Viagra Cardiovascular Impact Long-Term: What the Evidence Shows

What sildenafil does to the circulation

Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor approved for erectile dysfunction [6][1]. During sexual stimulation, nitric oxide raises cyclic GMP in the corpus cavernosum, and sildenafil blocks the enzyme that breaks cGMP down, so smooth muscle relaxes and blood flows in; at recommended doses it has no effect without sexual stimulation [1]. In pulmonary arterial hypertension the same cGMP effect relaxes pulmonary vascular smooth muscle [1].

The systemic blood pressure effect is small. In healthy volunteers, single 100 mg doses lowered supine blood pressure by a mean maximum of about 8.4/5.5 mm Hg, and the fall was not dose-related between 25 and 100 mg [1]. In hypertensive patients already taking amlodipine 5 or 10 mg, adding Viagra 100 mg produced an additional mean supine fall of 8/7 mm Hg [1]. Alcohol did not add to it: sildenafil 50 mg given with alcohol at a mean peak blood alcohol of 0.08% did not potentiate alcohol's hypotensive effect in healthy volunteers [1].

What the Viagra label says about the heart

The label's cardiovascular warning is about sexual activity as much as the drug: sexual activity carries cardiac risk in men with heart disease, and erectile dysfunction treatments including Viagra should not generally be used when sexual activity is inadvisable because of cardiovascular status [1]. The label names groups for which controlled safety or efficacy data are lacking: men who have had a heart attack, stroke or life-threatening arrhythmia within the last 6 months, resting blood pressure below 90/50 or above 170/110 mm Hg, cardiac failure, or unstable angina. It says that if Viagra is prescribed in these groups it should be done with caution [1]. It also advises caution in left ventricular outflow obstruction such as aortic stenosis and in severely impaired autonomic control of blood pressure [1]. Viagra carries no boxed warning [1].

Postmarketing reports include myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage and transient ischemic attack occurring in temporal association with Viagra. Most, but not all, of those patients had preexisting cardiovascular risk factors, many events happened during or shortly after sexual activity, and voluntary reports cannot establish cause [1].

Coronary blood flow: what a direct measurement showed

Herrmann and colleagues gave a single 100 mg oral dose of sildenafil to 14 men with more than 70% narrowing of at least one coronary artery who were awaiting percutaneous revascularization, and measured pressures and coronary flow with a Doppler guidewire [8]. Systemic and pulmonary arterial pressures fell by less than 10%; pulmonary capillary wedge pressure, right atrial pressure, heart rate and cardiac output were unchanged; and average peak coronary flow velocity, coronary artery diameter, volumetric coronary blood flow and coronary vascular resistance did not change significantly [8]. Coronary flow reserve rose about 13%, from 1.70 to 1.92 (P=0.003) [8]. The authors concluded that no adverse cardiovascular effects were detected, in 14 men given one dose [8].

What the erectile dysfunction trials actually measured

The pivotal 1998 program was an efficacy and safety study, not a cardiac outcomes study. It used two double-blind studies: a 24-week dose-response study in 532 men taking 25, 50 or 100 mg, and a 12-week flexible-dose study in 329 men escalating to 100 mg [9]. In the second, 69% of intercourse attempts were successful with sildenafil versus 22% with placebo, and headache, flushing and dyspepsia were the most common side effects at 6% to 18% [9]. The label adds that over 3,700 men were exposed in premarketing trials and that discontinuation for adverse reactions was 2.5% with Viagra versus 2.3% with placebo [1].

Heart failure: RELAX and a smaller one-year trial

Sildenafil is not approved for heart failure: Viagra is indicated for erectile dysfunction and Revatio for pulmonary arterial hypertension [6][10]. RELAX tested it in heart failure with preserved ejection fraction and found no significant difference from placebo in peak oxygen consumption [3]. RELAX randomized 216 stable outpatients with heart failure, ejection fraction of 50% or higher and either elevated natriuretic peptide or elevated invasively measured filling pressures, to sildenafil (113 patients) or placebo (103) at 26 North American centers [3]. In RELAX, patients took 20 mg three times daily for 12 weeks, then 60 mg three times daily for 12 weeks [3]. At 24 weeks, median peak oxygen consumption fell by 0.20 mL/kg/min in both the sildenafil and placebo groups (P=0.90) [3]. Secondary measures included a composite clinical status score based on time to death, hospitalization and quality of life [3].

A much smaller one-year study in systolic heart failure reported different results. Guazzi and colleagues randomized 45 patients in NYHA class II to III to sildenafil 50 mg three times daily or placebo for one year. In the sildenafil group they reported higher ejection fraction, improved diastolic indices, a fall in left atrial volume index from 32.0 to 29.0 mL/m2 and in left ventricular mass index from 148.0 to 130.0 g/m2, better peak oxygen consumption and better quality of life, with flushing in 4 patients and headache in 2 [4]. That study used a different population and dose from RELAX [4][3].

Pulmonary arterial hypertension: the longest follow-up

Revatio is a sildenafil product indicated for WHO Group 1 pulmonary arterial hypertension; its 20 mg tablet strength and dosing schedule differ from Viagra, which is indicated for erectile dysfunction [6][10]. SUPER-1 randomized 278 patients to placebo or sildenafil 20, 40 or 80 mg three times daily for 12 weeks; placebo-corrected six-minute walk distance gains were 45 m (+13.0%), 46 m (+13.3%) and 50 m (+14.7%) for the three doses (P<0.001 for all), and the study was not powered to assess mortality [2]. Clinical worsening did not differ significantly from placebo over the 12 weeks [2].

Of the 277 randomized and treated patients, 259 completed SUPER-1 and entered an open-label extension, SUPER-2, titrated to 80 mg three times daily and continued until the last patient completed 3 years of treatment [5]. SUPER-2 had no control group, so it cannot show benefit over placebo. Its estimated 3-year survival was 79%, or 68% if every censored patient was assumed to have died [5].

Nitrates, alpha-blockers and exposure

Nitric oxide donors such as organic nitrates or organic nitrites, in any form and taken regularly or intermittently, are contraindicated with Viagra, and the label states that after a dose it is unknown when nitrates can be safely administered [1]. At 24 hours after a dose, sildenafil levels are much lower than at peak, but the label says it is unknown whether nitrates can be safely co-administered then [1]. Levels at 24 hours are 3 to 8 times higher in men over 65, in liver or severe kidney impairment, and with erythromycin or strong CYP3A4 inhibitors [1].

Alpha-blockers also lower blood pressure, and the effect with Viagra is additive. The label says patients should be stable on alpha-blocker therapy before starting Viagra and that Viagra should be started at 25 mg [1]. With doxazosin, Viagra 25 mg produced a placebo-subtracted maximum standing systolic fall of 6.0 mm Hg (7.4 mm Hg supine), and one of four men given 100 mg had severe postural hypotension [1]. Sildenafil is cleared mainly by CYP3A4: ritonavir raised its AUC 11-fold, with a label maximum of 25 mg per 48 hours, while erythromycin raised peak concentration by 160% and AUC by 182%. Strong inhibitors such as ketoconazole and itraconazole are expected to have greater effects, and the label says to consider a 25 mg starting dose with them [1].

Putting the long-term question together

The available cardiac data for sildenafil describe short-term physiology and trials in other diseases. Its vasodilator effect is small in healthy volunteers and modestly larger when added to an antihypertensive such as amlodipine; it did not reduce coronary blood flow in 14 men with severe coronary disease after a single dose [1][8]. The longest controlled trials, 24 weeks in heart failure with preserved ejection fraction and one year in systolic heart failure, focused on exercise capacity and clinical status [3][4]. RELAX also included time to death and hospitalization in a secondary composite, but none of these trials tested whether years of Viagra use for erectile dysfunction change heart attack, stroke or death rates [3][4]. The label's cardiovascular cautions are the nitrate contraindication, use when sexual activity is itself inadvisable because of heart disease, and the groups lacking controlled data [1].