Calcium Channel Blockers
The hallmark of PAH is increased PVR, which compromises the ability of the right ventricle to maintain cardiac output [3]. Increased RV stroke work (volume of blood pumped × pressure against which the volume is pumped) against the abnormally increased PVR has been thought to be the cause of RV hypertrophy and dilatation and, eventually, failure to pump effectively (maintain cardiac output) against increasing resistance. The idea of attempting to decrease PVR in PAH by vasodilation has always been tempting [114]. Multiple basic science experiments and clinical studies suggest that in animal models of PAH and in patients who have PAH, the mediators of pulmonary vasodilation are decreased, whereas the mediators of vasoconstriction are overexpressed [115–117]. Clinical studies indicated that the ability to successfully produce vasodilation by certain agents with known vasodilator properties (eg, CCBs [118] , IV prostacyclin [119,120] , inhaled NO [121–124] , IV adenosine [125] , or inhaled iloprost [126]) in patients with PPH identifies the patients who have much better prognosis [29,32–34,127] , particularly if they are treated with high-dose CCBs (Table 3) [29,32–34]. Such testing (known as acute vasoreactivity testing [ Table 8 ]) became a routine for almost all patients who have PAH and are undergoing initial diagnostic right heart catheterization, except patients with low cardiac output or concurrent left heart failure, as indicated by elevated pulmonary capillary wedge pressure. Patients who have significant (see Table 6) pulmonary vasodilation without a significant systemic vasodilation (as assessed by change in PVR/SVR ratio or clinically unacceptable fall in systemic blood pressure) in acute vasoreactivity testing are called “responders” and are candidates for long-term CCB therapy. The current definition of a responder is a decrease in mean pulmonary arterial pressure of >10 mm Hg to a mean pulmonary artery pressure of ≤40 mm Hg with a maintained (or increased) cardiac output. “Responders” comprise 10% to 26% of IPAH patients undergoing such testing; unfortunately, the proportion of patients who are responders among APAH (eg, scleroderma or CTE-PHT) is even lower [128]. The role of acute vasoreactivity testing and the use of CCBs in patients who have APAH who demonstrate acute vasodilation are not known.
There are reports of patients who have IPAH and who were initially nonresponders to acute vasoreactivity testing, transforming to responders at repeat right heart catheterization after prolonged use of IV prostacyclin [129]. No data are available to define the safety or role of CCBs in such patients. A recent report suggests that only a small minority (6.8%) of all patients who have PAH can be managed by CCBs in the long-term without need for additional specific PAH therapy, because as many as half of the patients on CCBs deteriorate in the subsequent years [32]. Because of such reports and the availability of newer safe and effective oral and inhaled (rather than parenteral) PAH therapies, the enthusiasm to support the necessity of acute vasoreactivity testing as an essential part of PAH evaluation has somewhat decreased. Currently, however, acute vasoreactivity testing continues to be part of the algorithm for the evaluation of patients who have PAH (particularly IPAH). The predictors of long-term response to CCBs without the need for additional agent are listed in Table 3 [32].
It should be noted that 80% to 90% of all patients who have IPAH and a greater percentage of patients who have APAH are nonresponders at acute vasoreactivity testing, and these patients are treated with specific PAH therapies (eg, prostacyclin analogs, endothelial receptor antagonists, or 5-phosphodiestrase inhibitors). Importantly, the lack of response to acute vasoreactivity testing (ie, the administration of inhaled or IV prostacyclin, NO, or adenosine) does not rule out the likelihood of improvement with long-term use of prostacyclins or other specific PAH therapies [4–21].
The primary purpose of acute vasoreactivity testing is to determine whether CCBs could be used as PAH therapy. The CCBs are not used in patients who have significant acute RHF because of cardiodepressor effects. There is no role of acute vasoreactivity testing in patients who have PAH who are hospitalized with acute worsening of RHF. Similarly, if at the time of right heart catheterization (RHC) the cardiac output is determined to be low (CI <2.0) acute vasoreactivity should not be performed because it will have no impact on the treatment and it may be associated with an undesirable fall in systemic blood pressure or cardiac output. In any patient, acute vasoreactivity testing may precipitate acute pulmonary edema and marked worsening of hypoxemia [130]. It should be done with caution in patients who have a pulmonary capillary wedge pressure of ≥15 cm H 2 O. In the event of any sudden worsening in oxyhemoglobin saturation during acute vasoreactivity testing, acute pulmonary edema should be considered. The vasodilator agent should be discontinued and treatment with intravenous morphine, intravenous nitroglycerine, and furosemide may be considered [130]. It should be noted that acute severe pulmonary edema during acute vasoreactivity testing is not a contraindication to the use of pulmonary vasodilator agents, such as intravenous prostacyclin. This should be done with extreme caution, and dose escalation should be done slowly [130]. Some authorities favor testing with IV nitroprusside [131] in patients with high pulmonary capillary wedge pressure. A fall in systemic arterial blood pressure with IV nitroprusside causing increase in cardiac output and drop in pulmonary capillary wedge pressure highly suggests the possibility of concurrent LV diastolic dysfunction. Similarly, in patients with pulmonary veno-occlusive disease, the acute vasoreactivity testing may result in massive pulmonary edema, which may even be fatal. Death has been reported in a patient with pulmonary veno-occlusive disease as a result of administration of IV prostacyclin [132] at 2 ng/kg/min for only 5 minutes.
Inhaled NO, inhaled prostacyclin, IV prostacyclin, or IV adenosine may be used for acute testing [35–37]. These agents are short acting, easily administered and titrated, have minimal systemic effects at doses that can result in pulmonary arterial vasodilation, and demonstrate rapid reversal of effects if complications ensue. The CCBs should not be used for this testing because they are longer acting and their use may be associated with complications such as systemic hypotension and worsening of hypoxemia. These reactions to CCBs were primarily seen in patients who were actually nonresponders. Because of little likelihood of benefit and a risk of side effects and complications, empiric use of CCBs in all patients who have PAH without knowing acute vasoreactivity status is not indicated, is dangerous, and may be fatal.
In only a small subset (10%–26%) of patients who are responders and have no specific contraindication to CCBs, these agents may be started as an inpatient treatment with PA catheter in place (acute CCB dose escalation) or by slowly increasing the dose on an outpatient basis (see Table 8). The choice of agent depends on the resting heart rate of the patient [29,32–34]. If the patient's heart rate is >100 beats/min, diltiazem is used; if the heart rate is <100 beats/min, nifedipine is used. Verapamil is generally not used because of its strong cardiodepressor properties. Amlodipine is another choice, especially for patients who cannot tolerate the other CCBs secondary to side effects, such as worsening of peripheral edema, systemic hypotension, or abnormally low or high heart rate.
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