Pulmonary Arterial Hypertension (PAH)

Early trials of the treatment of pulmonary arterial hypertension (PAH) with calcium channel blockers (CCBs) were met with enthusiasm, but recent evidence suggests that CCBs play a limited role in many patients. In one frequently cited study, conducted in 1992, 64 patients who had primary PAH were treated with either nifedipine or diltiazem and followed for up to 5 years. The study reported that the 5-year survival rate among responders was 94%. It is noteworthy that the study involved a highly selected group of patients. In the trial analysis, the patients considered responsive to CCBs (defined as those whose pulmonary arterial pressure and pulmonary vascular resistance immediately decreased >20% after challenge) were compared with unresponsive patients. In this analysis, 26% of patients were considered responsive to therapy with CCBs.¹ 

Considerations for the Use of Calcium Channel Blockers in PAH

Vasoreactivity testing is indicated for a patient with PAH before CCB therapy is started to determine whether it the therapy suitable and to mitigate the risk for unnecessary adverse events (AEs). CCBs are associated with right ventricular failure, syncope, and hypotension.² Vasoreactivity testing is usually performed during the same catheterization procedure done to diagnose PAH. A vasodilator is administered intravenously or nitric oxide is inhaled (note: not CCBs) while hemodynamic parameters such as the mean pulmonary arterial pressure and peripheral vascular resistance are measured.³ 

The definition of vasoreactivity remains a debated topic. The American College of Cardiology Foundation and American Heart Association define vasoreactivity as a 20% decrease in both pulmonary arterial pressure and peripheral vascular resistance with either intravenous epoprostenol or inhaled nitric oxide. The European Society of Cardiology and American College of Chest Physicians define vasoreactivity as a reduction in mean pulmonary arterial pressure of more than 10 mm Hg to an absolute level below 40 mm Hg.³ 

Indications and Dosage

CCBs are considered as initial treatment for patients with idiopathic PAH or PAH due to drugs or toxins, but predictors of responsiveness to CCB therapy have not been established. A positive vasodilator response in a patient who has PAH in the setting of connective tissue disease, HIV infection, portopulmonary hypertension, or pulmonary veno-occlusive disease does not appear to predict a favorable long-term response to CCB treatment. A CCB may be initiated in a patient who meets the vasoreactivity criteria, followed by monitoring for treatment effectiveness. 

Three CCBs are used to treat PAH, and the choice of agent depends on the patient’s baseline heart rate. Patients with relative bradycardia are usually given either nifedipine or amlodipine. If the patient is relatively tachycardic at baseline, diltiazem is preferred. It should be noted that verapamil is avoided.² 

The recommended doses of CCBs for patients with PAH are high and are listed below²: 

1. Nifedipine: 120-240 mg/d
2. Diltiazem: 240-720 mg/d
3. Amlodipine: 20 mg/d

Monitoring

Common AEs associated with CCBs include systemic hypotension and lower limb peripheral edema. If these AEs develop, the dose should be titrated to an effective amount. Patients with idiopathic PAH who are started on CCB treatment should be closely monitored for safety and efficacy and should undergo a complete reassessment, including right heart catheterization, after 3 to 4 months of therapy. An adequate response is defined as attaining World Health Organization (WHO) functional class I or II (able to perform ordinary physical activity without symptoms [class I] or able to perform ordinary activity with symptoms of dyspnea, fatigue, or near syncope and comfortable at rest [class II]) and exhibiting marked hemodynamic improvement. The addition of a drug approved for the treatment of PAH to the CCB is an appropriate next step if a patient fails to respond to the CCB alone.²  

References

1. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327(2):76-81. doi:10.1056/NEJM199207093270203

2. Yaghi S, Novikov A, Trandafirescu T. Clinical update on pulmonary hypertension. J Investig Med. 2020;68(4):821-827. doi:10.1136/jim-2020-001291

3. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 Expert consensus document on pulmonary hypertension. Circulation. 2009;119(16):2250-2294. doi:10.1161/CIRCULATIONAHA.109.192230

Reviewed by Harshi Dhingra, MD, on 5/6/2022.

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Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.