Calcium Channel Blocker Therapy: When a Drug Works, it Works. When it Doesn't, it Doesn't

SHORT-ACTING VASODILATOR EVALUATION

Although a comprehensive discussion of the critical elements and techniques of acute vasodilator testing is beyond the scope of this article, 2 key elements inherent in this process include agent selection and setting of criteria for thresholds of acute response. The former by consensus has involved consideration of inhaled nitric oxide (iNO), epoprostenol, or adenosine. However, some evidence exists which suggests that adenosine and iNO may not be interchangeable in the detection of acute pulmonary vasodilation.9 Most current testing utilizes intravenous epoprostenol or iNO. The cost, method of administration, resources required, and side effects of these agents are different. Their protocols for administration have been published elsewhere.10–12

Threshold criteria for determination of acute vasodilator response in contrast to short-acting testing have evolved in at least 2 different iterations in guidelines. The initial suggestion for threshold of response was a >20% decrease in pulmonary artery pressure (PAP) with unchanged or increased cardiac index in the absence of systemic hypotension.4 These criteria were modified in 2004.13 The rationale for modification involved ongoing recognition that meaningful hemodynamic vasodilation and true response typically involved a dramatic decrease in pulmonary pressures. Since most idiopathic PAH (IPAH) patients present with mean PAP >50 mm Hg,14 modest reductions in PAP that satisfied the 20% criteria did represent populations that were likely to benefit from subsequent administration of CCBs. Table 1 represents the data from selected acute vasodilator responses in the literature.7 These responses are truly dramatic, and in our experience, represent typical hemodynamic patterns shown upon initial vasoreactivity testing in this unique group of patients.

Table 1. Baseline Values and Early and Late Effects of Calcium Channel Blockers on Mean Hemodynamic Variables in Patients Who Responded to Treatment

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An element not discussed above is the inclusion recommendation of vasodilator testing for all classes of PAH, although non-IPAH patients rarely, if ever, display short-acting vasodilator responsivity,1415 and if they do, they do not appear to benefit long term from CCB therapy.1617 This has led several practitioners to question the continued inclusion of a recommendation for inclusive testing for all PAH patients. Nonetheless, insurance approval for current PAH medications almost uniformly continues to require documentation of either failure of short-acting vasodilator trials or CCB trials in all groups of PAH patients.

ACUTE RECAPITULATION OF THE VASODILATOR RESPONSE AND DOSE FINDING VS OUTPATIENT UPTITRATION

The next step in the classic description of response to calcium channel antagonists involves recapitulating the initial acute vasodilator response with home-going oral medications. Nifedipine and diltiazem (not verapamil) were typically used in the initial descriptions of this step based on heart rate < or >100 beats per minute.6

Two approaches have been described. The first: a direct attempt at recreation of the acute vasodilator response by CCBs. Briefly, patients demonstrating vasoreactivity in response to short-acting vasodilators were taken to an intensive care unit for continuous hemodynamic monitoring. Efficacy of CCB was assessed by continued hemodynamic monitoring while sequential doses of CCB were given at 15 to 30 minutes. Simultaneous continuous monitoring of systemic blood pressure and cardiac index is necessary, as these agents could negatively impact one or both.6

Acute CCB trials are halted either with successful reproduction of the short-acting vasodilator response (a positive response) or with limiting decreases in either systemic blood pressure or cardiac index. Importantly, absence of systemic hypotension and maintenance or improvement of cardiac index is important. These agents can lead to dangerous decrease in systemic blood pressure, which may be particularly devastating in a PAH patient, and CCB trials have been reported to be associated with infrequent mortality.24 It is generally felt that patients with significant elements of right heart failure or depressed cardiac index should not undergo acute CCB trials for this reason.

A second approach consists of initial dosing with 10 mg of nifedipine or 60 mg of diltiazem TID with uptitration to 20 mg or 120 mg respectively if tolerated initially, with further dose increases as an outpatient according to tolerance.8 It bears re-emphasis that both approaches are only used in patients who have met the criteria for acute vasoreactivity. Empiric use of CCB in PAH patients is strictly forbidden. Indeed, CCB-induced systemic hypotension or fluid retention may be detrimental or dangerous in these patients. Regardless of the strategy, final daily doses of either approach were at or above typical dosing for patients receiving these drugs for labeled indications.

LONG-TERM PATIENT FOLLOW-UP

Short-term response to acute vasodilators and a positive initial response to a CCB trial does not guarantee a durable response. Patients need to be followed closely to ensure that their functional status, echocardiograms,18 and hemodynamics continue to improve over the months up to a year. There may be a substantial number of patients that fail to improve or initially have some benefit, which wanes in ensuing months. It is recommended that these patients be followed initially at 1- to 3-month intervals with assessments of exercise tolerance, physical examination, and echocardiography. True CCB responders will continue improvement toward normal. Failure to continue improvement or any deterioration should signal the need for alternate therapies. It is estimated that almost half the patients originally responsive to CCB therapy will fail in the first year.8 In this study, the patients who had the most robust response had a lower greater absolute drop during acute vasodilator testing and a lower mean pulmonary pressure compared to those who failed CCB therapy. As previously noted, however, continued improvement with ultimate normalization or near normalization does occur and is accompanied by a dramatic long-term survival eclipsing any other typical groups of patients receiving modern therapies.19

UNRAVELING THE BASIS OF CCB RESPONSIVENESS

A great deal of speculation regarding the mechanism of CCB sensitivity has occurred since the original recognition of this phenomenon. Theories have been advanced regarding aberrant smooth muscle contraction or alterations in calcium utilization, but heretofore have been unexplored or remain unsubstantiated. Certainly, understanding this uniquely favorable course in an otherwise fatal disease process may provide important insight, perhaps allowing other patients with PAH to benefit from cellular or genetic modifications or manipulations that could provide such a benefit.

Several recent studies have levered modern techniques of molecular characterization in the investigation of the CCB responder. Microarray analysis of polymerase chain reactions from peripheral lymphocytes identified unique expression profiles of vasoreactive IPAH patients, which could then be used in decision trees to identify vasoreactive patients in a validation cohort.20 A pathway-based analysis of whole exome sequencing (WES) was employed by Hemnes et al in the analysis of vasoreactive variants of IPAH compared to nonresponsive IPAH patients.21 Analysis demonstrated genetic variants representing cellular pathways such as cytoskeletal function and Wnt signaling. Vascular smooth muscle contraction–related genes were enriched in vasoreactive IPAH, suggesting a unique genetic predisposition in these patients. In that study, Wnt signaling was also shown to be increased in general in lung fibroblasts from PAH patients.

In another study utilizing proteomics, several groups of patients with and without PAH were compared, including CCB responders.22 Metabolites that were shown to discriminate PAH from normal patients were evaluated in CCB responders. These metabolites most closely resembled that of normal patients consistent with their essentially normal functional status and hemodynamics. Distinguishing expressions of the vasoreactive phenotype were not evident from this analysis.

The implications favor the theory that the vasoreactive patient may have a substantially different genetic basis, where specific gene expression may be utilized to identify these patients prospectively. Pathway analysis of WES suggests future areas for investigation both to better understand pathogenesis of PAH, vasoreactive phenotypes, and potential therapeutic targets.

CCB THERAPY IN OTHER TYPES OF PULMONARY HYERTENSION

CONCLUSION

Although included in all current guidelines, the true number of patients that can be effectively treated with CCBs is very small and essentially limited to IPAH patients, genetically associated PAH, or anorexigen-induced PAH. There is no role for empiric CCB treatment of PAH patients, and indeed hypotension or fluid retention may be detrimental or dangerous in these patients. It is important to remember that those who truly retain a long-term benefit are those that tend to have a dramatic initial response to vasodilators and will attain normal or near normal hemodynamics and functional class after starting CCBs. Should a patient do so, they may well enjoy dramatic long-term survival on this regimen.