Note:  MACITENTAN (OPSUMIT) AND RIOCIGUAT (ADEMPAS) REQUIRE PRECERTIFICATION.*

1. Aetna considers continuous intravenous infusion of prostacyclin (epoprostenol, PGI2, [brand names: Flolan, Veletri]), continuous subcutaneous infusion of treprostinil (Remodulin), treprostinil inhalation solution (Tyvaso), iloprost inhalation solution (Ventavis), sildenafil injection and tablets (Revatio), tadalafil tablets (Adcirca), bosentan tablets (Tracleer), macitentan tablets (Opsumit), riociguat tablets (Adempas) and ambrisentan tablets (Letairis) medically necessary for selected members with pulmonary hypertension who meet all of the following selection criteria:

   1. Member has pulmonary hypertension with World Health Organization (WHO) Class II to IV symptoms (see Appendix) for ambrisentan, bosentan, macitentan, riociguat, sidenafil or tadalafil, or WHO Class III to IV symptoms for epoprostenol, treprostinil or iloprost; and
   2. Mean pulmonary artery pressure greater than 25 mm Hg at rest or greater than 30 mm Hg with exertion, documented by right-heart catheterization or echocardiography; and
   3. For tadalafil and sildenafil only, member is 18 years of age or older and is not concurrently taking organic nitrates (e.g., isosorbide mononitrate, isosorbide dinitrate, nitroglycerin); and
   4. For riociguat only, member is not pregnant and is not taking nitrates, nitric oxide donors (e.g., amyl nitrate) or phosphodiesterase inhibitors (e.g., dipyridamole, theophylline, sildenafil, tadalafil, vardenafil); and
   5. For macitentan, bosentan and ambrisentan only, member is not pregnant; and
   6. Member has primary pulmonary hypertension, or has pulmonary hypertension secondary to any of the following conditions:
       
      

      1. Group 1 pulmonary hypertension:

         1. Anorectic agents (diet drugs); or
         2. Congenital heart disease with shunting; or
         3. Connective tissue diseases; or
         4. HIV infection; or
         5. Portopulmonary hypertension; or
         6. Familial pulmonary hypertension.
             
      2. Chronic thromboembolic pulmonary hypertension not adequately responsive to anticoagulants or surgical thromboendarterectomy; or
      3. Congenital diaphragmatic hernia; or
      4. Sarcoidosis.

      For members with severe pulmonary vascular disease refractory to medical therapy, continuous infusion of prostacyclin or treprostinil may be considered medically necessary for use as a bridge to either lung or combined heart-lung transplantation (see CPB 0597 - Heart-Lung Transplant and CPB 0598 - Lung Transplantation).

   7. An acute vasoreactivity test** is required for persons with primary pulmonary hypertension and other persons with Group 1 pulmonary hypertension. For persons with a positive acute vasoreactivity test result, documentation of a trial and failure of a calcium channel blocker (dihydropyridine or diltiazem) is required, unless contraindicated, such as in persons with right heart failure or hemodynamic instability. A trial of a calcium channel blocker is not required for persons with a negavie acute vasoreactivity test result. A vasoreactivity test and a trial of a calcium channel blocker is not required for other pulmonary hypertension groups (i.e., persons with pulmonary hypertension secondary to sarcoidosis, congenital diaphragmatic hernia, or chronic thromboembolic pulmonary hypertension).

2. Aetna considers pulmonary artery hypertension agents experimental and investigational in the treatment of pulmonary hypertension secondary to other conditions including the following because they are not effective for these indications:

   1. Asthma; or
   2. Chronic obstructive pulmonary disease; or
   3. Congestive heart failure; or
   4. Ischemic vascular diseases; or
   5. Lung resection.
       

3. Aetna considers imatinib mesylate, simvastatin, and sorafenib experimental and investigational for the treatment of pulmonary hypertension because their effectiveness for this indication has not been established.

4. Aetna considers prostanoids (epoprostenol and treprostinil) experimental and investigational for the treatment of chronic ulcers/limb-threatening ischemia and chronic inflammatory demylenating polyneuritis becasue their effectiveness for these indications has not been established.

5. Aetna considers ambrisentan and bosentan experimental and investigational for the treatment of exercise-induced pulmonary hypertension becasue their effectiveness for this indication has not been established. 

6. Aetna considers pulmonary artery denervation experimental and investigational for the treatment of pulmonary arterial hypertension because its efefctiveness has not been established.

Notes: * Precertification of macitentan (Opsimut) and riociguat (Adempas) is required of all Aetna participating providers and members in applicable plan designs.  For precertification, call (866) 503-0857, or fax (888) 267-3277.

**  Per ACCP guidelines, a positive response to acute vasodilator testing is defined as a decrease in mPAP (mean pulmonary artery pressure) by at least 10 mm Hg to an absolute level of less than 40 mg Hg without a decrease in cardiac output.

See Pharmacy CPB on Pulmonary Hypertension Agents for information on preferred agents for pulmonary hypertension: http://www.aetna.com/products/rx/pcpb_menu.html.

Primary pulmonary hypertension (PPH) is a rare but serious, life-threatening disease.  As the disease progresses and right ventricular after-load increases, the heart’s ability to increase cardiac output with activity declines, resulting in exertional dyspnea, chest pain, or syncope.  Eventually, progressive right heart dysfunction ensues, leading to right heart failure and death.  In the National Institutes of Health's PPH registry, the median survival from diagnosis was less than 2.5 years.  Medical management consists of anticoagulants, oral vasodilators (which are effective in 20 % to 25 % of cases), continuous intravenous infusions of prostacyclin, diuretics, and supplemental oxygen.

Initially, a hospital admission is required to evaluate the patient's pulmonary vascular responsiveness, as this determines selection of vasodilator treatment.  Incremental doses of a short-acting pulmonary vasodilator are administered intravenously until a positive hemodynamic response or negative endpoint is observed (e.g., hypotension, headache, chest pain, etc).  A decrease of 20 % or more in pulmonary vascular resistance and pulmonary arterial pressure, with no decrease in cardiac output, is considered a positive response.

Responders are usually treated with high doses of oral calcium antagonists (e.g., nifedipine, and diltiazem).  Continuous intravenous prostacyclin infusions are reserved for those patients who fail to respond to oral calcium antagonists, and may be used either as long-term therapy or as a bridge to transplantation.  Because of prostacyclin's very short half-life, it must be administered by continuous infusion by a portable, battery-operated syringe pump through a permanent central venous catheter.

Continuous prostacyclin infusion has been shown to improve hemodynamics, symptoms and survival time, and increase exercise tolerance in patients with pulmonary hypertension unresponsive to conventional therapy.  Both “responders” and “non-responders” to conventional therapy (including short-acting vasodilators and/or calcium channel blockers) can be treated with continuous intravenous epoprostenol or treprostinil and manifest improvements in exercise tolerance, hemodynamics and survival.  Intravenously administered prostacyclin is similar to the prostacyclin that is produced by the cells lining blood vessels.  Evidence suggests that pulmonary hypertension may be in part due to an abnormally low ratio of prostacyclin in relation to the endogenous vasoconstrictor thromboxane A2.

Secondary pulmonary hypertension is a complication of many pulmonary, cardiac and extra-thoracic conditions.  Chronic obstructive pulmonary diseases, left ventricular dysfunction and disorders associated with hypoxemia frequently result in pulmonary hypertension.  Regardless of the etiology, unrelieved pulmonary hypertension can lead to right-sided heart failure.  Secondary pulmonary hypertension can be treated with continuous intravenous infusion of prostacyclin or continuous subcutaneous infusion of treprostinil.

Continuous intravenous prostacyclin therapy may be limited by serious complications (e.g., sepsis, thromboembolism, or syncope) related to the need for an implanted central venous catheter.  Treprostinil sodium (Remodulin), a longer-acting, more chemically stable prostacyclin analog, can be administered by a continuous subcutaneous infusion, avoiding these risks.  In a 12-week, double-blind, placebo-controlled multi-center trial of 470 patients with pulmonary arterial hypertension (PAH), Simonneau and colleagues (2002) reported that exercise capacity improved with treprostinil and was unchanged with placebo.  The between treatment group difference in median 6-min walking distance (6MWD) was 16 meters.  Improvement in exercise capacity was greater in the sicker patients and was dose-related, but independent of disease etiology.  Concomitantly, treprostinil significantly improved indices of dyspnea, signs and symptoms of PAH, and hemodynamics.  These investigators concluded that chronic subcutaneous infusion of treprostinil is an effective treatment in patients with PAH.  In addition, Vachiery and associates (2002) reported that patients with PAH could be safely transitioned from treatment with intravenous prostacyclin to subcutaneous treprostinil.

The American College of Cardiology/American Heart Association's expert consensus document on pulmonary hypertension (McLaughlin et al, 2009) stated that "[m]ultiple randomized controlled trials of combination therapy are currently ongoing, and to adequately study the safety and efficacy of combination therapy, we encourage enrollment into randomized controlled trials".

Venatvis (iloprost) is a self-administered inhalation solution for the treatment of pulmonary arterial hypertension in patients with New York Heart Association (NYHA) Class III or IV symptoms.  It is intended to be inhaled using either of 2 pulmonary drug delivery devices: (i) the I-neb AAD System, or (ii) the Prodose AAD System.  Accroding to the Food and Drug Administration (FDA)-approved labeling, Ventavis should be taken 6 to 9 times per day (no more than once every 2 hours) during waking hours, according to individual need and tolerability.

In a phase II study, Ghofrani et al (2010) evaluated safety, tolerability, and efficacy of the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib in patients with PAH.  Patients with PAH in functional classes II to IV were enrolled in a 24-week randomized, double-blind, placebo-controlled pilot study.  Patients received imatinib 200 mg orally once-daily (or placebo), which was increased to 400 mg if the initial dose was well- tolerated.  The primary endpoints were safety and change from baseline in the 6MWD.  Secondary endpoints included hemodynamics and functional classification.  A total of 59 patients enrolled (imatinib [n = 28]; placebo [n = 31]); 42 completed the study.  Drop-outs were equally matched between the 2 groups.  In the intention-to-treat (ITT) population there was no significant change in the 6MWD (mean +/- SD) in the imatinib versus placebo group (+22 +/-  63 versus -1.0 +/- 53 m).  There was a significant decrease in pulmonary vascular resistance (imatinib -300 +/- 347 versus placebo -78 +/- 269 dynes/second/cm2, p < 0.01) and increase in cardiac output (imatinib +0.6 +/- 1.2 versus placebo -0.1 +/- 0.9 L/min, p = 0.02).  Serious adverse events occurred in 11 imatinib recipients (39 %) and 7 placebo recipients (23 %); 3 deaths occurred in each group.  Post-hoc subgroup analyses suggested that patients with greater hemodynamic impairment may respond better than patients with less impairment.  The authors concluded that these findings are consistent with imatinib being well-tolerated in patients with PAH, and provide proof of concept for further studies evaluating its safety, tolerability, and efficacy in PAH.

Chhina et al (2010) noted that various studies have implicated the PDGF pathway in the pathogenesis of PAH.  Inhibition with imatinib mesylate has shown efficacy in human case reports and experimental models of PAH.  Results from a phase II trial of imatinib mesylate in PAH did not meet the primary endpoint but showed improvement in several secondary endpoints and in a subgroup analysis.  As suggested by this study as well as a few case reports, imatinib may be effective in a subset of patients with more severe disease.  However, this remains to be further validated through a phase III study, which is already underway.

Wikins et al (2010) evaluated the therapeutic value of simvastatin in patients with PAH.  A total of 42 patients with PAH were randomized to receive either simvastatin (80 mg/day) or placebo in addition to current care for 6 months, and thereafter offered open-label simvastatin.  The primary outcome was change in right ventricular (RV) mass, assessed by cardiac MRI.  At 6 months, RV mass decreased by 5.2 +/- 11 g in the statin group (p = 0.045) and increased 3.9 +/- 14 g in the placebo group.  The treatment effect was -9.1 g (p = 0.028).  N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels decreased significantly in the statin group (-75 +/- 167 fmol/ml; p = 0.02) but not the placebo group (49 +/- 224 fmol/ml; p = 0.43; overall treatment effect -124 fmol/ml; p = 0.041).  There were no significant changes in other outcome measures (including 6MWD, cardiac index, and circulating cytokines).  From 6 to 12 months, both RV mass and NT-proBNP increased toward baseline values in 16 patients on active treatment who continued with simvastatin but remained stable in 18 patients who switched from placebo to simvastatin.  Two patients required a reduction in dose but not cessation of simvastatin.  The authors concluded that simvastatin added to conventional therapy produces a small and transient early reduction in RV mass and NT-proBNP levels in patients with PAH, but this is not sustained over 12 months.

Gomberg-Maitland and colleagues (2010) noted that PAH and cancer share elements of pathophysiology.  This provides an opportunity for the cross-development of anti-cancer agents that can be used in improving PAH care.  The adaptation of new drugs across these disease populations warrants a structured approach.  This study was a 16-week, phase Ib, single-center, open-label trial of the multi-kinase/angiogenesis inhibitor sorafenib.  In order to assess the safety of sorafenib in PAH, patients with advanced but stable disease on parenteral prostanoids (with or without oral sildenafil) were initiated on treatment at the lowest active dosage administered to cancer patients: 200 mg daily.  Patients underwent weekly clinical evaluations and monthly functional testing and dose escalations to a final dosage of 400 mg twice-daily.  Among 12 patients (10 of them women), sorafenib was well-tolerated at 200 mg twice-daily.  The most common adverse events were moderate skin reactions on the hands and feet and alopecia.  The authors concluded that this is a tolerable dosing regimen for testing the therapeutic activity of sorafenib in PAH patients.

Ruffolo et al (2010) noted that peripheral arterial occlusive disease (PAOD) is a common cause of morbidity and mortality due to cardiovascular diseases in the general population.  While numerous treatments have been adopted for different disease stages, there is no option other than amputation for patients presenting with critical limb ischemia (CLI), unsuitable for rescue or reconstructive intervention.  These researchers determined the safety and effectiveness of prostanoids in patients presenting with CLI.  The Cochrane Peripheral Vascular Diseases Group searched their trials register (last searched October 2009) and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (last searched 2009, Issue 4) for publications describing randomized controlled trials (RCTs) of prostanoids for CLI.  These researchers ran additional searches in MEDLINE, EMBASE, LILACS, and SciSearch, and we also contacted pharmaceutical companies and experts, in order to identify unpublished data and trials still underway.  Randomized controlled trials describing the safety and efficacy of prostanoids compared with placebo or other pharmacological control treatments, in patients presenting with CLI, without chance of rescue or reconstructive intervention.  Two authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data.  Disagreements were resolved by consensus or by the 3rd author.  These investigators retrieved 532 citations which after the first screening resulted in 111 potential studies.  Finally, after exclusion of studies of poor quality and a lack of sufficient information, 20 trials were included in the review.  Prostanoids seem to have efficacy regarding rest-pain relief (risk ratio (RR) 1.32, 95 % confidence interval (CI): 1.10 to 1.57; p = 0.003), and ulcer healing (RR 1.54, 95 % CI: 1.22 to 1.96).  Iloprost also shows favorable results regarding major amputations (RR 0.69, 95 % CI: 0.52 to 0.93).  The more frequently reported adverse events when using prostanoids were headache, facial flushing, nausea, vomiting and diarrhea.  The authors concluded that despite some positive results regarding rest-pain relief, ulcer healing and amputations, there is no conclusive evidence based on this meta-analysis of the long-term effectiveness and safety of different prostanoids in patients with CLI.  They stated that further well-conducted, high quality randomized double-blinded trials should be performed.  Furthermore, the 2007 TASC II consensus document on the management of peripheral arterial disease (Norgren et al, 2007) does not recommend epoprostenol or any other prostanoids for the management of limb-threatening ischemia.

In a randomized, double-blind, placebo-controlled, dose-ranging study, Barst et al (2012) examined the effects of oral sildenafil citrate in treatment-naive children with PAH.  Children (n = 235; weight greater than or equal to 8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study.  The primary comparison was percent change from baseline in peak oxygen consumption (PVo(2)) for the 3 sildenafil doses combined versus placebo.  Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population.  Secondary end points (assessed in all patients) included hemodynamics and functional class.  The estimated mean ± SE percent change in PVo(2) for the 3 doses combined versus placebo was 7.7 ± 4.0 % (95 % confidence interval [CI]: -0.2 % to 15.6 %; p = 0.056).  PVo(2), functional class, and hemodynamics improved with medium- and high-doses versus placebo; low-dose sildenafil was ineffective.  Most adverse events were mild-to-moderate in severity.  STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil.  In STARTS-2 (ongoing), increased mortality was observed with higher doses.  The authors concluded that 16-week sildenafil monotherapy is well-tolerated in pediatric PAH.  Percent change in PVo(2) for the 3 sildenafil doses combined was only marginally significant; however, PVo(2), functional class, and hemodynamic improvements with medium- and high- doses suggest efficacy with these doses.  Combined with STARTS-2 data, the overall profile favors the medium dose.  The authors stated that further investigation is needed to determine optimal dosing based on age and weight.

Johnson et al (2012) stated that warfarin is recommended in systemic sclerosis-associated PAH (SSc-PAH) and idiopathic PAH (IPAH) to improve survival.  There is no evidence to support this in SSc-PAH and the evidence in IPAH is conflicting.  These researchers evaluated the ability of warfarin to improve survival using 2 large SSc-PAH and IPAH cohorts.  The effect of warfarin on all-cause mortality was evaluated.  Bayesian propensity scores (PS) were used to adjust for baseline differences between patients exposed and not exposed to warfarin, and to assemble a matched cohort.  Bayesian Cox proportional hazards models were constructed using informative priors based on international PAH expert elicitation.  Review of 1,138 charts identified 275 patients with SSc-PAH (n = 78; 28 % treated with warfarin) and 155 patients with IPAH (n = 91; 59 % treated with warfarin).  Baseline differences in PAH severity and medications were resolved using PS matching.  In the matched cohort of 98 patients with SSc-PAH (49 treated with warfarin), the posterior median hazard ratio (HR) was 1.06 [95 % credible interval (CrI): 0.70 to 1.63].  In the matched cohort of 66 patients with IPAH (33 treated with warfarin), the posterior median HR was 1.07 (95 % CrI: 0.57 to 1.98).  The probabilities that warfarin improves median survival by 6 months or more are 23.5 % in SSc-PAH and 27.7 % in IPAH.  Conversely, there is a greater than 70 % probability that warfarin provides no significant benefit or is harmful.  The authors concluded that there is a low probability that warfarin improves survival in SSc-PAH and IPAH.  Given the availability of other PAH therapies with demonstrable benefits, there is little reason to use warfarin to improve survival for these patients.

Kovacs et al (2012) noted that borderline PAH, characterized by a marked exercise-induced increase in pulmonary artery pressure (PAP) with normal resting values, may precede overt PAH in SSc.  In a pilot study, these investigators examined if PAH treatment is safe in these patients and might attenuate hemodynamic progression.  SSc patients with borderline PAH underwent right heart catheterization at baseline, after a 12-month observation period, and subsequently after 6 months of bosentan therapy.  Changes in mean PAP at 50W during the observation period versus during therapy were compared.  A total of 10 patients completed the study.  Mean PAP at rest, at 50W, and during maximal exercise increased significantly during the observation period (mean +/- SD increases of 2.5 +/- 3.0 mm Hg [p = 0.03], 4.0 +/- 2.9 mm Hg [p = 0.002], and 6.8 +/- 4.1 mm Hg [p = 0.0005], respectively) and tended to decrease during the treatment period (decreases of 2.5 +/- 3.9 mm Hg [p = 0.07], 1.5 +/- 4.5 mm Hg [p = 0.32], and 1.8 +/- 7.0 mm Hg [p = 0.43], respectively).  The changes during the observation period versus the therapy period were significantly different (p = 0.03 at rest, p = 0.01 at 50W [primary end point], and p = 0.02 during maximal exercise).  The changes in resting pulmonary vascular resistance (PVR) were also significantly different during the observation period (increase of 8 +/- 25 dynes · seconds · cm(-5) ) versus during the therapy period (decrease of 45 +/- 22 dynes · seconds · cm(-5) ) (p < 0.0005).  Changes in resting pulmonary arterial wedge pressure were not significantly different between the observation period and the treatment period, despite the significant increase during the observation period (2.6 +/- 2.5 mm Hg [p = 0.01]).  No relevant adverse effects were reported.  The authors concluded that in SSc patients with borderline abnormal pulmonary hemodynamics, resting and exercise PAP may increase significantly within 1 year of observation.  Bosentan might be safe and effective to attenuate these changes.  They stated that RCTs are needed to confirm the exploratory findings of this hypothesis-generating pilot study.

In a prospective single-center, open-label, pilot study, Saggar et al (2012) described the changes in hemodynamics and exercise capacity in patients with SSc spectrum-associated exercise-induced pulmonary hypertension (ePH) treated with daily ambrisentan.  Patients were treated with ambrisentan, 5 mg or 10 mg once-daily, for 24 weeks.  At baseline and 24 weeks, patients with SSc spectrum disorders exercised in a supine position, on a lower extremity cycle ergometer.  All patients had normal hemodynamics at rest.  Baseline ePH was defined as a mean pulmonary artery pressure of greater than 30 mm Hg with maximum exercise and a trans-pulmonary gradient (TPG) of greater than 15 mm Hg.  The primary end point was change in PVR with exercise.  Secondary end points included an improvement from baseline in 6-min walking distance, health-related quality of life assessments, and cardiopulmonary hemodynamics.  Of the 12 enrolled patients, 11 completed the study.  At 24 weeks, there were improvements in mean exercise PVR (85.8 dynes × second/cm(5) ; p = 0.003) and mean distance covered during 6-min walk (44.5 meters; p = 0.0007).  Improvements were also observed in mean exercise cardiac output (1.4 liters/min; p = 0.006), mean pulmonary artery pressure (-4.1 mm Hg; p = 0.02), and total pulmonary resistance (-93.0 dynes × seconds/cm(5) ; p = 0.0008).  Three patients developed resting pulmonary arterial hypertension during the 24 weeks.  The authors concluded that exercise hemodynamics and exercise capacity in patients with SSc spectrum-associated ePH improved over 24 weeks with exposure to ambrisentan.  Moreover, they stated that placebo-controlled studies are needed to confirm whether this is a drug-related effect and to determine optimal therapeutic regimens for patients with ePH.

In a single-center, prospective trial, Chen et al (2013) evaluated the safety and effectiveness of pulmonary artery (PA) denervation (PADN) for patients with idiopathic PAH (IPAH) not responding optimally to medical therapy.  Of a total of 21 patients with IPAH, 13 patients received the PADN procedure, and the other 8 patients who refused the PADN procedure were assigned to the control group.  Pulmonary artery denervation was performed at the bifurcation of the main PA, and at the ostial right and left PA.  Serial echocardiography, right heart catheterization, and a 6-min walk test (6MWT) were performed.  The primary end-points were the change of PAP, tricuspid excursion (Tei) index, and 6MWT at 3 months follow-up.  Compared with the control group, at 3 months follow-up, the patients who underwent the PADN procedure showed significant reduction of mean PAP (from 55 ± 5 mm Hg to 36 ± 5 mm Hg, p < 0.01), and significant improvement of the 6MWT (from 324 ± 21 m to 491 ± 38 m, p < 0.006) and of the Tei index (from 0.7 ± 0.04 to 0.50 ± 0.04, p < 0.001).  The authors reported for the first time the effect of PADN on functional capacity and hemodynamics in patients with IPAH not responding optimally to medical therapy.  They stated that further randomized study is needed to confirm the effectiveness of PADN.  The major drawbacks of the study were its small sample size, as well as its non-placebo-controlled and non-double-blinded design.

In an editorial that accompanied the afore-mentioned study, Galie and Manes (2013) stated that the study by Chen et al (2013) should be considered a very preliminary proof-of-principle study that requires a formal and large multi-center RCT to appropriately evaluate a possible new area for the treatment of PAH patients.

Appendix

The World Health Organization (WHO) functional classification of pulmonary artery hypertension is as follows:

*Key symptoms of PAH include fatigue, dizziness and fainting (near syncope)