Tadalafil (Cialis) and Mortality: What Studies Show

Does tadalafil reduce the risk of dying?

Two kinds of data bear on death and tadalafil. One is a large Swedish cohort of men followed after a first heart attack [1]. The other is randomized trials in pulmonary arterial hypertension: tadalafil 40 mg daily delayed clinical worsening [3], and a separate trial measured clinical failure, a composite that included death, when tadalafil was combined with ambrisentan [4]. The effective PAH dose in both trials was 40 mg once daily, not the 2.5 to 20 mg doses Cialis uses for ED and BPH [2][3][4].

The Swedish cohort: 43,145 men after a heart attack

Andersson et al. used nationwide Swedish registers to follow men younger than 80 who had no prior heart attack or cardiac revascularization and were hospitalized for a first myocardial infarction between 2007 and 2013 [1]. Of 43,145 men (mean age 64), 7.1% filled a prescription for an ED treatment — a PDE5 inhibitor or alprostadil — during a mean 3.3 years of follow-up (141,739 person-years) [1].

Men dispensed an ED treatment (a PDE5 inhibitor or alprostadil) had 33% lower mortality than men who were not (adjusted HR 0.67, 95% CI 0.55 to 0.81) and 40% lower risk of hospitalization for heart failure (HR 0.60, 95% CI 0.44 to 0.82) [1]. The mortality difference appeared only with PDE5 inhibitors; alprostadil, a different ED treatment, showed no association with mortality [1]. Among PDE5 inhibitor users, mortality was lower with more prescriptions: 34% lower with one (HR 0.66, 95% CI 0.38 to 1.15), 53% lower with two to five (HR 0.47, 95% CI 0.26 to 0.87) and 81% lower with more than five (HR 0.19, 95% CI 0.08 to 0.45), each compared with alprostadil [1].

What that cohort cannot tell you

The study is observational, and a cohort design of this kind can only show an association between filling a prescription and living longer; it cannot establish that the drug caused the difference. The estimates are for PDE5 inhibitors as a class, not for tadalafil specifically, and the cohort enrolled only men who had already had a heart attack. Nothing in it tells you how a man without heart disease would fare on daily tadalafil.

What the Cialis label says about the heart

The label's position is cautious rather than protective. It states that sexual activity carries cardiac risk, so treatments for erectile dysfunction, including Cialis, should not be used in men for whom sexual activity is inadvisable because of their cardiovascular status [2]. In a clinical pharmacology study, tadalafil 20 mg produced a mean maximal fall in supine blood pressure relative to placebo of 1.6/0.8 mm Hg in healthy subjects [2].

The label lists groups that were not included in the clinical trials and for which Cialis is therefore not recommended: myocardial infarction within the last 90 days, unstable angina or angina occurring during intercourse, NYHA class 2 or greater heart failure within the last 6 months, uncontrolled arrhythmias, blood pressure below 90/50 mm Hg or uncontrolled hypertension, and stroke within the last 6 months [2].

Blood-pressure effects are larger when tadalafil is combined with other vasodilators. With doxazosin 8 mg daily, tadalafil 20 mg produced a placebo-subtracted maximal standing systolic fall of 9.8 mm Hg, and 16 of 24 subjects on doxazosin had a systolic reading below 85 mm Hg or a fall over 30 mm Hg after the morning tadalafil dose, versus 6 on placebo [2]. With tamsulosin 0.4 mg the standing fall was 1.7 mm Hg with tadalafil 10 mg and 2.3 mm Hg with 20 mg [2].

Nitrates: contraindicated in any form

Cialis is contraindicated in anyone using any form of organic nitrate, regularly or intermittently, because tadalafil was shown to potentiate the hypotensive effect of nitrates [2]. Guanylate cyclase stimulators such as riociguat are contraindicated for the same reason [2].

The label's only timing statement is an emergency rule. Where nitrate administration is medically necessary in a life-threatening situation, at least 48 hours should elapse after the last Cialis dose, and the nitrate should still be given only under close medical supervision with hemodynamic monitoring [2]. The timing comes from a 150-man crossover study in which men took tadalafil 20 mg or placebo daily for 7 days and then sublingual nitroglycerin 0.4 mg: standing systolic pressure fell below 85 mm Hg in more men on tadalafil at 4, 8 and 24 hours, with no difference at 48, 72 and 96 hours [5]. The label also says once-daily Cialis provides continuous plasma tadalafil levels and that physicians should consider this when evaluating interactions with nitrates, alpha-blockers, antihypertensives, potent CYP3A4 inhibitors and substantial alcohol [2].

Heart failure: the trial tested sildenafil, not tadalafil

A heart failure trial in this drug class did not use tadalafil. RELAX randomized 216 stable outpatients with heart failure and ejection fraction of 50% or higher to sildenafil or placebo — 20 mg three times daily for 12 weeks, then 60 mg three times daily, to 24 weeks [6]. Peak oxygen consumption changed by a median -0.20 mL/kg/min on placebo and -0.20 mL/kg/min on sildenafil (P=0.90) [6]. For tadalafil, the label simply does not recommend use in NYHA class 2 or greater heart failure within the previous 6 months, a group not studied [2].

Pulmonary arterial hypertension: where tadalafil did change outcomes

Adcirca, a separate tadalafil product (20 mg tablets) approved in 2009, is indicated for pulmonary arterial hypertension [7]. In PHIRST, 405 patients with PAH were randomized to placebo or tadalafil 2.5, 10, 20 or 40 mg once daily for 16 weeks; only the 40 mg dose met the prespecified significance level for six-minute walk distance (the overall mean placebo-corrected effect across the study was 33 m, 95% CI 15 to 50 m), and tadalafil 40 mg improved time to clinical worsening (P=0.041) [3].

AMBITION then randomized 500 treatment-naive PAH patients to ambrisentan plus tadalafil, ambrisentan alone, or tadalafil alone. A clinical failure event — a composite of death, hospitalization for worsening PAH, disease progression or unsatisfactory response — occurred in 18% on combination therapy, 34% on ambrisentan alone and 28% on tadalafil alone, versus 31% for the two monotherapy groups pooled (hazard ratio for combination versus pooled monotherapy 0.50, 95% CI 0.35 to 0.72, P<0.001) [4]. These are composites, not death rates, and they apply to PAH at 40 mg daily, not to ED or BPH dosing.

Endothelial function: one small surrogate study

A small randomized study tested whether tadalafil changed a measure of artery function in 32 people with increased cardiovascular risk [8]. They took tadalafil 20 mg on alternate days or placebo for 4 weeks [8]. Brachial artery flow-mediated dilation rose from 4.2% to 9.3% on tadalafil (P<0.01 versus baseline) and was unchanged on placebo (4.1% to 4.0%); the improvement persisted two weeks after stopping (9.1%) [8]. That measures artery function, not heart attacks or survival, and the authors called for larger studies to assess the clinical implications [8].