Hypertension: A Bridge to Trarbplantatioh? Stuart Rich, MD

Prhnary pulmonary hypertension is a progressive disease with a mean survival of <3 years from the thne of diagnosii. Recent advances in the medical management have shown that some pa-

tients may have an extremely good outcome de-

pendSng~t~ msponse to high doses of calcium antagonists. Anticoagulants are also associated with Improved survival, and prostacyclin is show- lng great promise in patients who are refractory to conventional therapy. At the same time, lung transplantation has developed into a viable treat- ment option for patientswho remain symptom-

atic and deteriorate on medical management. The role of the various medical treatment modali- ties, and the ideal timii of lung transplantation, is an issue that is continuing to evolve as Im- provements in all treatments develop. The cost and availabMty of the various treatments will likely affect the selection of treatments in indl-

vidual patients as well. (Am J Cardiol1995;75:63A-6&4)

From the Section of Cardiology, University of Illinois at Chicago College of Medicine, Chicago, Illinois.

Address for reprints: Stuart Rich, MD, University of Illinois at Chicago, Section of Cardiology (M/C 787), 840 S. Wood Street, Chicago, Illinois 60612.

P rimary pulmonary hypertension (PPH) is an uncommon disease that has been character- ized as progressive and incurable. Previous

reports describe the mean survival as <4 years,192 and the National Institutes of Health (NIH) Regis- try on Primary Pulmonary Hypertension has docu- mented a median survival of 2.8 years in a large cohort of patients followed prospectively for 7 years.3 Over the past 10 years, there have been extraordinary advances made in the treatment of PPH, which spans from daily oral medications to organ transplantation. This review will discuss the advances made in the medical treatment of PPH and place in perspective the relative role that these emerging therapies are playing, and their impact on the need for organ transplantation.

CALCIUM CHANNEL ANTAGONISTS Observations that the pulmonary artery pres-

sure and pulmonary vascular resistance could be lowered rapidly by a variety of vasodilator agents led to the speculation that vasoconstriction was a feature of PPH.@ Early on, patients were tested acutely, typically in a catheterization laboratory or intensive care unit setting under hemodynamic guidance, with decisions made regarding the effi- cacy of such drugs based on the acute reduction in pulmonary resistance that could be obtained.7 However, numerous reports of adverse effects in many patients seemed to indicate that long-term treatment with vasodilators based on this strategy did not change either the clinical outcome or survival.8-*1

More recently, a therapy using high doses of calcium channel antagonists that are titrated to the maximal response of the pulmonary artery pres- sure and pulmonary vascular resistance has been described, and associated with a dramatic improve- ment in quality of life and lifestyle, regression of right ventricular hypertrophy, and improved sur- vival.i2 This trial studied high doses of calcium channel antagonists (nifedipine up to 240 mg/day, diltiazem up to 720 mg/day) in 64 patients and documented a 95% 5-year survival in patients who

A SYMPOSIUM: CARDIOVASCULAR EFFECTS OF PROSTAGLANDINS 63A

responded, compared with a 36% survival for patients who were nonresponders, which was simi- lar to the survival rate of patients enrolled in the NIH Registry. The definition of a response, how- ever, was much more rigid than had been previ- ously characterized in the medical literature. Namely, patients had to manifest a 25% reduction in both mean pulmonary artery pressure and pulmo- nary vascular resistance. As a result, approximately only 1 in 4 patients were characterized as respond- ers to this medical therapy. To date, there has been no patient who has responded to the high-dose calcium antagonist regimen, showing regression of right ventricular hypertrophy (RVH), who has gone on and developed subsequent progression of the disease. Consequently, it can be reasonably assumed that the high-dose calcium antagonist therapy may be successful for an indefinite period of time, perhaps lifelong.

Cautions against empirically initiating calcium antagonist therapy in these patients has been underscored numerous times. Calcium antagonists have negative inotropic properties and when given to patients with right ventricular failure can cause dramatic worsening of symptoms and even lead to death.1°J”J4 The current experience suggests that patients being considered for treatment of PPH should be referred to specialized centers with expertise in administering these medications to avoid serious adverse consequences.15 Patients who present with clinically stable PPH are indistinguish- able as to whether they may or may not respond to calcium channel antagonists, necessitating a clini- cal challenge under hemodynamic guidance. Whether the ones who respond represent a subset of PPH, or merely just a different stage of PPH, has never been answered. It appears likely that pa- tients with this type of response need not be considered for lung transplantation while they remain responsive to treatment.

Of concern is that calcium antagonists may be used in inadequate doses in potentially responsive patients. In spite of the proven safety of using high-dose calcium antagonists in selected patients, many physicians prefer to initiate therapy at lower doses because of fear or their lack of familiarity. Unfortunately, some patients who could benefit from the higher doses may remain on conventional regimens and continue to deteriorate clinically. The ability to respond dramatically to vasodilators can become lost, and thus the opportunity to alter the progression of the disease in a patient signifi- cantly may become lost.16

A more common response to calcium antago- nists is for patients to have an increase in cardiac output, and thus a reduction in calculated pulmo- nary vascular resistance, without a reduction in mean pulmonary artery pressure.” Although many of these patients feel better and have improved effort tolerance, this type of response has not been associated with improved survival. In these cases the possibility remains that these patients may continue to deteriorate over time and thus may need more aggressive therapy in the future.

ANTlCOAGtlJlATlON Histologically, the presence of thrombosis at the

arteriolar level in patients with PPH is common.ls Both clinical and biochemical data substantiate a role for anticoagulant therapy in the long-term treatment of this disease.19,20 The clinical efficacy of anticoagulation as therapy of PPH, however, has been difficult to prove. A retrospective review of patients with PPH followed over a 15year period suggested that those who received warfarin antico- agulant therapy had improved survival compared with those patients who did not.21 More recently, the influence of warfarin therapy on clinical out- come was investigated in patients with PPH who failed to respond to high-dose calcium channel antagonists.12 A significant improvement in sur- vival occurred in those patients who were treated with coumadin anticoagulation, with a survival of 91%, 62%, and 47% after 1, 2, and 3 years compared with 52%, 31%, and 31%, respectively, in patients who did not receive anticoagulation.

As a rule, the anticoagulant therapy would not be expected to improve symptoms in these pa- tients. However, it appears that in some ways it retards the progression of disease and thus im- proves long-term survival. Since patients may un- dergo a stable clinical course with such treatment for many years, it should not be considered impera- tive or inevitable that such patients would need to receive lung transplantation as a treatment.

PROSTACYCUN Prostacyclin is a metabolite of arachidonic acid

produced by the vascular endothelium with a multitude of pharmacologic actions.22 These in- clude potent vasodilation of the pulmonary and systemic arterial and venous beds, inhibition of platelet aggregation, and inhibition of smooth muscle proliferation. For these reasons, it appears to be an ideal drug for testing in the treatment PPH. Prostacyclin, however, can only be given

84A THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 75 JANUARY 19, 1995

intravenously, and thus the clinical trials of its efficacy and safety have been difficult to conduct.

Prostacyclin has been used in the treatment of PPH in the United States and Europe.23,24 It causes efficacious effects with a reduction of pulmonary pressure and increases of cardiac output associated with reductions in pulmonary vascular resistance. Trials have shown the utility of long-term prostacy- clin as a bridge to transplantation for patients enrolled in such programs, with efficacy manifested by stabilizing the patients’ clinical condition.24 More recent trials have consistently shown that patients with PPH who receive prostacyclin have improved exercise capacity and survival as we11.25 Some patients improved to the point that they no longer wish to consider transplantation as a treat- ment option.

Prostacyclin is a difficult drug to use. It must be given continuously through a central intravenous catheter infusion system that requires daily mixing of medications, protection against heat, and an automated ambulatory pump. Side effects of the drug consist primarily of flushing, headache, nau- sea, and diarrhea but are relatively well tolerated. Complications related to this therapy have been attributed most often to the drug delivery system, including thrombosis or infection of the indwelling catheter and pump malfunction, rather than to the medication itself.

Clinical trials on prostacyclin have only utilized patients who were refractory to other medical therapy and were New York Heart Association (NYHA) functional class III-IV. As these patients appear to be those with the worst prognosis, prostacyclin appears to be effective as a bridge to transplantation. However, it remains unknown as to whether prostacyclin could have comparable effects to the calcium channel antagonists if given to patients with less severe symptoms. No head-to- head trials comparing the effects of calcium antago- nists versus prostacyclin as first line therapy in PPH have been conducted.

LUNG TRANSPIANTATION Heart-lung transplantation has been performed

successfully in patients with PPH for over a de- cade.26 The major limitations to its widespread application include the limited number of centers with expertise to perform this procedure, and the markedly limited availability of suitable donor organs. More recently, single and double lung transplantation has been performed successfully in patients with PPH. 27,28 Hemodynamic studies have shown an immediate reduction in pulmonary artery pressure and pulmonary vascular resistance associ-

ated with improvement in right ventricular func- tion.27 Because there are more potential suitable donors, single and double lung transplantation has received great attention and may, in fact, be the procedure of choice for patients with pulmonary hypertension as the underlying problem.

A concern regarding restoration of right ven- tricular function in these patients remains. How- ever, data showing regression of RVH in patients undergoing pulmonary thromboendarterectomy for pulmonary hypertension and in those being treated with high doses of calcium channel antagonists suggest that right ventricular dysfunction is revers- ible in the majority of these patients. The major long-term problem in patients who survive this operation has included the high incidence of a bronchiolitis obliterans in the transplanted lungs, acute organ rejection, and opportunistic infection. Centers with large experiences in doing lung trans- plantation have shown much better survival for patients whose indication is chronic obstructive airways disease than for pulmonary hypertension. Interestingly, the survival of patients receiving heart-lung versus single or double lung does not seem to be a significant factor, and thus the best procedure may be more suited to be determined by the center, depending on their expertise.29 How- ever, in most series 4-year survival remains < 60%.28,29 For this reason, as well as the expense and early mortality rate, organ transplantation must still be considered a treatment of last resort for PPH.

The major controversy has been the role of transplantation with respect to other medical thera- pies. The NIH Registry on PPH has documented that a patient’s clinical course can be stable until the onset of right ventricular failure.3 Patients who are NYHA functional class IV have a mean sur- vival of 6 months compared with >3 years for those who are functional class II-III. With the ever-improving efficacy of medical therapy for PPH, it is obvious that the relative roles of medical versus surgical treatment of this disease need to be constantly updated and evaluated.

RECOMMENDATIONS We believe we can make the following recom-

mendations: Data suggest that all patients with a diagnosis of PPH will benefit from long-term anti- coagulant therapy, and this should be a concomi- tant part of the treatment of PPH patients, irrespec- tive of the clinical efficacy of the other concurrent treatments.

A SYMPOSIUM: CARDIOVASCULAR EFFECTS OF PROSTAGLANDINS 85A

Patients diagnosed with PPH should undergo acute vasodilator testing in specialized referral centers to determine whether they will be respon- sive to calcium channel antagonists at higher doses. Patients who respond to calcium antagonists should be treated long-term on the appropriate doses. Patients who fail to respond to calcium antagonists, and those who respond initially but whose response is not maintained, should then be considered for intravenous prostacyclin treatment.

The efficacy of prostacyclin needs to be deter- mined for each patient. Since the clinical benefits do not seem to mirror the acute hemodynamic changes, functional tests such as exercise testing may be a more reliable way to determine the clinical response. In those patients who respond favorably to prostacyclin without evidence of right ventricular failure, it is our recommendation that they not be considered for lung transplantation. Patients who develop signs of right heart failure, while on calcium antagonists or prostacyclin, should be considered aggressively for lung transplanta- tion.

In spite of the aggressive practices of many transplant centers, we disagree with the opinion that a patient should be enrolled on a lung trans- plant list as soon as the diagnosis of PPH is made. Rather, we advocate that all patients with PPH be evaluated and informed regarding transplantation as an option, and they should pursue regional transplant centers to establish a dialogue. Once there is clinical documentation of the failure of medical management of these patients, they should then be evaluated for lung transplantation and placed on a wait list as soon as possible. It is hoped that this will result in a better allocation of these vital organs and maximize the medical benefits that these patients could otherwise receive. The medi- cal and surgical treatments of PPH appear to have markedly beneficial roles in select patients, depend- ing on the stage of the disease and response to conventional treatments. These roles continue to evolve.

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