg, 360 mg, and finally to 480 mg once daily to see a maximum benefit, which could be why the addition of diltiazem showed a greater reduction in blood pressure. Further, longer-term studies should be conducted to conclude the combination therapy of CCBs does not affect safety outcomes.

Verapamil and Nifedipine in Combination for the Treatment of Hypertension

Design

Retrospective study

N= 50

Objective

To examine the efficacy and safety of the combination of verapamil and nifedipine in the control of hypertension (HTN)

Study Groups

Inclusion Criteria

Patients who took a combination of verapamil and nifedipine

Exclusion Criteria

Methods

Investigators retrospectively reviewed patients' charts of patients treated with a dual therapy of verapamil and nifedipine. Blood pressure was normally measured three times in the sitting position by a mercury manometer. 

For people with moderate to severe HTN, either verapamil or nifedipine was initiated and each drug was titrated to the maximum daily target dose, 480 mg for verapamil and 180 mg for nifedipine, to achieve diastolic blood pressure (DBP) < 90 mm Hg. If DBP was still ≥ 90 mm Hg on the maximum dose of a single agent, then the alternative would be added and titrated to the maximum dose as well. 

For people with mild HTN, verapamil, and nifedipine were administered and titrated in a 4:1 ratio (120/30, 240/60, 360/90, 480/120 mg daily) to achieve DBP < 90 mm Hg. 

Duration

Outcome Measures

Baseline Characteristics

Verapamil and nifedipine cohort (n=50)

Age range, years 

Male

Black

Results

Endpoint

Verapamil and nifedipine cohort (n=50)

Failure of blood pressure control

Treatment discontinued due to adverse effects

3 (6%)

     Increased liver transaminases

2 (4%)

     Clinical hepatitis

1 (2%)

     Rash

1 (2%)

When the second medication was added, 24 of 27 (88%) of blood pressures were controlled.

Adverse Events

Common Adverse Events: leg edema 28%

Study Author Conclusions

Verapamil and nifedipine, a combination of a dihydropyridine and a non-dihydropyridine calcium antagonist, was effective and safe in this group of patients with difficult-to-manage hypertension.

InpharmD Researcher Critique

This was a small, single-center, retrospective study. Without comparison with either verapamil or nifedipine monotherapy, it's unlikely to determine whether the blood pressure lowering effects of verapamil plus nifedipine were more significant than the single agent used alone. 

 Acute Effects on Exercise Tolerance of Felodipine and Diltiazem, Alone and in Combination, in Stable Effort Angina

Design

Acute, double-blind, within-patient study

N= 12

Objective

Study Groups

Felodipine 10 mg

Diltiazem 60 mg

Felodipine + diltiazem

Placebo

Inclusion Criteria

History of effort induced angina pectoris, stable in previous three months, ST-segment depression > 2 mm, with or without anginal pain, during each of two qualifying exercise tests, carried out on two different days during the run-in phase, exercise test reproducibility (a difference in exercise duration to 1 mm ST depression of less than 15%) between the two qualifying tests

Exclusion Criteria

Methods

Duration

Study period: 7 days

Outcome Measures

Effects at rest and on exercise, and adverse effects 

Baseline Characteristics

All patients (N= 12) 

Age, years

Male

Mean duration of angina, months

Number of anginal attacks/week 

One

Two

Three

3 (25%)

2 (16.7%)

7 (58.3%)

Results

Endpoint

Felodipine

Diltiazem

Felodipine + diltiazem

Placebo

p-value

Effects at rest:

Recumbent values

Systolic BP, mmHg

Diastolic BP, mmHg

Heart rate, beats/min

Standing values

Systolic BP, mmHg

Diastolic BP, mmHg

Heart rate, beats/min

Total work at: 

Ischemic threshold

Peak exercise

< 0.001

0.0024

Systolic BP, mmHg

Ischemic threshold

Peak exercise

Heart rate, beats/min

Ischemic threshold

Peak exercise

Pressure-rate product, mmHg/beats/min

Ischemic threshold

Peak exercise

0.84

0.87

< 0.001

< 0.001

< 0.05

0.41

Exercise time to the ischaemic threshold (ST-segment depression = 1 mm) and peak exercise was significantly prolonged by the felodipine-diltiazem combination (492 s and 504 s, respectively) compared to placebo (301 s, 370 s; p < 001), felodipine alone (381 s, 428 s; p < 001) and diltiazem alone (367 s, 422 s; p < 001).

Adverse Events

Study Author Conclusions

InpharmD Researcher Critique

The study had a small sample size, with only 12 patients. Given the short duration of the research and likely different exercise tests conducted at other facilities, the external validity of these results may be very limited. 

Dihydropyridine/Nondihydropyridine Calcium Channel Blocker Combination Therapy

Design

Case series

Case 1

An 80-year-old woman with refractory stage 2 isolated systolic hypertension was transferred to a hospital for evaluation. She has a past medical history of stroke in 2002, a medication history of antihypertensives for  35 years, and a history of thiazide-related hyponatremia. At the hospital, she was given a clonidine patch 0.2mg, lisinopril 40mg, and verapamil sr 120mg, and her BP the next morning was 162/87 mmHg and around 156-164/76-88 mmHg after discharge before hypertensive clinic evaluation. 

When her medication was changed to dihydropyridine and non-dihydropyridine CCB combination, felodipine 20mg and verapamil SR 120mg daily with lisinopril 40mg, her follow-up clinic BP was 128-138/68-72 mmHg.

Case 2

A 79-year-old woman with refractory stage 2 systolic hypertension was evaluated at a hypertension clinic. She has a medication history of taking antihypertensives for about 45 years, specifically hydrochlorothiazide(HCTZ)/triamterene and diltiazem. In the last 4 years, her systolic BP has been in the 150s, and in the past 6 months, it has ranged from 152-184 mmHg though clonidine was added to her regime. Furosemide was added but discontinued due to hyponatremia. Her BP was recorded at 212-216/82-84 mmHg over the last two months while on atenolol 50 mg bid, diltiazem 240mg in the morning, and 120mg in the evening, and clonidine 0.1mg in the morning and 0.2mg at bedtime.

When her medication was changed to dihydropyridine and non-dihydropyridine CCB combination, lisinopril 40mg, nifedipine extended-release 60 mg, and diltiazem extended-release 240mg, follow-up clinic BP was 136-138/80-82 mmHg.

Case 3

A 62-year-old black man with persistent stage 1 hypertension despite treatment with verapamil sr 240mg bid and lisinopril 20mg daily presents to the hypertension clinic. When on verapamil sr 240mg bid and lisinopril 20mg/HCTZ 25mg, his BP was 146-152/84-92 mmHg.

When his medication was changed to dihydropyridine and non-dihydropyridine CCB combination, nifedipine extended-release 30mg, verapamil SR 240mg daily, and lisinopril 20mg/HCTZ 25mg, follow-up clinic BP was 126-134/82-86 mmHg.

Study Author’s Conclusion

Calcium channel blockers(CCB) lower BP by vasodilation but a subclass called non-dihydropyridines also slow down heart rate thus should not be used with other rate slowing agents such as beta-blockers and clonidine. The other subclass of CCB, dihydropyridines can safely be used with beta-blockers. A combination of dihydropyridine/non-dihydropyridine CCB has shown to not only reduce blood pressure but also improved exercise tolerance, and side effects due to dose reduction of each CCB subclass.

Elderly patients and blacks share a low renin hypertensive pathophysiology and clinical trials have demonstrated these populations to be especially responsive to calcium channel treatment. Guidelines for the management of African American hypertension state, “thiazide diuretics and calcium channel blockers may have greater blood-pressure-lowering effects than do other classes in African Americans than in whites.” An effective option for individuals in these populations refractory to the usual stepped care treatment regimens can be combination therapy with dihydropyridine and nondihydropyridine CCBs.