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(Chest. 2005;127:1446-1452.)
© 2005 American College of Chest Physicians

Simvastatin Treatment of Pulmonary Hypertension*

An Observational Case Series

Peter N. Kao, MD, PhD

* From the Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, CA.

Correspondence to: Peter N. Kao, MD, PhD, Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, CA 94305-5236; e-mail: peterkao{at}stanford.edu e-mail


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Statins confer cardiovascular benefits beyond the reduction of serum cholesterol through antiproliferative and antiinflammatory mechanisms and induction of endothelial nitric oxide expression. In pneumonectomized rats injected with monocrotaline, simvastatin reversed established pulmonary hypertension and conferred a 100% survival advantage.

Study objectives: To evaluate the safety and efficacy of simvastatin for treatment of patients with pulmonary arterial hypertension (PAH).

Design: Open-label observational study performed at Stanford University Medical Center. Sixteen patients with primary and secondary causes of PAH, World Health Organization (WHO) classes I (n = 2), II (n = 4), III (n = 3), IV (n = 7), are described. Simvastatin was prescribed at 20 to 80 mg/d and continued in the absence of adverse effects.

Measurements and results: Serial measurements of 6-min walk (6MW) performance, hemodynamics, and echocardiographic estimates of right ventricular systolic pressures (RVSPs) were recorded on each patient. Simvastatin treatment was not associated with hepatic dysfunction, muscle necrosis, or other adverse events. Individual patients demonstrated improvements in 6MW performance, improvements in cardiac output, or decreases in RVSP that may be attributable to simvastatin treatment. Overall, the rate of disease progression appeared to be attenuated, and WHO class IV patients demonstrated improved survival.

Conclusions: Simvastatin treatment appears safe in patients with PAH.

Key Words: chronic thromboembolic disease • congenital heart disease • Eisenmenger syndrome • pulmonary vascular disease • scleroderma • ventricular septal defect


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Pulmonary arterial hypertension (PAH) develops as a consequence of progressive luminal obliteration of small pulmonary arteries. The pathogenesis involves inappropriate proliferation and constriction of vascular smooth-muscle cells, and deficiencies of endogenous vasodilators such as prostacyclin and endothelial-derived nitric oxide.1 The increase in pulmonary arterial pressure leads to right ventricular congestive failure and ultimately to death. Current treatment strategies for PAH include diuretics, anticoagulation, digoxin, and supplemental oxygen for congestive heart failure, and pulmonary vasodilating agents such as calcium-channel antagonists, prostanoids—especially IV epoprostenol and endothelin-receptor antagonists. New therapies, especially ones directed at suppressing inappropriate neointimal proliferation in pulmonary arteries, are warranted.2345

Statins are a class of drugs with cardiovascular benefits that exceed their effects on lowering serum cholesterol. Statins exert potent antiproliferative and proapoptotic effects on vascular smooth-muscle cells, through inhibition of ras and rho GTPase activities important for cell proliferation.6 Furthermore, statins enhance endothelial production of nitric oxide through synergistic mechanisms of stabilizing endothelial nitric oxide synthase messenger RNA7 and augmenting endothelial nitric oxide synthase phosphorylation and catalytic activity.8 Statins also increase circulating endothelial progenitor cells910 and stabilize endothelial barrier function in response to injury.11 Statins have antiinflammatory and immunosuppressive effects1213 and decrease atherogenesis.14 If statin treatment improved pulmonary endothelial barrier function and nitric oxide production in vivo, these effects might serve to suppress or reverse inappropriate smooth-muscle cell proliferation, neointimal formation, and pulmonary hypertension.

We tested the effects of statins for prevention and reversal of experimental pulmonary hypertension.1516 Simvastatin, 2 mg/kg/d, was substantially better than SDZ-RAD (an oral derivative of rapamycin)17 and was the best agent examined for prevention of PAH with neointimal formation in pneumonectomized rats injected with monocrotaline.16 We showed that simvastatin reversed neointimal vascular occlusion, pulmonary hypertension, and right ventricular hypertrophy, and conferred a 100% survival advantage on rats with established severe PAH.15

Simvastatin is well tolerated at and above the US Food and Drug Administration-approved maximum dose of 80 mg/d for treatment of elevated cholesterol.18192021 Phase I studies22 of statins in cancer defined a maximal tolerable dose of lovastatin of 25 to 35 mg/kg/d. Lovastatin was explored in a phase II clinical trial23 for efficacy against advanced gastric carcinoma at a dose of 35 mg/kg/d for 7 days, repeated monthly. The toxicity of high-dose lovastatin was principally anorexia with no liver inflammation; muscle inflammation developed in 2 of 14 patients. Lovastatin was explored in a phase I-II study for efficacy against anaplastic astrocytoma and glioblastoma multiforme at a dose of 20 to 30 mg/kg/d for 7 days, with or without radiotherapy, repeated monthly. High-dose lovastatin treatment showed minimal toxicity; no patients had myalgias, and no ubiquinone supplementation was required.24 These two clinical trials in advanced cancer patients independently support the safety of statins, even at high doses of 20 to 30 mg/kg/d. Pharmacokinetic studies suggest that simvastatin is more potent than lovastatin in reducing low-density lipoprotein cholesterol.18 To investigate the safety and efficacy of statins for treatment of pulmonary hypertension, we conducted an open-label observational study of simvastatin at Stanford University Medical Center.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The study was approved by the Stanford University Institutional Review Board, and all subjects provided written informed consent to participate. Baseline measurements of 6-min walk (6MW) performance, hemodynamics (mean pulmonary arterial pressure [mPAP], cardiac index [CI], and vasodilator responses), echocardiographic Doppler assessments of right ventricular systolic pressures (RVSPs), and clinical chemistries (including aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, and cholesterol) were obtained. Patients were treated with simvastatin, beginning at 20 mg/d for 2 weeks, then increasing to 40 mg/d. After at least 2 months with no adverse effects or a history of liver disease, simvastatin was raised to 80 mg/d. Simvastatin treatment was continued in the absence of adverse effects, such as liver or muscle inflammation. Serial measurements of 6MW performance, hemodynamics, RVSP, and clinical chemistries were collected at 3- to 5-month intervals. Since each patient was used as her/his own control and the measurement interval varied between patients, the data are presented separately for each individual, and are not averaged. Individual cases were selected for presentation based on the availability of hemodynamic measurements, or to illustrate the safety of simvastatin in various forms of advanced pulmonary hypertension.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Sixteen patients with primary pulmonary hypertension (PPH) or secondary pulmonary hypertension entered the open-label trial of simvastatin for treatment of pulmonary hypertension (Table 1 ). Twelve patients had PPH; of these, 3 patients had coexisting liver disease (patients 3, 7, and 11), and 2 patients had Graves hyperthyroidism that was treated with 131I radioablation (patients 10 and 11). Two patients had Eisenmenger pulmonary hypertension that had developed years after closure of ventricular septal defects (VSDs) [patients 4 and 12]. Two patients had chronic thromboembolic disease, one patient underwent thromboendarterectomy 8 years prior (patient 5), and one patient had coexisting liver cirrhosis (patient 16). Six patients were not receiving prostanoid therapy during the interval of measurement of simvastatin effects (patients 1 to 6); two of the surviving four patients went on to treatment with subcutaneous treprostinil (patients 1 and 3). In these two patients, treprostinil was initiated 18 months after simvastatin for management of persistent elevated RVSP (> 100 mm Hg) and moderate-to-severe right ventricular dysfunction on echocardiography. Ten patients were receiving stable doses of prostanoid therapy (change < 1 ng/kg/min within the preceding 4 weeks) with IV epoprostenol (prostacyclin, 9 patients) or subcutaneous treprostinil (patient 15) at the time of initiating treatment with simvastatin. During the initial interval (at least 3 months) of measuring simvastatin effects, every effort was made to keep the dose of prostanoid therapy unchanged. Two patients receiving IV epoprostenol, each with liver cirrhosis (patients 7 and 16) acquired symptoms suggesting high-output cardiac state within 3 months of initiating treatment with simvastatin. These two patients underwent hemodynamic monitoring that confirmed a hyperdynamic state, and the dose of epoprostenol infusion was reduced to achieve a reasonable CI.25 The only prescribed drugs with potential interactions with statins were diltiazem and warfarin.


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  		Table 1. Characteristics, Treatment, and Outcomes of 16 Patients With Pulmonary Arterial Hypertension Treated With Simvastatin*

 
Case 1
A 54-year-old woman presented with PPH (World Health Organization [WHO] class II) and hemodynamic testing revealed a positive vasodilator response (with 5 ppm nitric oxide and 100% oxygen, her mPAP decreased from 48 to 29 mm Hg). She was treated with diuretics, a calcium-channel antagonist, warfarin, and simvastatin (20 mg raised to 80 mg/d over 2 months). Within 2 months, she reported full resolution of her dyspnea. Her 6MW improved by 76 m over 9 months (Table 1). An increase in her RVSP by echocardiography prompted repeat hemodynamic measurement after 12 months of simvastatin treatment, which revealed that the CI had improved from 1.9 to 2.7, associated with modest reduction in pulmonary vascular resistance (PVR). This improvement in CI is probably larger than would have been achieved with calcium-channel antagonist alone. Six months later, dyspnea recurred and echocardiography revealed RVSP of 106 mm Hg. She was urged to begin prostanoid therapy and elected for treatment with subcutaneous treprostinil. She improved with treprostinil dose escalation (now WHO class I on treprostinil, 61 ng/kg/min), her most recent 6MW is 165 m further than at initial presentation, and her RVSP has decreased to 77 mm Hg.

Case 2
A 46-year-old woman was referred for management of PPH (WHO class I), and hemodynamic testing revealed a moderate vasodilator response to adenosine. Treatment with diuretics, calcium-channel antagonists, warfarin, and nighttime oxygen was initiated for 3 months, but the interval echocardiographic RVSP measurements showed increasing pulmonary pressures. Simvastatin treatment was added on (cholesterol was 262 mg/dl), and the patient described complete resolution of her exertional dyspnea 3 months later. The 6MW was 700 m on a treadmill and did not change during the measurement interval. Serial echocardiographic measurements every 4 months demonstrated progressively falling RVSPs, and a repeat right-heart catheterization after 3 years of simvastatin treatment confirmed a substantial decrease in mPAP (40 to 28 mm Hg), improved CI, and decreased PVR. These clinical and hemodynamic improvements were associated with the addition of simvastatin to the calcium-channel antagonist.

Case 4
A 21-year-old man was referred in April 2003 for management of pulmonary hypertension associated with congenital heart disease. He had congenital VSD and atrial septal defect (ASD) closed at 6 months of age, and serial echocardiographic evaluations through adolescence revealed a patent ASD and bicuspid aortic valve. He exercised without limitations at Lake Tahoe (elevation 1,830 m) until severe dyspnea and cyanosis developed while shoveling snow in December 2002. Cardiac catheterization revealed moderate pulmonary hypertension and a positive vasodilator response (adenosine increased CI from 3.0 to 4.2 and decreased PVR from 8.7 to 6.0). The patient was already appropriately managed with diuretics, calcium-channel antagonists, warfarin, and digoxin, but symptoms persisted and RVSP was 57 mm Hg. Simvastatin was initiated (40 mg/d), and 5 months later the patient was able to hike 6 miles at Lake Tahoe without dyspnea; RVSP was 55 mm Hg. After 8 months of simvastatin, RVSP was 44 mm Hg and decreased to 37 mm Hg after 11 months of treatment. This patient’s clinical improvement and decreasing RVSP coincided with the addition of simvastatin to conventional therapy.

Case 5
A 72-year-old woman with chronic thromboembolic pulmonary hypertension was referred with end-stage disease for compassionate trial of simvastatin. She had undergone thromboendarterectomy at the University of California, San Diego in 1994 with moderate benefits. At the time of referral, she was hypotensive and tachycardic, with right atrial pressure of 20 mm Hg estimated by echocardiography. Simvastatin treatment (40 mg/d, then 80 mg/d) was tolerated without adverse effects. She demonstrated clinical stabilization and survived for an additional 19 months, until dying at home of presumed arrhythmia. This patient demonstrated clinical stabilization of end-stage disease, and lived approximately 12 months longer than anticipated at presentation.

Case 6
A 59-year-old women with CREST (scleroderma with calcinosis, Raynaud esophagus, sclerodactyly, and telangectasia) syndrome and end-stage pulmonary hypertension failed initiation of epoprostenol, acquiring pulmonary edema and hypoxemia, suggesting a diagnosis of pulmonary veno-occlusive disease. At baseline before simvastatin. she was wheelchair bound. After 3 months of simvastatin treatment (40 then 80 mg/d), her 6MW increased from 0 to 298 m. Following this transient clinical improvement, she died at home 3 months later of progression of pulmonary hypertension.

Case 7
A 70-year-old woman with PPH and liver cirrhosis was receiving a stable dose of epoprostenol (initiated in May 1999). In August 2001, she agreed to add on treatment with simvastatin (40 mg/d). After 3 months of simvastatin treatment, she noted dyspnea that was related to a new high-output cardiac state while receiving the original dose of epoprostenol. The epoprostenol dose was titrated down to achieve a reasonable CI.25 During the initial 5 months of simvastatin treatment, RVSP decreased from 162 to 109 mm Hg, 6MW increased 69 m, and epoprostenol maintenance dose decreased from 26 to 12 ng/kg/min. Over the ensuing 31 months, there was slow progression of disease complicated by GI bleeding and renal insufficiency. The patient died at home of apparent arrhythmia.

Case 9
A 61-year-old woman with scleroderma and severe pulmonary hypertension was referred and initiated on epoprostenol therapy in November 2000. While epoprostenol was held constant, simvastatin was introduced (40 mg/d for 4 months, then 80 mg/d), and the 6MW improved by 37 m over 7 months. Over the ensuing 38 months receiving simvastatin, epoprostenol has been titrated up to 32 ng/kg/min, and the rate of clinical deterioration has been slow. Her survival (currently 44 months on epoprostenol) exceeds the median survival of 1 year described for scleroderma/pulmonary hypertension patients treated with epoprostenol.26

Case 12
A 58-year-old man was referred from congenital heart disease clinic for management of Eisenmenger syndrome with pulmonary hypertension. A VSD was closed at age 21 years, and the patient did well until atrial fibrillation developed at age 50 years (cardioverted) and exertional dyspnea developed at age 53 years. At the time of referral, catheterization revealed severe pulmonary hypertension with right-to-left shunting and no vasodilator response. The right atrial pressure was 20 mm Hg, and the pulmonary blood flow index was 1.2. Epoprostenol therapy was initiated, but the dose increase was limited by the development of epoprostenol-associated exudative ascites.27 A peritoneal dialysis catheter was placed (under local anesthesia) so that the patient could drain the ascites at home (0.5 to 1 L/d). While receiving a stable dose of epoprostenol, simvastatin was added, and 6MW improved 70 m and RVSP decreased from 134 to 118 mm. The patient died of progression of pulmonary hypertension and weakness 26 months after initiation of simvastatin (42 months from catheterization).

Case 16
A 54-year-old man was referred for management of pulmonary hypertension and liver cirrhosis. Initial treatment with subcutaneous treprostinil was ineffective and associated with severe site discomfort. When he was converted to IV epoprostenol, he improved substantially. While receiving a constant dose of epoprostenol, simvastatin was introduced (40 mg/d). Within 3 months on epoprostenol and simvastatin, new dyspnea and fatigue developed. Pulmonary artery catheterization revealed a high-output cardiac state (CI, 4.5) on epoprostenol; when epoprostenol was titrated off, the CI (3.5) and pulmonary pressures (mPAP, 29 mm Hg) were nearly normal. The patient was discharged receiving oral medications: simvastatin, diuretics, and warfarin. However, by 3 months, the patient complained of dyspnea and echocardiography revealed recurrent pulmonary hypertension (RVSP, 67 mm Hg). IV epoprostenol was reinitiated at a low dose to avoid high-output cardiac state (4 ng/kg/min). Due to multiple catheter infections, the patient’s epoprostenol treatment was converted back to subcutaneous treprostinil. While undergoing evaluation for potential orthotopic liver transplantation, a new 5-cm mass was detected in the left lower lobe. A thoracotomy was performed, the mass was sampled by biopsy, and was determined to be a well-differentiated carcinoid tumor; a wedge resection was performed. One day following hospital discharge, the patient was readmitted with weakness, and then died in 12 h. An autopsy revealed hemorrhage and clot in the left thorax, and the cause of death was likely a combination of intrathoracic bleeding exacerbated by pulmonary hypertension. The pathology of the pulmonary vascular lesions was consistent with chronic thromboembolic disease. The large pulmonary arteries of this patient treated with simvastatin showed little to no evidence of atherogenic changes (Fig 1 , left, A). In contrast, the pulmonary artery of a patient with severe pulmonary hypertension due to Eisenmenger syndrome (not treated with statins) shows atheroma formation (Fig 1, right, B), a frequent feature of chronic pulmonary hypertension.28 This case illustrates that simvastatin treatment may have diminished atheromatous plaque deposition in a patient with chronic PAH.



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  		Figure 1. Atheroma formation in chronic pulmonary hypertension was less prominent in a patient who received simvastatin. Left, A: Patient 16 with chronic thromboembolic pulmonary hypertension and cirrhosis was treated with simvastatin for 21 months and muscular pulmonary arteries showed little to no evidence of atherosclerosis. Right, B: Patient with Eisenmenger pulmonary hypertension showing atherosclerotic plaque formation in the pulmonary artery.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this case series of pulmonary hypertension patients treated with simvastatin, there was no detectable evidence of toxicity. Six of the seven patients who died during the time of observation were WHO class IV, and their deaths were attributable to progression of disease, and the other patient died of complications after thoracic surgery. No patient ever demonstrated liver function abnormalities or evidence of muscle inflammation. Simvastatin is widely used for treatment of elevated cholesterol and for cardiovascular benefits, and its toxicity profile is extremely safe.

Simvastatin treatment appeared to confer clinical benefits in this study. Individual patients reported improved energy and exercise tolerance, and this improvement was supported by increases in 6MW performances. Because this was an uncontrolled study, each patient served as her/his own control. One limitation to this design is that the natural history of pulmonary hypertension is progressive deterioration. The results of the oral beraprost trial (which enrolled WHO class II and III patients only) include the 6MW performance for patients who received placebo.29 Patients who received placebo showed stability of 6MW at 3 months, and mean decreases of 15 m at 6 months and 25 m at 9 months.29 The beraprost treatment group showed mean increases in 6MW of 18 m at 3 months and 16 m at 6 months. The statistical significance of the treatment effect at 3 months and 6 months (but not at 9 months and 12 months) was due to a combination of the increase of 6MW from baseline with beraprost, and the decrease from baseline with natural progression of disease while receiving placebo. A controlled trial of bosentan showed an increase of 36 m from baseline after 16 weeks while the placebo group showed a deterioration of 8 m during the same interval.30 The controlled study of epoprostenol vs conventional therapy in New York Heart Association class III and IV patients showed an improvement of 47 m in the treatment group and a deterioration of 66 m in the conventional therapy group after 12 weeks.31 Hemodynamic measurements revealed that the mean changes in pulmonary artery pressure and PVR were – 8% and – 21% for the epoprostenol group and + 3% and + 9% for the control group. respectively. In this observational study of simvastatin treatment, individual patients showed improvements in exercise performance that are comparable to improvements achieved with US Food and Drug Administration-approved therapies for pulmonary hypertension such as epoprostenol and bosentan. Hemodynamic data demonstrated that simvastatin was associated with improvements in PVR even in the absence of prostanoid therapy (patients 1 and 2). In this study, it was the investigator’s impression that the addition of simvastatin to a calcium-channel antagonist in WHO class I and II patients with a modest vasodilator response improved the likelihood of reversing pulmonary hypertension, compared to a calcium-channel antagonist alone.

Combination therapy is widely used in the treatment of pulmonary hypertension, yet few studies have been performed to identify optimal combinations of therapeutic agents. Here, we present the first results of simvastatin treatment in combination with IV epoprostenol. Not one epoprostenol patient demonstrated any evidence of simvastatin-associated liver or muscle toxicity. Furthermore, 8 of 10 patients receiving epoprostenol treated with simvastatin showed improved 6MW performance over a 3- to 5-month interval. Two patients with liver cirrhosis required a decrease in their epoprostenol infusion rate and demonstrated decreased pulmonary artery pressures within 3 months of initiating treatment with simvastatin. In this study, it was the investigator’s impression that the rate of clinical deterioration was slower in WHO class III and IV patients treated with epoprostenol and simvastatin than with epoprostenol alone.

As pulmonary hypertension is a progressive disease characterized by inappropriate neointimal vascular occlusion in pulmonary arteries, there is rationale motivation for exploration of antiproliferative therapies.234 Treatment with epoprostenol is associated with tachyphylaxis, and continuing dose escalations are necessary for efficacy but expose the patient to increased risk of adverse or toxic side effects. The efficacy of other orally active vasodilating agents may also be attenuated by tachyphylaxis over time.429 In contrast, the apparent efficacy of an antiproliferative agent may be revealed in proportion to its remodeling effects on the pulmonary vasculature, and reversal of vascular occlusion might become more apparent over longer intervals of observation.4

This uncontrolled observational study of 16 patients with PPH and secondary pulmonary hypertension revealed no incidences of toxicity associated with simvastatin. The suggestions of efficacy in the majority of these patients warrant additional studies. Future investigations of statins for treatment and prevention of pulmonary hypertension should include randomized, double-blinded, and placebo-controlled clinical trials that will measure changes in exercise performance, hemodynamics, time to clinical worsening, and survival.


   Acknowledgements
 
Ronald G. Pearl, Toshihiko Nishimura, and Virginia Adi for encouragement; Gerald J. Berry for preparation of the Figure; and John L. Faul for critical reading of the manuscript.


   Footnotes
 
Abbreviations: ASD = atrial septal defect; CI = cardiac index; mPAP = mean pulmonary artery pressure; PAH = pulmonary arterial hypertension; PPH = primary pulmonary hypertension; PVR = pulmonary vascular resistance; RVSP = right ventricular systolic pressure; VSD = ventricular septal defect; WHO =World Health Organization; 6MW = 6-min walk

Supported by the Donald E. and Delia B. Baxter Foundation.

Received for publication July 26, 2004. Accepted for publication November 12, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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