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Children who are exposed to valproate in utero were more likely to be diagnosed with ADHD. Also today, one expert calls for better ways to preserve beta cell function in youth, synthetic opioids drive a spike in the number of fatal overdoses, and mothers may play a role in the link between depression in fathers and daughters.

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Children who are exposed to valproate in utero were more likely to be diagnosed with ADHD. Also today, one expert calls for better ways to preserve beta cell function in youth, synthetic opioids drive a spike in the number of fatal overdoses, and mothers may play a role in the link between depression in fathers and daughters.

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When treating high blood pressure, how low should we try to go? Debate continues about optimal blood pressure goals after publication of guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) in 2017 that set or permitted a treatment goal of less than 130 mm Hg, depending on the population.¹

In this article, we summarize the evolution of hypertension guidelines and the evidence behind them.

HOW THE GOALS EVOLVED

JNC 7, 2003: 140/90 or 130/80

The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),² published in 2003, specified treatment goals of:

• < 140/90 mm Hg for most patients
• < 130/80 mm Hg for those with diabetes or chronic kidney disease.

JNC 7 provided much-needed clarity and uniformity to managing hypertension. Since then, various scientific groups have published their own guidelines (Table 1).^1–9

ACC/AHA/CDC 2014: 140/90

In 2014, the ACC, AHA, and US Centers for Disease Control and Prevention (CDC) published an evidence-based algorithm for hypertension management.³ As in JNC 7, they suggested a blood pressure goal of less than 140/90 mm Hg, lifestyle modification, and polytherapy, eg, a thiazide diuretic for stage 1 hypertension (< 160/100 mm Hg) and combination therapy with a thiazide diuretic and an angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), or calcium channel blocker for stage 2 hypertension (≥ 160/100 mm Hg).

JNC 8 2014: 140/90 or 150/90

Soon after, the much-anticipated report of the panel members appointed to the eighth JNC (JNC 8) was published.⁴ Previous JNC reports were written and published under the auspices of the National Heart, Lung, and Blood Institute, but while the JNC 8 report was being prepared, this government body announced it would no longer publish guidelines.

In contrast to JNC 7, the JNC 8 panel based its recommendations on a systematic review of randomized clinical trials. However, the process and methodology were controversial, especially as the panel excluded some important clinical trials from the analysis.

JNC 8 relaxed the targets in several subgroups, such as patients over age 60 and those with diabetes and chronic kidney disease, due to a lack of definitive evidence on the impact of blood pressure targets lower than 140/90 mm Hg in these groups. Thus, their goals were:

• < 140/90 mm Hg for patients under age 60
• < 150/90 mm Hg for patients age 60 and older.

Of note, a minority of the JNC 8 panel disagreed with the new targets and provided evidence for keeping the systolic blood pressure target below 140 mm Hg for patients 60 and older.⁵ Further, the JNC 8 report was not endorsed by several important societies, ie, the AHA, ACC, National Heart, Lung, and Blood Institute, and American Society of Hypertension (ASH). These issues compromised the acceptance and applicability of the guidelines.

ASH/ISH 2014: 140/90 or 150/90

Also in 2014, the ASH and the International Society of Hypertension released their own report.⁶ Their goals:

• < 140/90 mm Hg for most patients
• < 150/90 mm Hg for patients age 80 and older.

AHA/ACC/ASH 2015: Goals in subgroups

In 2015, the AHA, ACC, and ASH released a joint scientific statement outlining hypertension goals for specific patient populations⁷:

• < 150/90 mm Hg for those age 80 and older
• < 140/90 mm Hg for those with coronary artery disease
• < 130/80 mm Hg for those with comorbidities such as diabetes and cardiovascular disease.

ADA 2016: Goals for patients with diabetes

In 2016, the American Diabetes Association (ADA) set the following blood pressure goals for patients with diabetes⁸:

• < 140/90 mm Hg for adults with diabetes
• < 130/80 mm Hg for younger adults with diabetes and adults with a high risk of cardiovascular disease
• 120–160/80–105 mm Hg for pregnant patients with diabetes and preexisting hypertension who are treated with antihypertensive therapy.

In 2017, the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) recommended a relaxed systolic blood pressure target, ie, below 150 mm Hg, for adults over age 60, but a tighter goal of less than 140 mm Hg for the same age group if they have transient ischemic attack, stroke, or high cardiovascular risk.⁹

ACC/AHA 2017: 130/80

The 2017 ACC/AHA guidelines recommended a more aggressive goal of below 130/80 for all, including patients age 65 and older.¹

This is a class I (strong) recommendation for patients with known cardiovascular disease or a 10-year risk of a cardiovascular event of 10% or higher, with a B-R level of evidence for the systolic goal (ie, moderate-quality, based on systematic review of randomized controlled trials) and a C-EO level of evidence for the diastolic goal (ie, based on expert opinion).

For patients who do not have cardiovascular disease and who are at lower risk of it, this is a class IIb (weak) recommendation, ie, it “may be reasonable,” with a B-NR level of evidence (moderate-quality, based on nonrandomized studies) for the systolic goal and C-EO (expert opinion) for the diastolic goal.

For many patients, this involves drug treatment. For those with known cardiovascular disease or a 10-year risk of an atherosclerotic cardiovascular disease event of 10% or higher, the ACC/AHA guidelines say that drug treatment “is recommended” if their average blood pressure is 130/80 mm Hg or higher (class I recommendation, based on strong evidence for the systolic threshold and expert option for the diastolic). For those without cardiovascular disease and at lower risk, drug treatment is recommended if their average blood pressure is 140/90 mm Hg or higher (also class I, but based on limited data).

EVERYONE AGREES ON LIFESTYLE

Although the guidelines differ in their blood pressure targets, they consistently recommend lifestyle modifications.

Lifestyle modifications, first described in JNC 7, included weight loss, sodium restriction, and the DASH diet, which is rich in fruits, vegetables, low-fat dairy products, whole grains, poultry, and fish, and low in red meat, sweets, cholesterol, and total and saturated fat.²

These recommendations were based on results from 3 large randomized controlled trials in patients with and without hypertension.^10–12 In patients with no history of hypertension, interventions to promote weight loss and sodium restriction significantly reduced blood pressure and the incidence of hypertension (the latter by as much as 77%) compared with usual care.^10,11

In patients with and without hypertension, lowering sodium intake in conjunction with the DASH diet was associated with substantially larger reductions in systolic blood pressure.¹²

The recommendation to lower sodium intake has not changed in the guideline revisions. Meanwhile, other modifications have been added, such as incorporating both aerobic and resistance exercise and moderating alcohol intake. These recommendations have a class I level of evidence (ie, strongest level) in the 2017 ACC/AHA guidelines.¹

HYPERTENSION BEGINS AT 130/80

The definition of hypertension changed in the 2017 ACC/AHA guidelines¹: previously set at 140/90 mm Hg or higher, it is now 130/80 mm Hg or higher for all age groups. Adults with systolic blood pressure of 130 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg are now classified as having stage 1 hypertension.

Under the new definition, the number of US adults who have hypertension expanded to 45.6% of the general population,¹³ up from 31.9% under the JNC 7 definition. Thus, overall, 103.3 million US adults now have hypertension, compared with 72.2 million under the JNC 7 criteria.

In addition, the new guidelines expanded the population of adults for whom antihypertensive drug treatment is recommended to 36.2% (81.9 million). However, this represents only a 1.9% absolute increase over the JNC 7 recommendations (34.3%) and a 5.1% absolute increase over the JNC 8 recommendations.¹⁴

SPRINT: INTENSIVE TREATMENT IS BENEFICIAL

The new ACC/AHA guidelines¹ were based on evidence from several trials, including the Systolic Blood Pressure Intervention Trial (SPRINT).¹⁵

This multicenter trial investigated the effect of intensive blood pressure treatment on cardiovascular disease risk.¹⁶ The primary outcome was a composite of myocardial infarction, acute coronary syndrome, stroke, and heart failure.

The trial enrolled 9,361 participants at least 50 years of age with systolic blood pressure 130 mm Hg or higher and at least 1 additional risk factor for cardiovascular disease. It excluded anyone with a history of diabetes mellitus, stroke, symptomatic heart failure, or end-stage renal disease.

Two interventions were compared: 

• Intensive treatment, with a systolic blood pressure goal of less than 120 mm Hg: the protocol called for polytherapy, even for participants who were 75 or older if their blood pressure was 140 mm Hg or higher
• Standard treatment, with a systolic blood pressure goal of less than 140 mm Hg: it used polytherapy for patients whose systolic blood pressure was 160 mm Hg or higher.

The trial was intended to last 5 years but was stopped early at a median of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group: 1.65% per year vs 2.19%, a 25% relative risk reduction (P < .001) or a 0.54% absolute risk reduction. We calculate the number needed to treat (NNT) for 1 year to prevent 1 event as 185, and over the 3.26 years of the trial, the investigators calculated the NNT as 61. Similarly, the rate of death from any cause was also lower with intensive treatment, 1.03% per year vs 1.40% per year, a 27% relative risk reduction (P = .003) or a 0.37% absolute risk reduction, NNT 270.

Using these findings, Bress et al¹⁶ estimated that implementing intensive blood pressure goals could prevent 107,500 deaths annually.

The downside is adverse effects. In SPRINT,¹⁵ the intensive-treatment group experienced significantly higher rates of serious adverse effects than the standard-treatment group, ie:

• Hypotension 2.4% vs 1.4%, P = .001
• Syncope 2.3% vs 1.7%, P = .05
• Electrolyte abnormalities 3.1% vs 2.3%, P = .02)
• Acute kidney injury or kidney failure 4.1% vs 2.5%, P < .001
• Any treatment-related adverse event 4.7% vs 2.5%, P = .001.

Thus, Bress et al¹⁶ estimated that fully implementing the intensive-treatment goals could cause an additional 56,100 episodes of hypotension per year, 34,400 cases of syncope, 43,400 serious electrolyte disorders, and 88,700 cases of acute kidney injury. All told, about 3 million Americans could suffer a serious adverse effect under the intensive-treatment goals.

SPRINT¹⁵ was stopped early, after 3.26 years instead of the planned 5 years. The true risk-benefit ratio may have been different if the trial had been extended longer.

In addition, SPRINT used automated office blood pressure measurements in which patients were seated alone and a device (Model 907, Omron Healthcare) took 3 blood pressure measurements at 1-minute intervals after 5 minutes of quiet rest. This was designed to reduce elevated blood pressure readings in the presence of a healthcare professional in a medical setting (ie, “white coat” hypertension).

Many physicians are still taking blood pressure manually, which tends to give higher readings. Therefore, if they aim for a lower goal, they may risk overtreating the patient.

About 50% of patients did not achieve the target systolic blood pressure (< 120 mm Hg) despite receiving an average of 2.8 antihypertensive medications in the intensive-treatment group and 1.8 in the standard-treatment group. The use of antihypertensive medications, however, was not a controlled variable in the trial, and practitioners chose the appropriate drugs for their patients.

Diastolic pressure, which can be markedly lower in older hypertensive patients, was largely ignored, although lower diastolic pressure may have contributed to higher syncope rates in response to alpha blockers and calcium blockers.

Moreover, the trial excluded those with significant comorbidities and those younger than 50 (the mean age was 67.9), which limits the generalizability of the results.

JNC 8 VS SPRINT GOALS: WHAT'S THE EFFECT ON OUTCOMES?

JNC 8⁴ recommended a relaxed target of less than 140/90 mm Hg for adults younger than 60, including those with chronic kidney disease or diabetes, and less than 150/90 mm Hg for adults 60 and older. The SPRINT findings upended those recommendations, showing that intensive treatment in adults age 75 or older significantly improved the composite cardiovascular disease outcome (2.59 vs 3.85 events per year; P < .001) and all-cause mortality (1.78 vs 2.63 events per year; P < .05) compared with standard treatment.¹⁷ Also, a subset review of SPRINT trial data found no difference in benefit based on chronic kidney disease status.¹⁸

A meta-analysis of 74 clinical trials (N = 306,273) offers a compromise between the SPRINT findings and the JNC 8 recommendations.¹⁹ It found that the beneficial effect of blood pressure treatment depended on the patient’s baseline systolic blood pressure. In those with a baseline systolic pressure of 160 mm Hg or higher, treatment reduced cardiovascular mortality by about 15% (relative risk [RR] 0.85; 95% confidence interval [CI] 0.77–0.95). In patients with systolic pressure below 140 mm Hg, treatment effects were neutral (RR 1.03, 95% CI 0.87–1.20) and not associated with any benefit as primary prevention, although data suggest it may reduce the risk of adverse outcomes in patients with coronary heart disease.

OTHER TRIALS THAT INFLUENCED THE GUIDELINES

SHEP and HYVET (the Systolic Hypertension in the Elderly Program²⁰ and the Hypertension in the Very Elderly Trial)²¹ supported intensive blood pressure treatment for older patients by reporting a reduction in fatal and nonfatal stroke risks for those with a systolic blood pressure above 160 mm Hg.

FEVER (the Felodipine Event Reduction study)²² found that treatment with a calcium channel blocker in even a low dose can significantly decrease cardiovascular events, cardiovascular disease, and heart failure compared with no treatment.

JATOS and VALISH (the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients²³ and the Valsartan in Elderly Isolated Systolic Hypertension study)²⁴ found that outcomes were similar with intensive vs standard treatment.

Ettehad et al²⁵ performed a meta-analysis of 123 studies with more than 600,000 participants that provided strong evidence supporting blood pressure treatment goals below 130/90 mm Hg, in line with the SPRINT trial results.

BLOOD PRESSURE ISN’T EVERYTHING

Other trials remind us that although blood pressure is important, it is not the only factor affecting cardiovascular risk.

HOPE (the Heart Outcomes Prevention Evaluation)²⁶ investigated the use of ramipril (an ACE inhibitor) in preventing myocardial infarction, stroke, or cardiovascular death in patients at high risk of cardiovascular events. The study included 9,297 participants over age 55 (mean age 66) with a baseline blood pressure 139/79 mm Hg. Follow-up was 4.5 years.

Ramipril was better than placebo, with significantly fewer patients experiencing adverse end points in the ramipril group compared with the placebo group:

• Myocardial infarction 9.9% vs 12.3%, RR 0.80, P < .001
• Cardiovascular death 6.1% vs 8.1%, RR  0.74, P < .001
• Stroke 3.4% vs 4.9%, RR = .68, P < .001
• The composite end point 14.0% vs 17.8%, RR 0.78, P < .001).

Results were even better in the subset of patients who had diabetes.²⁷ However, the decrease in blood pressure attributable to anti­hypertensive therapy with ramipril was minimal (3–4 mm Hg systolic and 1–2 mm Hg diastolic). This slight change should not have been enough to produce significant differences in clinical outcomes, a major limitation of this trial. The investigators speculated that the positive results may be due to a class effect of ACE inhibitors.²⁶

HOPE 3^28–30 explored the effect of blood pressure- and cholesterol-controlling drugs on the same primary end points but in patients at intermediate risk of major cardiovascular events. Investigators randomized the 12,705 patients to 4 treatment groups:

• Blood pressure control with candesartan (an ARB) plus hydrochlorothiazide (a thiazide diuretic)
• Cholesterol control with rosuvastatin (a statin)
• Blood pressure plus cholesterol control
• Placebo.

Therapy was started at a systolic blood pressure above 140 mm Hg.

Compared with placebo, the rate of composite events was significantly reduced in the rosuvastatin group (3.7% vs 4.8%, HR 0.76, P = .002)²⁸ and the candesartan-hydrochlorothiazide-rosuvastatin group (3.6% vs 5.0%, HR 0.71; P = .005)²⁹ but not in the candesartan-hydrochlorothiazide group (4.1% vs 4.4%; HR 0.93; P = .40).³⁰

In addition, a subgroup analysis comparing active treatment vs placebo found a significant reduction in major cardiovascular events for treated patients whose baseline systolic blood pressure was in the upper third (> 143.5 mm Hg, mean 154.1 mm Hg), while treated patients in the lower middle and lower thirds had no significant reduction.³⁰

These results suggest that intensive treatment to achieve a systolic blood pressure below 140 mm Hg in patients at intermediate risk may not be helpful. Nevertheless, there seems to be agreement that intensive treatment generally leads to a reduction in cardiovascular events. The results also show the benefit of lowering cholesterol.

Bundy et al³¹ performed a meta-analysis that provides support for intensive antihypertensive treatment. Reviewing 42 clinical trials in more than 144,000 patients, they found that treating to reach a target systolic blood pressure of 120 to 124 mm Hg can reduce cardiovascular events and all-cause mortality.

The trade-off is a minimal increase in the risk of adverse events. Also, the risk-benefit ratio of intensive treatment seems to vary in different patient subgroups.

WHAT ABOUT PATIENTS WITH COMORBIDITIES?

The debate over intensive vs standard treatment in blood pressure management extends beyond hypertension and includes important comorbidities such as diabetes, stroke, and renal disease. Patients with a history of stroke or end-stage renal disease have only a minimal mention in the AHA/ACC guidelines.

Diabetes

Emdin et al,³² in a meta-analysis of 40 trials that included more than 100,000 patients with diabetes, concluded that a 10-mm Hg lowering of systolic blood pressure significantly reduces the rates of all-cause mortality, cardiovascular disease, coronary heart disease, stroke, albuminuria, and retinopathy. Stratifying the results according to the systolic blood pressure achieved (≥ 130 or < 130 mm Hg), the relative risks of mortality, coronary heart disease, cardiovascular disease, heart failure, and albuminuria were actually lower in the higher stratum than in the lower.

ACCORD (the Action to Control Cardiovascular Risk in Diabetes)³³ study provides contrary results. It examined intensive and standard blood pressure control targets in patients with type 2 diabetes at high risk of cardiovascular events, using primary outcome measures similar to those in SPRINT. It found no significant difference in fatal and nonfatal cardiovascular events between the intensive and standard blood pressure target arms.

Despite those results, the ACC/AHA guidelines still advocate for more intensive treatment (goal < 130/80 mm Hg) in all patients, including those with diabetes.¹

The ADA position statement (September 2017) recommended a target below 140/90 mm Hg in patients with diabetes and hypertension.⁸ However, they also noted that lower systolic and diastolic blood pressure targets, such as below 130/80 mm Hg, may be appropriate for patients at high risk of cardiovascular disease “if they can be achieved without undue treatment burden.”⁸ Thus, it is not clear which blood pressure targets in patients with diabetes are the best.

Stroke

In patients with stroke, AHA/ACC guidelines¹ recommend treatment if the blood pressure is 140/90 mm Hg or higher because antihypertensive therapy has been associated with a decrease in the recurrence of transient ischemic attack and stroke. The ideal target blood pressure is not known, but a goal of less than 130/80 mm Hg may be reasonable.

In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, a retrospective open-label trial, a target blood pressure below 130/80 mm Hg in patients with a history of lacunar stroke was associated with a lower risk of intracranial hemorrhage, but the difference was not statistically significant.³⁴ For this reason, the ACC/AHA guidelines consider it reasonable to aim for a systolic blood pressure below 130 mm Hg in these patients.¹

Renal disease

The ACC/AHA guidelines do not address how to manage hypertension in patients with end-stage renal disease, but for patients with chronic kidney disease they recommend a blood pressure target below 130/80 mm Hg.¹ This recommendation is derived from the SPRINT trial,¹⁵ in which patients with stage 3 or 4 chronic kidney disease accounted for 28% of the study population. In that subgroup, intensive blood pressure control seemed to provide the same benefits for reduction in cardiovascular death and all-cause mortality.

TREAT PATIENTS, NOT NUMBERS

Blood pressure targets should be applied in the appropriate clinical context and on a patient-by-patient basis. In clinical practice, one size does not always fit all, as special cases exist.

For example, blood pressure can oscillate widely in patients with autonomic nerve disorders, making it difficult to strive for a specific target, especially an intensive one. Thus, it may be necessary to allow higher systolic blood pressure in these patients. Similarly, patients with diabetes or chronic kidney disease may be at higher risk of kidney injury with more intensive blood pressure management.

Treating numbers rather than patients may result in unbalanced patient care. The optimal approach to blood pressure management relies on a comprehensive risk factor assessment and shared decision-making with the patient before setting specific blood pressure targets.

OUR APPROACH

We aim for a blood pressure goal below 130/80 mm Hg for all patients with cardiovascular disease, according to the AHA/ACC guidelines. We aim for that same target in patients without cardiovascular disease but who have an elevated estimated cardiovascular risk (> 10%) over the next 10 years.

We recognize, however, that the benefits of aggressive blood pressure reduction may not be as clear in all patients, such as those with diabetes. We also recognize that some patient subgroups are at high risk of adverse events, including those with low diastolic pressure, chronic kidney disease, a history of falls, and older age. In those patients, we are extremely judicious when titrating antihypertensive medications. We often make smaller titrations, at longer intervals, and with more frequent laboratory testing and in-office follow-up.

Our process of managing hypertension through intensive blood pressure control to achieve lower systolic blood pressure targets requires a concerted effort among healthcare providers at all levels. It especially requires more involvement and investment from primary care providers to individualize treatment in their patients. This process has helped us to reach our treatment goals while limiting adverse effects of lower blood pressure targets.

MOVING FORWARD

Hypertension is a major risk factor for cardiovascular disease, and intensive blood pressure control has the potential to significantly reduce rates of morbidity and death associated with cardiovascular disease. Thus, a general consensus on the definition of hypertension and treatment goals is essential to reduce the risk of cardiovascular events in this large patient population.

Intensive blood pressure treatment has shown efficacy, but it has a small accompanying risk of adverse events, which varies in patient subgroups and affects the benefit-risk ratio of this therapy. For example, the cardiovascular benefit of intensive treatment is less clear in diabetic patients, and the risk of adverse events may be higher in older patients with chronic kidney disease.

Moving forward, more research is needed into the effects of intensive and standard treatment on patients of all ages, those with common comorbid conditions, and those with other important factors such as diastolic hypertension.

Finally, the various medical societies should collaborate on hypertension guideline development. This would require considerable planning and coordination but would ultimately be useful in creating a generalizable approach to hypertension management.

When treating high blood pressure, how low should we try to go? Debate continues about optimal blood pressure goals after publication of guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) in 2017 that set or permitted a treatment goal of less than 130 mm Hg, depending on the population.¹

In this article, we summarize the evolution of hypertension guidelines and the evidence behind them.

HOW THE GOALS EVOLVED

JNC 7, 2003: 140/90 or 130/80

The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),² published in 2003, specified treatment goals of:

• < 140/90 mm Hg for most patients
• < 130/80 mm Hg for those with diabetes or chronic kidney disease.

JNC 7 provided much-needed clarity and uniformity to managing hypertension. Since then, various scientific groups have published their own guidelines (Table 1).^1–9

ACC/AHA/CDC 2014: 140/90

In 2014, the ACC, AHA, and US Centers for Disease Control and Prevention (CDC) published an evidence-based algorithm for hypertension management.³ As in JNC 7, they suggested a blood pressure goal of less than 140/90 mm Hg, lifestyle modification, and polytherapy, eg, a thiazide diuretic for stage 1 hypertension (< 160/100 mm Hg) and combination therapy with a thiazide diuretic and an angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), or calcium channel blocker for stage 2 hypertension (≥ 160/100 mm Hg).

JNC 8 2014: 140/90 or 150/90

Soon after, the much-anticipated report of the panel members appointed to the eighth JNC (JNC 8) was published.⁴ Previous JNC reports were written and published under the auspices of the National Heart, Lung, and Blood Institute, but while the JNC 8 report was being prepared, this government body announced it would no longer publish guidelines.

In contrast to JNC 7, the JNC 8 panel based its recommendations on a systematic review of randomized clinical trials. However, the process and methodology were controversial, especially as the panel excluded some important clinical trials from the analysis.

JNC 8 relaxed the targets in several subgroups, such as patients over age 60 and those with diabetes and chronic kidney disease, due to a lack of definitive evidence on the impact of blood pressure targets lower than 140/90 mm Hg in these groups. Thus, their goals were:

• < 140/90 mm Hg for patients under age 60
• < 150/90 mm Hg for patients age 60 and older.

Of note, a minority of the JNC 8 panel disagreed with the new targets and provided evidence for keeping the systolic blood pressure target below 140 mm Hg for patients 60 and older.⁵ Further, the JNC 8 report was not endorsed by several important societies, ie, the AHA, ACC, National Heart, Lung, and Blood Institute, and American Society of Hypertension (ASH). These issues compromised the acceptance and applicability of the guidelines.

ASH/ISH 2014: 140/90 or 150/90

Also in 2014, the ASH and the International Society of Hypertension released their own report.⁶ Their goals:

• < 140/90 mm Hg for most patients
• < 150/90 mm Hg for patients age 80 and older.

AHA/ACC/ASH 2015: Goals in subgroups

In 2015, the AHA, ACC, and ASH released a joint scientific statement outlining hypertension goals for specific patient populations⁷:

• < 150/90 mm Hg for those age 80 and older
• < 140/90 mm Hg for those with coronary artery disease
• < 130/80 mm Hg for those with comorbidities such as diabetes and cardiovascular disease.

ADA 2016: Goals for patients with diabetes

In 2016, the American Diabetes Association (ADA) set the following blood pressure goals for patients with diabetes⁸:

• < 140/90 mm Hg for adults with diabetes
• < 130/80 mm Hg for younger adults with diabetes and adults with a high risk of cardiovascular disease
• 120–160/80–105 mm Hg for pregnant patients with diabetes and preexisting hypertension who are treated with antihypertensive therapy.

In 2017, the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) recommended a relaxed systolic blood pressure target, ie, below 150 mm Hg, for adults over age 60, but a tighter goal of less than 140 mm Hg for the same age group if they have transient ischemic attack, stroke, or high cardiovascular risk.⁹

ACC/AHA 2017: 130/80

The 2017 ACC/AHA guidelines recommended a more aggressive goal of below 130/80 for all, including patients age 65 and older.¹

This is a class I (strong) recommendation for patients with known cardiovascular disease or a 10-year risk of a cardiovascular event of 10% or higher, with a B-R level of evidence for the systolic goal (ie, moderate-quality, based on systematic review of randomized controlled trials) and a C-EO level of evidence for the diastolic goal (ie, based on expert opinion).

For patients who do not have cardiovascular disease and who are at lower risk of it, this is a class IIb (weak) recommendation, ie, it “may be reasonable,” with a B-NR level of evidence (moderate-quality, based on nonrandomized studies) for the systolic goal and C-EO (expert opinion) for the diastolic goal.

For many patients, this involves drug treatment. For those with known cardiovascular disease or a 10-year risk of an atherosclerotic cardiovascular disease event of 10% or higher, the ACC/AHA guidelines say that drug treatment “is recommended” if their average blood pressure is 130/80 mm Hg or higher (class I recommendation, based on strong evidence for the systolic threshold and expert option for the diastolic). For those without cardiovascular disease and at lower risk, drug treatment is recommended if their average blood pressure is 140/90 mm Hg or higher (also class I, but based on limited data).

EVERYONE AGREES ON LIFESTYLE

Although the guidelines differ in their blood pressure targets, they consistently recommend lifestyle modifications.

Lifestyle modifications, first described in JNC 7, included weight loss, sodium restriction, and the DASH diet, which is rich in fruits, vegetables, low-fat dairy products, whole grains, poultry, and fish, and low in red meat, sweets, cholesterol, and total and saturated fat.²

These recommendations were based on results from 3 large randomized controlled trials in patients with and without hypertension.^10–12 In patients with no history of hypertension, interventions to promote weight loss and sodium restriction significantly reduced blood pressure and the incidence of hypertension (the latter by as much as 77%) compared with usual care.^10,11

In patients with and without hypertension, lowering sodium intake in conjunction with the DASH diet was associated with substantially larger reductions in systolic blood pressure.¹²

The recommendation to lower sodium intake has not changed in the guideline revisions. Meanwhile, other modifications have been added, such as incorporating both aerobic and resistance exercise and moderating alcohol intake. These recommendations have a class I level of evidence (ie, strongest level) in the 2017 ACC/AHA guidelines.¹

HYPERTENSION BEGINS AT 130/80

The definition of hypertension changed in the 2017 ACC/AHA guidelines¹: previously set at 140/90 mm Hg or higher, it is now 130/80 mm Hg or higher for all age groups. Adults with systolic blood pressure of 130 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg are now classified as having stage 1 hypertension.

Under the new definition, the number of US adults who have hypertension expanded to 45.6% of the general population,¹³ up from 31.9% under the JNC 7 definition. Thus, overall, 103.3 million US adults now have hypertension, compared with 72.2 million under the JNC 7 criteria.

In addition, the new guidelines expanded the population of adults for whom antihypertensive drug treatment is recommended to 36.2% (81.9 million). However, this represents only a 1.9% absolute increase over the JNC 7 recommendations (34.3%) and a 5.1% absolute increase over the JNC 8 recommendations.¹⁴

SPRINT: INTENSIVE TREATMENT IS BENEFICIAL

The new ACC/AHA guidelines¹ were based on evidence from several trials, including the Systolic Blood Pressure Intervention Trial (SPRINT).¹⁵

This multicenter trial investigated the effect of intensive blood pressure treatment on cardiovascular disease risk.¹⁶ The primary outcome was a composite of myocardial infarction, acute coronary syndrome, stroke, and heart failure.

The trial enrolled 9,361 participants at least 50 years of age with systolic blood pressure 130 mm Hg or higher and at least 1 additional risk factor for cardiovascular disease. It excluded anyone with a history of diabetes mellitus, stroke, symptomatic heart failure, or end-stage renal disease.

Two interventions were compared: 

• Intensive treatment, with a systolic blood pressure goal of less than 120 mm Hg: the protocol called for polytherapy, even for participants who were 75 or older if their blood pressure was 140 mm Hg or higher
• Standard treatment, with a systolic blood pressure goal of less than 140 mm Hg: it used polytherapy for patients whose systolic blood pressure was 160 mm Hg or higher.

The trial was intended to last 5 years but was stopped early at a median of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group: 1.65% per year vs 2.19%, a 25% relative risk reduction (P < .001) or a 0.54% absolute risk reduction. We calculate the number needed to treat (NNT) for 1 year to prevent 1 event as 185, and over the 3.26 years of the trial, the investigators calculated the NNT as 61. Similarly, the rate of death from any cause was also lower with intensive treatment, 1.03% per year vs 1.40% per year, a 27% relative risk reduction (P = .003) or a 0.37% absolute risk reduction, NNT 270.

Using these findings, Bress et al¹⁶ estimated that implementing intensive blood pressure goals could prevent 107,500 deaths annually.

The downside is adverse effects. In SPRINT,¹⁵ the intensive-treatment group experienced significantly higher rates of serious adverse effects than the standard-treatment group, ie:

• Hypotension 2.4% vs 1.4%, P = .001
• Syncope 2.3% vs 1.7%, P = .05
• Electrolyte abnormalities 3.1% vs 2.3%, P = .02)
• Acute kidney injury or kidney failure 4.1% vs 2.5%, P < .001
• Any treatment-related adverse event 4.7% vs 2.5%, P = .001.

Thus, Bress et al¹⁶ estimated that fully implementing the intensive-treatment goals could cause an additional 56,100 episodes of hypotension per year, 34,400 cases of syncope, 43,400 serious electrolyte disorders, and 88,700 cases of acute kidney injury. All told, about 3 million Americans could suffer a serious adverse effect under the intensive-treatment goals.

SPRINT¹⁵ was stopped early, after 3.26 years instead of the planned 5 years. The true risk-benefit ratio may have been different if the trial had been extended longer.

In addition, SPRINT used automated office blood pressure measurements in which patients were seated alone and a device (Model 907, Omron Healthcare) took 3 blood pressure measurements at 1-minute intervals after 5 minutes of quiet rest. This was designed to reduce elevated blood pressure readings in the presence of a healthcare professional in a medical setting (ie, “white coat” hypertension).

Many physicians are still taking blood pressure manually, which tends to give higher readings. Therefore, if they aim for a lower goal, they may risk overtreating the patient.

About 50% of patients did not achieve the target systolic blood pressure (< 120 mm Hg) despite receiving an average of 2.8 antihypertensive medications in the intensive-treatment group and 1.8 in the standard-treatment group. The use of antihypertensive medications, however, was not a controlled variable in the trial, and practitioners chose the appropriate drugs for their patients.

Diastolic pressure, which can be markedly lower in older hypertensive patients, was largely ignored, although lower diastolic pressure may have contributed to higher syncope rates in response to alpha blockers and calcium blockers.

Moreover, the trial excluded those with significant comorbidities and those younger than 50 (the mean age was 67.9), which limits the generalizability of the results.

JNC 8 VS SPRINT GOALS: WHAT'S THE EFFECT ON OUTCOMES?

JNC 8⁴ recommended a relaxed target of less than 140/90 mm Hg for adults younger than 60, including those with chronic kidney disease or diabetes, and less than 150/90 mm Hg for adults 60 and older. The SPRINT findings upended those recommendations, showing that intensive treatment in adults age 75 or older significantly improved the composite cardiovascular disease outcome (2.59 vs 3.85 events per year; P < .001) and all-cause mortality (1.78 vs 2.63 events per year; P < .05) compared with standard treatment.¹⁷ Also, a subset review of SPRINT trial data found no difference in benefit based on chronic kidney disease status.¹⁸

A meta-analysis of 74 clinical trials (N = 306,273) offers a compromise between the SPRINT findings and the JNC 8 recommendations.¹⁹ It found that the beneficial effect of blood pressure treatment depended on the patient’s baseline systolic blood pressure. In those with a baseline systolic pressure of 160 mm Hg or higher, treatment reduced cardiovascular mortality by about 15% (relative risk [RR] 0.85; 95% confidence interval [CI] 0.77–0.95). In patients with systolic pressure below 140 mm Hg, treatment effects were neutral (RR 1.03, 95% CI 0.87–1.20) and not associated with any benefit as primary prevention, although data suggest it may reduce the risk of adverse outcomes in patients with coronary heart disease.

OTHER TRIALS THAT INFLUENCED THE GUIDELINES

SHEP and HYVET (the Systolic Hypertension in the Elderly Program²⁰ and the Hypertension in the Very Elderly Trial)²¹ supported intensive blood pressure treatment for older patients by reporting a reduction in fatal and nonfatal stroke risks for those with a systolic blood pressure above 160 mm Hg.

FEVER (the Felodipine Event Reduction study)²² found that treatment with a calcium channel blocker in even a low dose can significantly decrease cardiovascular events, cardiovascular disease, and heart failure compared with no treatment.

JATOS and VALISH (the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients²³ and the Valsartan in Elderly Isolated Systolic Hypertension study)²⁴ found that outcomes were similar with intensive vs standard treatment.

Ettehad et al²⁵ performed a meta-analysis of 123 studies with more than 600,000 participants that provided strong evidence supporting blood pressure treatment goals below 130/90 mm Hg, in line with the SPRINT trial results.

BLOOD PRESSURE ISN’T EVERYTHING

Other trials remind us that although blood pressure is important, it is not the only factor affecting cardiovascular risk.

HOPE (the Heart Outcomes Prevention Evaluation)²⁶ investigated the use of ramipril (an ACE inhibitor) in preventing myocardial infarction, stroke, or cardiovascular death in patients at high risk of cardiovascular events. The study included 9,297 participants over age 55 (mean age 66) with a baseline blood pressure 139/79 mm Hg. Follow-up was 4.5 years.

Ramipril was better than placebo, with significantly fewer patients experiencing adverse end points in the ramipril group compared with the placebo group:

• Myocardial infarction 9.9% vs 12.3%, RR 0.80, P < .001
• Cardiovascular death 6.1% vs 8.1%, RR  0.74, P < .001
• Stroke 3.4% vs 4.9%, RR = .68, P < .001
• The composite end point 14.0% vs 17.8%, RR 0.78, P < .001).

Results were even better in the subset of patients who had diabetes.²⁷ However, the decrease in blood pressure attributable to anti­hypertensive therapy with ramipril was minimal (3–4 mm Hg systolic and 1–2 mm Hg diastolic). This slight change should not have been enough to produce significant differences in clinical outcomes, a major limitation of this trial. The investigators speculated that the positive results may be due to a class effect of ACE inhibitors.²⁶

HOPE 3^28–30 explored the effect of blood pressure- and cholesterol-controlling drugs on the same primary end points but in patients at intermediate risk of major cardiovascular events. Investigators randomized the 12,705 patients to 4 treatment groups:

• Blood pressure control with candesartan (an ARB) plus hydrochlorothiazide (a thiazide diuretic)
• Cholesterol control with rosuvastatin (a statin)
• Blood pressure plus cholesterol control
• Placebo.

Therapy was started at a systolic blood pressure above 140 mm Hg.

Compared with placebo, the rate of composite events was significantly reduced in the rosuvastatin group (3.7% vs 4.8%, HR 0.76, P = .002)²⁸ and the candesartan-hydrochlorothiazide-rosuvastatin group (3.6% vs 5.0%, HR 0.71; P = .005)²⁹ but not in the candesartan-hydrochlorothiazide group (4.1% vs 4.4%; HR 0.93; P = .40).³⁰

In addition, a subgroup analysis comparing active treatment vs placebo found a significant reduction in major cardiovascular events for treated patients whose baseline systolic blood pressure was in the upper third (> 143.5 mm Hg, mean 154.1 mm Hg), while treated patients in the lower middle and lower thirds had no significant reduction.³⁰

These results suggest that intensive treatment to achieve a systolic blood pressure below 140 mm Hg in patients at intermediate risk may not be helpful. Nevertheless, there seems to be agreement that intensive treatment generally leads to a reduction in cardiovascular events. The results also show the benefit of lowering cholesterol.

Bundy et al³¹ performed a meta-analysis that provides support for intensive antihypertensive treatment. Reviewing 42 clinical trials in more than 144,000 patients, they found that treating to reach a target systolic blood pressure of 120 to 124 mm Hg can reduce cardiovascular events and all-cause mortality.

The trade-off is a minimal increase in the risk of adverse events. Also, the risk-benefit ratio of intensive treatment seems to vary in different patient subgroups.

WHAT ABOUT PATIENTS WITH COMORBIDITIES?

The debate over intensive vs standard treatment in blood pressure management extends beyond hypertension and includes important comorbidities such as diabetes, stroke, and renal disease. Patients with a history of stroke or end-stage renal disease have only a minimal mention in the AHA/ACC guidelines.

Diabetes

Emdin et al,³² in a meta-analysis of 40 trials that included more than 100,000 patients with diabetes, concluded that a 10-mm Hg lowering of systolic blood pressure significantly reduces the rates of all-cause mortality, cardiovascular disease, coronary heart disease, stroke, albuminuria, and retinopathy. Stratifying the results according to the systolic blood pressure achieved (≥ 130 or < 130 mm Hg), the relative risks of mortality, coronary heart disease, cardiovascular disease, heart failure, and albuminuria were actually lower in the higher stratum than in the lower.

ACCORD (the Action to Control Cardiovascular Risk in Diabetes)³³ study provides contrary results. It examined intensive and standard blood pressure control targets in patients with type 2 diabetes at high risk of cardiovascular events, using primary outcome measures similar to those in SPRINT. It found no significant difference in fatal and nonfatal cardiovascular events between the intensive and standard blood pressure target arms.

Despite those results, the ACC/AHA guidelines still advocate for more intensive treatment (goal < 130/80 mm Hg) in all patients, including those with diabetes.¹

The ADA position statement (September 2017) recommended a target below 140/90 mm Hg in patients with diabetes and hypertension.⁸ However, they also noted that lower systolic and diastolic blood pressure targets, such as below 130/80 mm Hg, may be appropriate for patients at high risk of cardiovascular disease “if they can be achieved without undue treatment burden.”⁸ Thus, it is not clear which blood pressure targets in patients with diabetes are the best.

Stroke

In patients with stroke, AHA/ACC guidelines¹ recommend treatment if the blood pressure is 140/90 mm Hg or higher because antihypertensive therapy has been associated with a decrease in the recurrence of transient ischemic attack and stroke. The ideal target blood pressure is not known, but a goal of less than 130/80 mm Hg may be reasonable.

In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, a retrospective open-label trial, a target blood pressure below 130/80 mm Hg in patients with a history of lacunar stroke was associated with a lower risk of intracranial hemorrhage, but the difference was not statistically significant.³⁴ For this reason, the ACC/AHA guidelines consider it reasonable to aim for a systolic blood pressure below 130 mm Hg in these patients.¹

Renal disease

The ACC/AHA guidelines do not address how to manage hypertension in patients with end-stage renal disease, but for patients with chronic kidney disease they recommend a blood pressure target below 130/80 mm Hg.¹ This recommendation is derived from the SPRINT trial,¹⁵ in which patients with stage 3 or 4 chronic kidney disease accounted for 28% of the study population. In that subgroup, intensive blood pressure control seemed to provide the same benefits for reduction in cardiovascular death and all-cause mortality.

TREAT PATIENTS, NOT NUMBERS

Blood pressure targets should be applied in the appropriate clinical context and on a patient-by-patient basis. In clinical practice, one size does not always fit all, as special cases exist.

For example, blood pressure can oscillate widely in patients with autonomic nerve disorders, making it difficult to strive for a specific target, especially an intensive one. Thus, it may be necessary to allow higher systolic blood pressure in these patients. Similarly, patients with diabetes or chronic kidney disease may be at higher risk of kidney injury with more intensive blood pressure management.

Treating numbers rather than patients may result in unbalanced patient care. The optimal approach to blood pressure management relies on a comprehensive risk factor assessment and shared decision-making with the patient before setting specific blood pressure targets.

OUR APPROACH

We aim for a blood pressure goal below 130/80 mm Hg for all patients with cardiovascular disease, according to the AHA/ACC guidelines. We aim for that same target in patients without cardiovascular disease but who have an elevated estimated cardiovascular risk (> 10%) over the next 10 years.

We recognize, however, that the benefits of aggressive blood pressure reduction may not be as clear in all patients, such as those with diabetes. We also recognize that some patient subgroups are at high risk of adverse events, including those with low diastolic pressure, chronic kidney disease, a history of falls, and older age. In those patients, we are extremely judicious when titrating antihypertensive medications. We often make smaller titrations, at longer intervals, and with more frequent laboratory testing and in-office follow-up.

Our process of managing hypertension through intensive blood pressure control to achieve lower systolic blood pressure targets requires a concerted effort among healthcare providers at all levels. It especially requires more involvement and investment from primary care providers to individualize treatment in their patients. This process has helped us to reach our treatment goals while limiting adverse effects of lower blood pressure targets.

MOVING FORWARD

Hypertension is a major risk factor for cardiovascular disease, and intensive blood pressure control has the potential to significantly reduce rates of morbidity and death associated with cardiovascular disease. Thus, a general consensus on the definition of hypertension and treatment goals is essential to reduce the risk of cardiovascular events in this large patient population.

Intensive blood pressure treatment has shown efficacy, but it has a small accompanying risk of adverse events, which varies in patient subgroups and affects the benefit-risk ratio of this therapy. For example, the cardiovascular benefit of intensive treatment is less clear in diabetic patients, and the risk of adverse events may be higher in older patients with chronic kidney disease.

Moving forward, more research is needed into the effects of intensive and standard treatment on patients of all ages, those with common comorbid conditions, and those with other important factors such as diastolic hypertension.

Finally, the various medical societies should collaborate on hypertension guideline development. This would require considerable planning and coordination but would ultimately be useful in creating a generalizable approach to hypertension management.

When treating high blood pressure, how low should we try to go? Debate continues about optimal blood pressure goals after publication of guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) in 2017 that set or permitted a treatment goal of less than 130 mm Hg, depending on the population.¹

In this article, we summarize the evolution of hypertension guidelines and the evidence behind them.

HOW THE GOALS EVOLVED

JNC 7, 2003: 140/90 or 130/80

The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),² published in 2003, specified treatment goals of:

• < 140/90 mm Hg for most patients
• < 130/80 mm Hg for those with diabetes or chronic kidney disease.

JNC 7 provided much-needed clarity and uniformity to managing hypertension. Since then, various scientific groups have published their own guidelines (Table 1).^1–9

ACC/AHA/CDC 2014: 140/90

In 2014, the ACC, AHA, and US Centers for Disease Control and Prevention (CDC) published an evidence-based algorithm for hypertension management.³ As in JNC 7, they suggested a blood pressure goal of less than 140/90 mm Hg, lifestyle modification, and polytherapy, eg, a thiazide diuretic for stage 1 hypertension (< 160/100 mm Hg) and combination therapy with a thiazide diuretic and an angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), or calcium channel blocker for stage 2 hypertension (≥ 160/100 mm Hg).

JNC 8 2014: 140/90 or 150/90

Soon after, the much-anticipated report of the panel members appointed to the eighth JNC (JNC 8) was published.⁴ Previous JNC reports were written and published under the auspices of the National Heart, Lung, and Blood Institute, but while the JNC 8 report was being prepared, this government body announced it would no longer publish guidelines.

In contrast to JNC 7, the JNC 8 panel based its recommendations on a systematic review of randomized clinical trials. However, the process and methodology were controversial, especially as the panel excluded some important clinical trials from the analysis.

JNC 8 relaxed the targets in several subgroups, such as patients over age 60 and those with diabetes and chronic kidney disease, due to a lack of definitive evidence on the impact of blood pressure targets lower than 140/90 mm Hg in these groups. Thus, their goals were:

• < 140/90 mm Hg for patients under age 60
• < 150/90 mm Hg for patients age 60 and older.

Of note, a minority of the JNC 8 panel disagreed with the new targets and provided evidence for keeping the systolic blood pressure target below 140 mm Hg for patients 60 and older.⁵ Further, the JNC 8 report was not endorsed by several important societies, ie, the AHA, ACC, National Heart, Lung, and Blood Institute, and American Society of Hypertension (ASH). These issues compromised the acceptance and applicability of the guidelines.

ASH/ISH 2014: 140/90 or 150/90

Also in 2014, the ASH and the International Society of Hypertension released their own report.⁶ Their goals:

• < 140/90 mm Hg for most patients
• < 150/90 mm Hg for patients age 80 and older.

AHA/ACC/ASH 2015: Goals in subgroups

In 2015, the AHA, ACC, and ASH released a joint scientific statement outlining hypertension goals for specific patient populations⁷:

• < 150/90 mm Hg for those age 80 and older
• < 140/90 mm Hg for those with coronary artery disease
• < 130/80 mm Hg for those with comorbidities such as diabetes and cardiovascular disease.

ADA 2016: Goals for patients with diabetes

In 2016, the American Diabetes Association (ADA) set the following blood pressure goals for patients with diabetes⁸:

• < 140/90 mm Hg for adults with diabetes
• < 130/80 mm Hg for younger adults with diabetes and adults with a high risk of cardiovascular disease
• 120–160/80–105 mm Hg for pregnant patients with diabetes and preexisting hypertension who are treated with antihypertensive therapy.

In 2017, the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) recommended a relaxed systolic blood pressure target, ie, below 150 mm Hg, for adults over age 60, but a tighter goal of less than 140 mm Hg for the same age group if they have transient ischemic attack, stroke, or high cardiovascular risk.⁹

ACC/AHA 2017: 130/80

The 2017 ACC/AHA guidelines recommended a more aggressive goal of below 130/80 for all, including patients age 65 and older.¹

This is a class I (strong) recommendation for patients with known cardiovascular disease or a 10-year risk of a cardiovascular event of 10% or higher, with a B-R level of evidence for the systolic goal (ie, moderate-quality, based on systematic review of randomized controlled trials) and a C-EO level of evidence for the diastolic goal (ie, based on expert opinion).

For patients who do not have cardiovascular disease and who are at lower risk of it, this is a class IIb (weak) recommendation, ie, it “may be reasonable,” with a B-NR level of evidence (moderate-quality, based on nonrandomized studies) for the systolic goal and C-EO (expert opinion) for the diastolic goal.

For many patients, this involves drug treatment. For those with known cardiovascular disease or a 10-year risk of an atherosclerotic cardiovascular disease event of 10% or higher, the ACC/AHA guidelines say that drug treatment “is recommended” if their average blood pressure is 130/80 mm Hg or higher (class I recommendation, based on strong evidence for the systolic threshold and expert option for the diastolic). For those without cardiovascular disease and at lower risk, drug treatment is recommended if their average blood pressure is 140/90 mm Hg or higher (also class I, but based on limited data).

EVERYONE AGREES ON LIFESTYLE

Although the guidelines differ in their blood pressure targets, they consistently recommend lifestyle modifications.

Lifestyle modifications, first described in JNC 7, included weight loss, sodium restriction, and the DASH diet, which is rich in fruits, vegetables, low-fat dairy products, whole grains, poultry, and fish, and low in red meat, sweets, cholesterol, and total and saturated fat.²

These recommendations were based on results from 3 large randomized controlled trials in patients with and without hypertension.^10–12 In patients with no history of hypertension, interventions to promote weight loss and sodium restriction significantly reduced blood pressure and the incidence of hypertension (the latter by as much as 77%) compared with usual care.^10,11

In patients with and without hypertension, lowering sodium intake in conjunction with the DASH diet was associated with substantially larger reductions in systolic blood pressure.¹²

The recommendation to lower sodium intake has not changed in the guideline revisions. Meanwhile, other modifications have been added, such as incorporating both aerobic and resistance exercise and moderating alcohol intake. These recommendations have a class I level of evidence (ie, strongest level) in the 2017 ACC/AHA guidelines.¹

HYPERTENSION BEGINS AT 130/80

The definition of hypertension changed in the 2017 ACC/AHA guidelines¹: previously set at 140/90 mm Hg or higher, it is now 130/80 mm Hg or higher for all age groups. Adults with systolic blood pressure of 130 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg are now classified as having stage 1 hypertension.

Under the new definition, the number of US adults who have hypertension expanded to 45.6% of the general population,¹³ up from 31.9% under the JNC 7 definition. Thus, overall, 103.3 million US adults now have hypertension, compared with 72.2 million under the JNC 7 criteria.

In addition, the new guidelines expanded the population of adults for whom antihypertensive drug treatment is recommended to 36.2% (81.9 million). However, this represents only a 1.9% absolute increase over the JNC 7 recommendations (34.3%) and a 5.1% absolute increase over the JNC 8 recommendations.¹⁴

SPRINT: INTENSIVE TREATMENT IS BENEFICIAL

The new ACC/AHA guidelines¹ were based on evidence from several trials, including the Systolic Blood Pressure Intervention Trial (SPRINT).¹⁵

This multicenter trial investigated the effect of intensive blood pressure treatment on cardiovascular disease risk.¹⁶ The primary outcome was a composite of myocardial infarction, acute coronary syndrome, stroke, and heart failure.

The trial enrolled 9,361 participants at least 50 years of age with systolic blood pressure 130 mm Hg or higher and at least 1 additional risk factor for cardiovascular disease. It excluded anyone with a history of diabetes mellitus, stroke, symptomatic heart failure, or end-stage renal disease.

Two interventions were compared: 

• Intensive treatment, with a systolic blood pressure goal of less than 120 mm Hg: the protocol called for polytherapy, even for participants who were 75 or older if their blood pressure was 140 mm Hg or higher
• Standard treatment, with a systolic blood pressure goal of less than 140 mm Hg: it used polytherapy for patients whose systolic blood pressure was 160 mm Hg or higher.

The trial was intended to last 5 years but was stopped early at a median of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group: 1.65% per year vs 2.19%, a 25% relative risk reduction (P < .001) or a 0.54% absolute risk reduction. We calculate the number needed to treat (NNT) for 1 year to prevent 1 event as 185, and over the 3.26 years of the trial, the investigators calculated the NNT as 61. Similarly, the rate of death from any cause was also lower with intensive treatment, 1.03% per year vs 1.40% per year, a 27% relative risk reduction (P = .003) or a 0.37% absolute risk reduction, NNT 270.

Using these findings, Bress et al¹⁶ estimated that implementing intensive blood pressure goals could prevent 107,500 deaths annually.

The downside is adverse effects. In SPRINT,¹⁵ the intensive-treatment group experienced significantly higher rates of serious adverse effects than the standard-treatment group, ie:

• Hypotension 2.4% vs 1.4%, P = .001
• Syncope 2.3% vs 1.7%, P = .05
• Electrolyte abnormalities 3.1% vs 2.3%, P = .02)
• Acute kidney injury or kidney failure 4.1% vs 2.5%, P < .001
• Any treatment-related adverse event 4.7% vs 2.5%, P = .001.

Thus, Bress et al¹⁶ estimated that fully implementing the intensive-treatment goals could cause an additional 56,100 episodes of hypotension per year, 34,400 cases of syncope, 43,400 serious electrolyte disorders, and 88,700 cases of acute kidney injury. All told, about 3 million Americans could suffer a serious adverse effect under the intensive-treatment goals.

SPRINT¹⁵ was stopped early, after 3.26 years instead of the planned 5 years. The true risk-benefit ratio may have been different if the trial had been extended longer.

In addition, SPRINT used automated office blood pressure measurements in which patients were seated alone and a device (Model 907, Omron Healthcare) took 3 blood pressure measurements at 1-minute intervals after 5 minutes of quiet rest. This was designed to reduce elevated blood pressure readings in the presence of a healthcare professional in a medical setting (ie, “white coat” hypertension).

Many physicians are still taking blood pressure manually, which tends to give higher readings. Therefore, if they aim for a lower goal, they may risk overtreating the patient.

About 50% of patients did not achieve the target systolic blood pressure (< 120 mm Hg) despite receiving an average of 2.8 antihypertensive medications in the intensive-treatment group and 1.8 in the standard-treatment group. The use of antihypertensive medications, however, was not a controlled variable in the trial, and practitioners chose the appropriate drugs for their patients.

Diastolic pressure, which can be markedly lower in older hypertensive patients, was largely ignored, although lower diastolic pressure may have contributed to higher syncope rates in response to alpha blockers and calcium blockers.

Moreover, the trial excluded those with significant comorbidities and those younger than 50 (the mean age was 67.9), which limits the generalizability of the results.

JNC 8 VS SPRINT GOALS: WHAT'S THE EFFECT ON OUTCOMES?

JNC 8⁴ recommended a relaxed target of less than 140/90 mm Hg for adults younger than 60, including those with chronic kidney disease or diabetes, and less than 150/90 mm Hg for adults 60 and older. The SPRINT findings upended those recommendations, showing that intensive treatment in adults age 75 or older significantly improved the composite cardiovascular disease outcome (2.59 vs 3.85 events per year; P < .001) and all-cause mortality (1.78 vs 2.63 events per year; P < .05) compared with standard treatment.¹⁷ Also, a subset review of SPRINT trial data found no difference in benefit based on chronic kidney disease status.¹⁸

A meta-analysis of 74 clinical trials (N = 306,273) offers a compromise between the SPRINT findings and the JNC 8 recommendations.¹⁹ It found that the beneficial effect of blood pressure treatment depended on the patient’s baseline systolic blood pressure. In those with a baseline systolic pressure of 160 mm Hg or higher, treatment reduced cardiovascular mortality by about 15% (relative risk [RR] 0.85; 95% confidence interval [CI] 0.77–0.95). In patients with systolic pressure below 140 mm Hg, treatment effects were neutral (RR 1.03, 95% CI 0.87–1.20) and not associated with any benefit as primary prevention, although data suggest it may reduce the risk of adverse outcomes in patients with coronary heart disease.

OTHER TRIALS THAT INFLUENCED THE GUIDELINES

SHEP and HYVET (the Systolic Hypertension in the Elderly Program²⁰ and the Hypertension in the Very Elderly Trial)²¹ supported intensive blood pressure treatment for older patients by reporting a reduction in fatal and nonfatal stroke risks for those with a systolic blood pressure above 160 mm Hg.

FEVER (the Felodipine Event Reduction study)²² found that treatment with a calcium channel blocker in even a low dose can significantly decrease cardiovascular events, cardiovascular disease, and heart failure compared with no treatment.

JATOS and VALISH (the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients²³ and the Valsartan in Elderly Isolated Systolic Hypertension study)²⁴ found that outcomes were similar with intensive vs standard treatment.

Ettehad et al²⁵ performed a meta-analysis of 123 studies with more than 600,000 participants that provided strong evidence supporting blood pressure treatment goals below 130/90 mm Hg, in line with the SPRINT trial results.

BLOOD PRESSURE ISN’T EVERYTHING

Other trials remind us that although blood pressure is important, it is not the only factor affecting cardiovascular risk.

HOPE (the Heart Outcomes Prevention Evaluation)²⁶ investigated the use of ramipril (an ACE inhibitor) in preventing myocardial infarction, stroke, or cardiovascular death in patients at high risk of cardiovascular events. The study included 9,297 participants over age 55 (mean age 66) with a baseline blood pressure 139/79 mm Hg. Follow-up was 4.5 years.

Ramipril was better than placebo, with significantly fewer patients experiencing adverse end points in the ramipril group compared with the placebo group:

• Myocardial infarction 9.9% vs 12.3%, RR 0.80, P < .001
• Cardiovascular death 6.1% vs 8.1%, RR  0.74, P < .001
• Stroke 3.4% vs 4.9%, RR = .68, P < .001
• The composite end point 14.0% vs 17.8%, RR 0.78, P < .001).

Results were even better in the subset of patients who had diabetes.²⁷ However, the decrease in blood pressure attributable to anti­hypertensive therapy with ramipril was minimal (3–4 mm Hg systolic and 1–2 mm Hg diastolic). This slight change should not have been enough to produce significant differences in clinical outcomes, a major limitation of this trial. The investigators speculated that the positive results may be due to a class effect of ACE inhibitors.²⁶

HOPE 3^28–30 explored the effect of blood pressure- and cholesterol-controlling drugs on the same primary end points but in patients at intermediate risk of major cardiovascular events. Investigators randomized the 12,705 patients to 4 treatment groups:

• Blood pressure control with candesartan (an ARB) plus hydrochlorothiazide (a thiazide diuretic)
• Cholesterol control with rosuvastatin (a statin)
• Blood pressure plus cholesterol control
• Placebo.

Therapy was started at a systolic blood pressure above 140 mm Hg.

Compared with placebo, the rate of composite events was significantly reduced in the rosuvastatin group (3.7% vs 4.8%, HR 0.76, P = .002)²⁸ and the candesartan-hydrochlorothiazide-rosuvastatin group (3.6% vs 5.0%, HR 0.71; P = .005)²⁹ but not in the candesartan-hydrochlorothiazide group (4.1% vs 4.4%; HR 0.93; P = .40).³⁰

In addition, a subgroup analysis comparing active treatment vs placebo found a significant reduction in major cardiovascular events for treated patients whose baseline systolic blood pressure was in the upper third (> 143.5 mm Hg, mean 154.1 mm Hg), while treated patients in the lower middle and lower thirds had no significant reduction.³⁰

These results suggest that intensive treatment to achieve a systolic blood pressure below 140 mm Hg in patients at intermediate risk may not be helpful. Nevertheless, there seems to be agreement that intensive treatment generally leads to a reduction in cardiovascular events. The results also show the benefit of lowering cholesterol.

Bundy et al³¹ performed a meta-analysis that provides support for intensive antihypertensive treatment. Reviewing 42 clinical trials in more than 144,000 patients, they found that treating to reach a target systolic blood pressure of 120 to 124 mm Hg can reduce cardiovascular events and all-cause mortality.

The trade-off is a minimal increase in the risk of adverse events. Also, the risk-benefit ratio of intensive treatment seems to vary in different patient subgroups.

WHAT ABOUT PATIENTS WITH COMORBIDITIES?

The debate over intensive vs standard treatment in blood pressure management extends beyond hypertension and includes important comorbidities such as diabetes, stroke, and renal disease. Patients with a history of stroke or end-stage renal disease have only a minimal mention in the AHA/ACC guidelines.

Diabetes

Emdin et al,³² in a meta-analysis of 40 trials that included more than 100,000 patients with diabetes, concluded that a 10-mm Hg lowering of systolic blood pressure significantly reduces the rates of all-cause mortality, cardiovascular disease, coronary heart disease, stroke, albuminuria, and retinopathy. Stratifying the results according to the systolic blood pressure achieved (≥ 130 or < 130 mm Hg), the relative risks of mortality, coronary heart disease, cardiovascular disease, heart failure, and albuminuria were actually lower in the higher stratum than in the lower.

ACCORD (the Action to Control Cardiovascular Risk in Diabetes)³³ study provides contrary results. It examined intensive and standard blood pressure control targets in patients with type 2 diabetes at high risk of cardiovascular events, using primary outcome measures similar to those in SPRINT. It found no significant difference in fatal and nonfatal cardiovascular events between the intensive and standard blood pressure target arms.

Despite those results, the ACC/AHA guidelines still advocate for more intensive treatment (goal < 130/80 mm Hg) in all patients, including those with diabetes.¹

The ADA position statement (September 2017) recommended a target below 140/90 mm Hg in patients with diabetes and hypertension.⁸ However, they also noted that lower systolic and diastolic blood pressure targets, such as below 130/80 mm Hg, may be appropriate for patients at high risk of cardiovascular disease “if they can be achieved without undue treatment burden.”⁸ Thus, it is not clear which blood pressure targets in patients with diabetes are the best.

Stroke

In patients with stroke, AHA/ACC guidelines¹ recommend treatment if the blood pressure is 140/90 mm Hg or higher because antihypertensive therapy has been associated with a decrease in the recurrence of transient ischemic attack and stroke. The ideal target blood pressure is not known, but a goal of less than 130/80 mm Hg may be reasonable.

In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, a retrospective open-label trial, a target blood pressure below 130/80 mm Hg in patients with a history of lacunar stroke was associated with a lower risk of intracranial hemorrhage, but the difference was not statistically significant.³⁴ For this reason, the ACC/AHA guidelines consider it reasonable to aim for a systolic blood pressure below 130 mm Hg in these patients.¹

Renal disease

The ACC/AHA guidelines do not address how to manage hypertension in patients with end-stage renal disease, but for patients with chronic kidney disease they recommend a blood pressure target below 130/80 mm Hg.¹ This recommendation is derived from the SPRINT trial,¹⁵ in which patients with stage 3 or 4 chronic kidney disease accounted for 28% of the study population. In that subgroup, intensive blood pressure control seemed to provide the same benefits for reduction in cardiovascular death and all-cause mortality.

TREAT PATIENTS, NOT NUMBERS

Blood pressure targets should be applied in the appropriate clinical context and on a patient-by-patient basis. In clinical practice, one size does not always fit all, as special cases exist.

For example, blood pressure can oscillate widely in patients with autonomic nerve disorders, making it difficult to strive for a specific target, especially an intensive one. Thus, it may be necessary to allow higher systolic blood pressure in these patients. Similarly, patients with diabetes or chronic kidney disease may be at higher risk of kidney injury with more intensive blood pressure management.

Treating numbers rather than patients may result in unbalanced patient care. The optimal approach to blood pressure management relies on a comprehensive risk factor assessment and shared decision-making with the patient before setting specific blood pressure targets.

OUR APPROACH

We aim for a blood pressure goal below 130/80 mm Hg for all patients with cardiovascular disease, according to the AHA/ACC guidelines. We aim for that same target in patients without cardiovascular disease but who have an elevated estimated cardiovascular risk (> 10%) over the next 10 years.

We recognize, however, that the benefits of aggressive blood pressure reduction may not be as clear in all patients, such as those with diabetes. We also recognize that some patient subgroups are at high risk of adverse events, including those with low diastolic pressure, chronic kidney disease, a history of falls, and older age. In those patients, we are extremely judicious when titrating antihypertensive medications. We often make smaller titrations, at longer intervals, and with more frequent laboratory testing and in-office follow-up.

Our process of managing hypertension through intensive blood pressure control to achieve lower systolic blood pressure targets requires a concerted effort among healthcare providers at all levels. It especially requires more involvement and investment from primary care providers to individualize treatment in their patients. This process has helped us to reach our treatment goals while limiting adverse effects of lower blood pressure targets.

MOVING FORWARD

Hypertension is a major risk factor for cardiovascular disease, and intensive blood pressure control has the potential to significantly reduce rates of morbidity and death associated with cardiovascular disease. Thus, a general consensus on the definition of hypertension and treatment goals is essential to reduce the risk of cardiovascular events in this large patient population.

Intensive blood pressure treatment has shown efficacy, but it has a small accompanying risk of adverse events, which varies in patient subgroups and affects the benefit-risk ratio of this therapy. For example, the cardiovascular benefit of intensive treatment is less clear in diabetic patients, and the risk of adverse events may be higher in older patients with chronic kidney disease.

Moving forward, more research is needed into the effects of intensive and standard treatment on patients of all ages, those with common comorbid conditions, and those with other important factors such as diastolic hypertension.

Finally, the various medical societies should collaborate on hypertension guideline development. This would require considerable planning and coordination but would ultimately be useful in creating a generalizable approach to hypertension management.

Carol Bernstein, MD, joins Nick Andrews once again this week to talk about physician burnout and physician suicide.

Apple Podcasts
Google Podcasts
 

Carol Bernstein, MD, joins Nick Andrews once again this week to talk about physician burnout and physician suicide.

Apple Podcasts
Google Podcasts
 

Carol Bernstein, MD, joins Nick Andrews once again this week to talk about physician burnout and physician suicide.

Apple Podcasts
Google Podcasts
 

Leave policies for residents who become new parents are uneven, often ignored by training boards, and provide less time off than similar policies for faculty physicians. Also today, exercise is important for patients with sickle cell, COPD patients are experiencing a risk in non-TB mycobacteria infections, and how to be an influencer on social media.
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Google Podcasts
Spotify
 

Leave policies for residents who become new parents are uneven, often ignored by training boards, and provide less time off than similar policies for faculty physicians. Also today, exercise is important for patients with sickle cell, COPD patients are experiencing a risk in non-TB mycobacteria infections, and how to be an influencer on social media.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

Leave policies for residents who become new parents are uneven, often ignored by training boards, and provide less time off than similar policies for faculty physicians. Also today, exercise is important for patients with sickle cell, COPD patients are experiencing a risk in non-TB mycobacteria infections, and how to be an influencer on social media.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

To the Editor: In their article on men’s health,¹Chaitoff and colleagues present the scenario of a 60-year-old patient, with no other history given, whose recent screening prostate-specific antigen (PSA) level was 5.1 ng/mL, and who asks his doctor:

1. Should I have agreed to the screening?
2. How effective is the screening?
3. What are the next steps?

These questions are consistent with the patient having read the latest US Preventive Services Task Force (USPSTF) report on PSA screening, which states: “Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results…”²

I would tell the patient that he can expect greater benefit from PSA screening than reported by the USPSTF simply by adhering to the screening protocol. Intention-to-treat analysis applied to the trial results diminished the apparent benefits of PSA screening by counting fatal prostate cancers experienced by nonadherent study participants as screening failures.³ In other words, screening works better in those who actually get screened!

The authors state¹ that “in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it.” Nevertheless, prostate cancer remains the second most common cause of cancer deaths in American men, after lung cancer.⁴ In addition to the reduction in prostate cancer-specific mortality with screening, patients should consider the reduction in morbidity from painful bone metastases and pathologic fractures, which are common in advanced prostate cancer.

A false-positive elevated PSA can be caused by reversible benign conditions, such as prostate infection or trauma, which can resolve over time, returning the PSA to its baseline level. Studies have demonstrated that simply repeating the PSA test a few weeks later will significantly reduce the number of false-positive PSA screening tests.⁵

Also, it is not optimal to screen for prostate cancer using a single PSA measurement. This patient’s PSA of 5.1 ng/mL cannot distinguish between chronic benign prostatic hyperplasia and a fast-growing but still curable malignancy. If the patient’s PSA had been tested annually and was known to be stable at its current level, a benign or indolent condition would be most likely, allowing for the possibility of continuing noninvasive observation. If his PSA was 1.1 ng/mL a year ago, and his PSA remains elevated when retested in a few weeks, the likelihood of malignancy would increase, increasing the yield of biopsy.

Lastly, consider false-negatives. A man with a PSA of 2.0 ng/mL would not have undergone biopsy in any of the trials, but if he had a history of several consecutive annual PSA levels less than 1.0 ng/mL, the doubling of his PSA during an interval less than or equal to 1 year could signal an early aggressive prostate cancer. Increases in PSA velocity can reveal the rapid proliferation of malignant prostate cells before the tumor is large enough to cross a static threshold PSA. We have zero data indicating how much benefit can be derived from the use of PSA velocity in this fashion. However, clinicians who carefully track serial PSA changes in each patient have anecdotes of success in early detection and cure of aggressive prostate cancers that would not have been detected by the trial protocols using fixed PSA thresholds. Until such trials are done, we can only tell patients that the ability to compute PSA velocity may be another source of benefit of annual screening of PSA.

To the Editor: In their article on men’s health,¹Chaitoff and colleagues present the scenario of a 60-year-old patient, with no other history given, whose recent screening prostate-specific antigen (PSA) level was 5.1 ng/mL, and who asks his doctor:

1. Should I have agreed to the screening?
2. How effective is the screening?
3. What are the next steps?

These questions are consistent with the patient having read the latest US Preventive Services Task Force (USPSTF) report on PSA screening, which states: “Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results…”²

I would tell the patient that he can expect greater benefit from PSA screening than reported by the USPSTF simply by adhering to the screening protocol. Intention-to-treat analysis applied to the trial results diminished the apparent benefits of PSA screening by counting fatal prostate cancers experienced by nonadherent study participants as screening failures.³ In other words, screening works better in those who actually get screened!

The authors state¹ that “in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it.” Nevertheless, prostate cancer remains the second most common cause of cancer deaths in American men, after lung cancer.⁴ In addition to the reduction in prostate cancer-specific mortality with screening, patients should consider the reduction in morbidity from painful bone metastases and pathologic fractures, which are common in advanced prostate cancer.

A false-positive elevated PSA can be caused by reversible benign conditions, such as prostate infection or trauma, which can resolve over time, returning the PSA to its baseline level. Studies have demonstrated that simply repeating the PSA test a few weeks later will significantly reduce the number of false-positive PSA screening tests.⁵

Also, it is not optimal to screen for prostate cancer using a single PSA measurement. This patient’s PSA of 5.1 ng/mL cannot distinguish between chronic benign prostatic hyperplasia and a fast-growing but still curable malignancy. If the patient’s PSA had been tested annually and was known to be stable at its current level, a benign or indolent condition would be most likely, allowing for the possibility of continuing noninvasive observation. If his PSA was 1.1 ng/mL a year ago, and his PSA remains elevated when retested in a few weeks, the likelihood of malignancy would increase, increasing the yield of biopsy.

Lastly, consider false-negatives. A man with a PSA of 2.0 ng/mL would not have undergone biopsy in any of the trials, but if he had a history of several consecutive annual PSA levels less than 1.0 ng/mL, the doubling of his PSA during an interval less than or equal to 1 year could signal an early aggressive prostate cancer. Increases in PSA velocity can reveal the rapid proliferation of malignant prostate cells before the tumor is large enough to cross a static threshold PSA. We have zero data indicating how much benefit can be derived from the use of PSA velocity in this fashion. However, clinicians who carefully track serial PSA changes in each patient have anecdotes of success in early detection and cure of aggressive prostate cancers that would not have been detected by the trial protocols using fixed PSA thresholds. Until such trials are done, we can only tell patients that the ability to compute PSA velocity may be another source of benefit of annual screening of PSA.

To the Editor: In their article on men’s health,¹Chaitoff and colleagues present the scenario of a 60-year-old patient, with no other history given, whose recent screening prostate-specific antigen (PSA) level was 5.1 ng/mL, and who asks his doctor:

1. Should I have agreed to the screening?
2. How effective is the screening?
3. What are the next steps?

These questions are consistent with the patient having read the latest US Preventive Services Task Force (USPSTF) report on PSA screening, which states: “Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results…”²

I would tell the patient that he can expect greater benefit from PSA screening than reported by the USPSTF simply by adhering to the screening protocol. Intention-to-treat analysis applied to the trial results diminished the apparent benefits of PSA screening by counting fatal prostate cancers experienced by nonadherent study participants as screening failures.³ In other words, screening works better in those who actually get screened!

The authors state¹ that “in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it.” Nevertheless, prostate cancer remains the second most common cause of cancer deaths in American men, after lung cancer.⁴ In addition to the reduction in prostate cancer-specific mortality with screening, patients should consider the reduction in morbidity from painful bone metastases and pathologic fractures, which are common in advanced prostate cancer.

A false-positive elevated PSA can be caused by reversible benign conditions, such as prostate infection or trauma, which can resolve over time, returning the PSA to its baseline level. Studies have demonstrated that simply repeating the PSA test a few weeks later will significantly reduce the number of false-positive PSA screening tests.⁵

Also, it is not optimal to screen for prostate cancer using a single PSA measurement. This patient’s PSA of 5.1 ng/mL cannot distinguish between chronic benign prostatic hyperplasia and a fast-growing but still curable malignancy. If the patient’s PSA had been tested annually and was known to be stable at its current level, a benign or indolent condition would be most likely, allowing for the possibility of continuing noninvasive observation. If his PSA was 1.1 ng/mL a year ago, and his PSA remains elevated when retested in a few weeks, the likelihood of malignancy would increase, increasing the yield of biopsy.

Lastly, consider false-negatives. A man with a PSA of 2.0 ng/mL would not have undergone biopsy in any of the trials, but if he had a history of several consecutive annual PSA levels less than 1.0 ng/mL, the doubling of his PSA during an interval less than or equal to 1 year could signal an early aggressive prostate cancer. Increases in PSA velocity can reveal the rapid proliferation of malignant prostate cells before the tumor is large enough to cross a static threshold PSA. We have zero data indicating how much benefit can be derived from the use of PSA velocity in this fashion. However, clinicians who carefully track serial PSA changes in each patient have anecdotes of success in early detection and cure of aggressive prostate cancers that would not have been detected by the trial protocols using fixed PSA thresholds. Until such trials are done, we can only tell patients that the ability to compute PSA velocity may be another source of benefit of annual screening of PSA.

In the article by Chaitoff et al (Men’s health 2018: BPH, prostate cancer, erectile dysfunction, supplements. Cleve Clin J Med 2018; 85(11):871–880, doi:10.3949/ccjm.85a.18011), the prostate-specific antigen level of a 60-year-old man was given as 5.1 mg/dL. The unit of measure should have been 5.1 ng/mL. This has been corrected online.

In the article by Chaitoff et al (Men’s health 2018: BPH, prostate cancer, erectile dysfunction, supplements. Cleve Clin J Med 2018; 85(11):871–880, doi:10.3949/ccjm.85a.18011), the prostate-specific antigen level of a 60-year-old man was given as 5.1 mg/dL. The unit of measure should have been 5.1 ng/mL. This has been corrected online.

In the article by Chaitoff et al (Men’s health 2018: BPH, prostate cancer, erectile dysfunction, supplements. Cleve Clin J Med 2018; 85(11):871–880, doi:10.3949/ccjm.85a.18011), the prostate-specific antigen level of a 60-year-old man was given as 5.1 mg/dL. The unit of measure should have been 5.1 ng/mL. This has been corrected online.

Testosterone treatment has potential as an adjunct therapy for men with depressive disorders, a meta-analysis has suggested. However, more research is needed.

“This meta-analysis provides important new evidence that testosterone treatment may also be effective and efficacious for eugonadal and older men when higher testosterone dosages are administered,” Andreas Walther, PhD, and his coauthors wrote Nov. 14 in JAMA Psychiatry. However, they noted that safety monitoring in testosterone treatment trials remained important because of an absence of sufficiently powered, long-term studies to assess the increased risk of adverse events with treatment.

The link between testosterone and depression has been debated extensively because testosterone is a neuroactive steroid hormone known to influence mood and appetitive behavior, Dr. Walther and his coauthors wrote. Although testosterone treatment for various disorders in hypogonadal men has been backed by evidence, the results of randomized, placebo-controlled clinical trials for its use in depression have been inconsistent. Indeed, testosterone treatment was currently not recommended in national or international guidelines because of an “prevailing uncertainty about its efficacy, age criteria, dosage, ideal duration and method of application,” wrote Dr. Walther, of the department of biological psychology at Technische Universität Dresden (Germany).

For the current review, the researchers identified 27 randomized, controlled trials altogether including 1,890 men who were receiving testosterone treatment and had reported depressive symptoms on validated depression scales.

Results showed evidence for a moderate antidepressant association of testosterone treatment, compared with placebo (Hedges g, 0.21; 95% confidence interval, 0.10-0.32), and an efficacy odds ratio of 2.30 (95% CI, 1.30-4.06). According to the researchers, based on reference ranges for depressive symptoms, the effect translated into a clinically relevant symptom reduction of 2.2 points on the Beck Depression Inventory II. “The National Institute for Health and Care Excellence guidelines on depression suggest a reduction of 3.0 and 2.0 points on BDI scores to be clinically significant for normal depression and treatment-resistant depression, respectively,” they wrote.

Testosterone treatment also showed an efficacy OR of 2.30, a finding that the authors said suggested the “potential of testosterone treatment as adjunct therapy for men with depressive disorders.”

They said the results suggested that better treatment response might require higher doses but acknowledged that the finding required replication.

In addition, Dr. Walther and his coauthors found acceptability of testosterone treatment was high, with an OR of 0.79 for testosterone treatment–related loss to follow-up, compared with placebo. Remarkably, they added, initial testosterone status did not moderate the effects of testosterone treatment on depressive symptoms.

“Large, preregistered RCTs of good quality investigating testosterone treatment’s effect in men on depression as the primary outcome” are needed, they concluded.

Dr. Walther and his coauthors cited a few limitations, including the low number of randomized, controlled trials addressing the effects of testosterone treatment in men who were depressed but otherwise healthy.

No conflicts of interest were reported.
 

SOURCE: Walther A et al. JAMA Psychiatry. 2018 14 Nov. doi: 10.1001/jamapsychiatry.2018.2734.

Testosterone treatment has potential as an adjunct therapy for men with depressive disorders, a meta-analysis has suggested. However, more research is needed.

“This meta-analysis provides important new evidence that testosterone treatment may also be effective and efficacious for eugonadal and older men when higher testosterone dosages are administered,” Andreas Walther, PhD, and his coauthors wrote Nov. 14 in JAMA Psychiatry. However, they noted that safety monitoring in testosterone treatment trials remained important because of an absence of sufficiently powered, long-term studies to assess the increased risk of adverse events with treatment.

The link between testosterone and depression has been debated extensively because testosterone is a neuroactive steroid hormone known to influence mood and appetitive behavior, Dr. Walther and his coauthors wrote. Although testosterone treatment for various disorders in hypogonadal men has been backed by evidence, the results of randomized, placebo-controlled clinical trials for its use in depression have been inconsistent. Indeed, testosterone treatment was currently not recommended in national or international guidelines because of an “prevailing uncertainty about its efficacy, age criteria, dosage, ideal duration and method of application,” wrote Dr. Walther, of the department of biological psychology at Technische Universität Dresden (Germany).

For the current review, the researchers identified 27 randomized, controlled trials altogether including 1,890 men who were receiving testosterone treatment and had reported depressive symptoms on validated depression scales.

Results showed evidence for a moderate antidepressant association of testosterone treatment, compared with placebo (Hedges g, 0.21; 95% confidence interval, 0.10-0.32), and an efficacy odds ratio of 2.30 (95% CI, 1.30-4.06). According to the researchers, based on reference ranges for depressive symptoms, the effect translated into a clinically relevant symptom reduction of 2.2 points on the Beck Depression Inventory II. “The National Institute for Health and Care Excellence guidelines on depression suggest a reduction of 3.0 and 2.0 points on BDI scores to be clinically significant for normal depression and treatment-resistant depression, respectively,” they wrote.

Testosterone treatment also showed an efficacy OR of 2.30, a finding that the authors said suggested the “potential of testosterone treatment as adjunct therapy for men with depressive disorders.”

They said the results suggested that better treatment response might require higher doses but acknowledged that the finding required replication.

In addition, Dr. Walther and his coauthors found acceptability of testosterone treatment was high, with an OR of 0.79 for testosterone treatment–related loss to follow-up, compared with placebo. Remarkably, they added, initial testosterone status did not moderate the effects of testosterone treatment on depressive symptoms.

“Large, preregistered RCTs of good quality investigating testosterone treatment’s effect in men on depression as the primary outcome” are needed, they concluded.

Dr. Walther and his coauthors cited a few limitations, including the low number of randomized, controlled trials addressing the effects of testosterone treatment in men who were depressed but otherwise healthy.

No conflicts of interest were reported.
 

SOURCE: Walther A et al. JAMA Psychiatry. 2018 14 Nov. doi: 10.1001/jamapsychiatry.2018.2734.

Testosterone treatment has potential as an adjunct therapy for men with depressive disorders, a meta-analysis has suggested. However, more research is needed.

“This meta-analysis provides important new evidence that testosterone treatment may also be effective and efficacious for eugonadal and older men when higher testosterone dosages are administered,” Andreas Walther, PhD, and his coauthors wrote Nov. 14 in JAMA Psychiatry. However, they noted that safety monitoring in testosterone treatment trials remained important because of an absence of sufficiently powered, long-term studies to assess the increased risk of adverse events with treatment.

The link between testosterone and depression has been debated extensively because testosterone is a neuroactive steroid hormone known to influence mood and appetitive behavior, Dr. Walther and his coauthors wrote. Although testosterone treatment for various disorders in hypogonadal men has been backed by evidence, the results of randomized, placebo-controlled clinical trials for its use in depression have been inconsistent. Indeed, testosterone treatment was currently not recommended in national or international guidelines because of an “prevailing uncertainty about its efficacy, age criteria, dosage, ideal duration and method of application,” wrote Dr. Walther, of the department of biological psychology at Technische Universität Dresden (Germany).

For the current review, the researchers identified 27 randomized, controlled trials altogether including 1,890 men who were receiving testosterone treatment and had reported depressive symptoms on validated depression scales.

Results showed evidence for a moderate antidepressant association of testosterone treatment, compared with placebo (Hedges g, 0.21; 95% confidence interval, 0.10-0.32), and an efficacy odds ratio of 2.30 (95% CI, 1.30-4.06). According to the researchers, based on reference ranges for depressive symptoms, the effect translated into a clinically relevant symptom reduction of 2.2 points on the Beck Depression Inventory II. “The National Institute for Health and Care Excellence guidelines on depression suggest a reduction of 3.0 and 2.0 points on BDI scores to be clinically significant for normal depression and treatment-resistant depression, respectively,” they wrote.

Testosterone treatment also showed an efficacy OR of 2.30, a finding that the authors said suggested the “potential of testosterone treatment as adjunct therapy for men with depressive disorders.”

They said the results suggested that better treatment response might require higher doses but acknowledged that the finding required replication.

In addition, Dr. Walther and his coauthors found acceptability of testosterone treatment was high, with an OR of 0.79 for testosterone treatment–related loss to follow-up, compared with placebo. Remarkably, they added, initial testosterone status did not moderate the effects of testosterone treatment on depressive symptoms.

“Large, preregistered RCTs of good quality investigating testosterone treatment’s effect in men on depression as the primary outcome” are needed, they concluded.

Dr. Walther and his coauthors cited a few limitations, including the low number of randomized, controlled trials addressing the effects of testosterone treatment in men who were depressed but otherwise healthy.

No conflicts of interest were reported.
 

SOURCE: Walther A et al. JAMA Psychiatry. 2018 14 Nov. doi: 10.1001/jamapsychiatry.2018.2734.

This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission, and treatment.

EPIDEMIOLOGY

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.²

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.² The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.²

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.³ Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.⁴

Influenza C exists but is rare

Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.⁵ Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains?

While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.⁶ With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza

Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.⁷

Influenza a cardiovascular risk factor

Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epi­demiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.^8,9

Which strain is the biggest threat?

Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.¹⁰

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.¹¹

TRANSMISSION

Humidity may not block transmission

Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.¹²

One sick passenger may not infect the whole plane

Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.¹³

WHAT’S IN THE NEW FLU SHOT?

The 2018–2019 quadrivalent vaccine for the Northern Hemisphere¹⁴ contains the following strains:

• A/Michigan/45/2015 A(H1N1)pdm09-like virus
• A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
• B/Colorado/06/2017-like virus (Victoria lineage)
• B/Phuket/3073/2013-like virus (Yamagata lineage).

The A(H3N2) (Singapore) and B/Victoria lineage components are new this year. The A(H3N2) strain was the main cause of the 2018 influenza epidemic in the Southern Hemisphere.

The quadrivalent live-attenuated vaccine, which was not recommended during the 2016–2017 and 2017–2018 influenza seasons, has made a comeback and is recommended for the 2018–2019 season in people for whom it is appropriate based on age and comorbidities.¹⁵ Although it was effective against influenza B and A(H3N2) viruses, it was less effective against the influenza A(H1N1)pdm09-like viruses during the 2013–2014 and 2015–2016 seasons.

A/Slovenia/2903/2015, the new A(H1N1)pdm09-like virus included in the 2018–2019 quadrivalent live-attenuated vaccine, is significantly more immunogenic than its predecessor, A/Bolivia/559/2013, but its clinical effectiveness remains to be seen.

How effective is it?

Influenza vaccine effectiveness in the 2017–2018 influenza season was 36% overall, 67% against A(H1N1), 42% against influenza B, and 25% against A(H3N2).¹⁶ It is estimated that influenza vaccine prevents 300 to 4,000 deaths annually in the United States alone.¹⁷

A 2018 Cochrane review¹⁷ concluded that vaccination reduced the incidence of influenza by about half, with 2.3% of the population contracting the flu without vaccination compared with 0.9% with vaccination (risk ratio 0.41, 95% confidence interval 0.36–0.47). The same review found that 71 healthy adults need to be vaccinated to prevent 1 from experiencing influenza, and 29 to prevent 1 influenza-like illness.

Several recent studies showed that influenza vaccine effectiveness varied based on age and influenza serotype, with higher effectiveness in people ages 5 to 17 and ages 18 to 64 than in those age 65 and older.^18–20 A mathematical model of influenza transmission and vaccination in the United States determined that even relatively low-efficacy influenza vaccines can be very useful if optimally distributed across age groups.²¹

Vaccination rates are low, and ‘antivaxxers’ are on the rise

Although the influenza vaccine is recommended in the United States for all people age 6 months and older regardless of the state of their health, vaccination rates remain low. In 2016, only 37% of employed adults were vaccinated. The highest rate was for government employees (45%), followed by private employees (36%), followed by the self-employed (30%).²²

A national goal is to immunize 80% of all Americans and 90% of at-risk populations (which include children and the elderly).²³ The number of US hospitals that require their employees to be vaccinated increased from 37.1% in 2013 to 61.4% in 2017.²⁴ Regrettably, as of March 2018, 14 lawsuits addressing religious objections to hospital influenza vaccination mandates have been filed.²⁵

Despite hundreds of studies demonstrating the efficacy, safety, and cost savings of influenza vaccination, the antivaccine movement has been growing in the United States and worldwide.²⁶ All US states except West Virginia, Mississippi, and California allow nonmedical exemptions from vaccination based on religious or personal belief.²⁷ Several US metropolitan areas represent “hot spots” for these exemptions.²⁸ This may render such areas vulnerable to vaccine-preventable diseases, including influenza.

Herd immunity: We’re all in this together

Some argue that the potential adverse effects and the cost of vaccination outweigh the benefits, but the protective benefits of herd immunity are significant for those with comorbidities or compromised immunity.

Educating the public about herd immunity and local influenza vaccination uptake increases people’s willingness to be vaccinated.²⁹ A key educational point is that at least 70% of a community needs to be vaccinated to prevent community outbreaks; this protects everyone, including those who do not mount a protective antibody response to influenza vaccination and those who are not vaccinated.

DOES ANNUAL VACCINATION BLUNT ITS EFFECTIVENESS?

Some studies from the 1970s and 1980s raised concern over a possible negative effect of annual influenza vaccination on vaccine effectiveness. The “antigenic distance hypothesis” holds that vaccine effectiveness is influenced by antigenic similarity between the previous season’s vaccine serotypes and the epidemic serotypes, as well as the antigenic similarity between the serotypes of the current and previous seasons.

A meta-analysis of studies from 2010 through 2015 showed significant inconsistencies in repeat vaccination effects within and between seasons and serotypes. It also showed that vaccine effectiveness may be influenced by more than 1 previous season, particularly for influenza A(H3N2), in which repeated vaccination can blunt the hemagglutinin antibody response.³⁰

A study from Japan showed that people who needed medical attention for influenza in the previous season were at lower risk of a similar event in the current season.³¹ Prior-season influenza vaccination reduced current-season vaccine effectiveness only in those who did not have medically attended influenza in the prior season. This suggests that infection is more immunogenic than vaccination, but only against the serotype causing the infection and not the other serotypes included in the vaccine.

An Australian study showed that annual influenza vaccination did not decrease vaccine effectiveness against influenza-associated hospitalization. Rather, effectiveness increased by about 15% in those vaccinated in both current and previous seasons compared with those vaccinated in either season alone.³²

European investigators showed that repeated seasonal influenza vaccination in the elderly prevented the need for hospitalization due to influenza A(H3N2) and B, but not A(H1N1)pdm09.³³

High-dose vaccine for older adults

The high-dose influenza vaccine has been licensed since 2009 for use in the United States for people ages 65 and older.

Recent studies confirmed that high-dose vaccine is more effective than standard-dose vaccine in veterans³⁴ and US Medicare beneficiaries.³⁵

The high-dose vaccine is rapidly becoming the primary vaccine given to people ages 65 and older in retail pharmacies, where vaccination begins earlier in the season than in providers’ offices.³⁶ Some studies have shown that the standard-dose vaccine wanes in effectiveness toward the end of the influenza season (particularly if the season is long) if it is given very early. It remains to be seen whether the same applies to the high-dose influenza vaccine.

Some advocate twice-annual influenza vaccination, particularly for older adults living in tropical and subtropical areas, where influenza seasons are more prolonged. However, a recently published study observed reductions in influenza-specific hemagglutination inhibition and cell-mediated immunity after twice-annual vaccination.³⁷

Vaccination is beneficial during pregnancy

Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants.

One recently published study showed that 18% of infants who developed influenza required hospitalization.³⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively.

Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.³⁹

Some studies have shown that influenza virus infection can increase susceptibility to certain bacterial infections. A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.⁴⁰

Factors that make vaccination less effective

Several factors including age-related frailty and iatrogenic and disease-related immunosuppression can affect vaccine effectiveness.

Frailty. A recent study showed that vaccine effectiveness was 77.6% in nonfrail older adults but only 58.7% in frail older adults.⁴¹

Immunosuppression. Temporary discontinuation of methotrexate for 2 weeks after influenza vaccination in patients with rheumatoid arthritis improves vaccine immunogenicity without precipitating disease flare.⁴² Solid-organ and hematopoietic stem cell transplant recipients who received influenza vaccine were less likely to develop pneumonia and require intensive care unit admission.⁴³

The high-dose influenza vaccine is more immunogenic than the standard-dose vaccine in solid-organ transplant recipients.⁴⁴

Statins are widely prescribed and have recently been associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness, but their benefits in preventing cardiovascular events outweigh this risk.⁴⁵

FUTURE VACCINE CONSIDERATIONS

Moving away from eggs

During the annual egg-based production process, which takes several months, the influenza vaccine acquires antigenic changes that allow replication in eggs, particularly in the hemagglutinin protein, which mediates receptor binding. This process of egg adaptation may cause antigenic changes that decrease vaccine effectiveness against circulating viruses.

The cell-based baculovirus influenza vaccine grown in dog kidney cells has higher antigenic content and is not subject to the limitations of egg-based vaccine, although it still requires annual updates. A recombinant influenza vaccine reduces the probability of influenza-like illness by 30% compared with the egg-based influenza vaccine, but also still requires annual updates.⁴⁶ The market share of these non-egg-based vaccines is small, and thus their effectiveness has yet to be demonstrated.

The US Department of Defense administered the cell-based influenza vaccine to about one-third of Armed Forces personnel, their families, and retirees in the 2017–2018 influenza seasons, and data on its effectiveness are expected in the near future.⁴⁷

A universal vaccine would be ideal

The quest continues for a universal influenza vaccine, one that remains protective for several years and does not require annual updates.⁴⁸ Such a vaccine would protect against seasonal epidemic influenza drift variants and pandemic strains. More people could likely be persuaded to be vaccinated once rather than every year.

David Schumick, medical illustrator; adapted from reference 49; illustration of the influenza hemagglutinin created in part with data from reference 50.

An ideal universal vaccine would be suitable for all age groups, at least 75% effective against symptomatic influenza virus infection, protective against all influenza A viruses (influenza A, not B, causes pandemics and seasonal epidemics), and durable through multiple influenza seasons.⁵¹

Research and production of such a vaccine are expected to require funding of about $1 billion over the next 5 years.

Boosting effectiveness

Estimates of influenza vaccine effectiveness range from 40% to 60% in years when the vaccine viruses closely match the circulating viruses, and variably lower when they do not match. The efficacy of most other vaccines given to prevent other infections is much higher.

New technologies to improve influenza vaccine effectiveness are needed, particularly for influenza A(H3N2) viruses, which are rapidly evolving and are highly susceptible to egg-adaptive mutations in the manufacturing process.

In one study, a nanoparticle vaccine formulated with a saponin-based adjuvant induced hemagglutination inhibition responses that were even greater than those induced by the high-dose vaccine.⁵²

Immunoglobulin A (IgA) may be a more effective vaccine target than traditional influenza vaccines that target IgG, since different parts of IgA may engage the influenza virus simultaneously.⁵³

Vaccines can be developed more quickly than in the past. The timeline from viral sequencing to human studies with deoxyribonucleic acid plasmid vaccines decreased from 20 months in 2003 for the severe acquired respiratory syndrome coronavirus to 11 months in 2006 for influenza A/Indonesia/2006 (H5), to 4 months in 2009 for influenza A/California/2009 (H1), to 3.5 months in 2016 for Zika virus.⁵⁴ This is because it is possible today to sequence a virus and insert the genetic material into a vaccine platform without ever having to grow the virus.

Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.⁵⁵ Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza.⁵⁵

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.⁵⁶ Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients⁵⁷ and with a lower risk of otitis media in children.⁵⁸

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.⁵⁹

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.⁶⁰

Baloxavir marboxil

Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits cap-dependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.⁶¹

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation, and similar side effects.⁶² Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

CLOSING THE GAPS

Several gaps in the management of influenza persist since the 1918 pandemic.¹ These include gaps in epidemiology, prevention, diagnosis, treatment, and prognosis.

• Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
• Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
• Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
• Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
• In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread. In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
• A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.⁶³
• Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.

This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission, and treatment.

EPIDEMIOLOGY

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.²

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.² The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.²

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.³ Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.⁴

Influenza C exists but is rare

Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.⁵ Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains?

While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.⁶ With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza

Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.⁷

Influenza a cardiovascular risk factor

Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epi­demiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.^8,9

Which strain is the biggest threat?

Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.¹⁰

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.¹¹

TRANSMISSION

Humidity may not block transmission

Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.¹²

One sick passenger may not infect the whole plane

Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.¹³

WHAT’S IN THE NEW FLU SHOT?

The 2018–2019 quadrivalent vaccine for the Northern Hemisphere¹⁴ contains the following strains:

• A/Michigan/45/2015 A(H1N1)pdm09-like virus
• A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
• B/Colorado/06/2017-like virus (Victoria lineage)
• B/Phuket/3073/2013-like virus (Yamagata lineage).

The A(H3N2) (Singapore) and B/Victoria lineage components are new this year. The A(H3N2) strain was the main cause of the 2018 influenza epidemic in the Southern Hemisphere.

The quadrivalent live-attenuated vaccine, which was not recommended during the 2016–2017 and 2017–2018 influenza seasons, has made a comeback and is recommended for the 2018–2019 season in people for whom it is appropriate based on age and comorbidities.¹⁵ Although it was effective against influenza B and A(H3N2) viruses, it was less effective against the influenza A(H1N1)pdm09-like viruses during the 2013–2014 and 2015–2016 seasons.

A/Slovenia/2903/2015, the new A(H1N1)pdm09-like virus included in the 2018–2019 quadrivalent live-attenuated vaccine, is significantly more immunogenic than its predecessor, A/Bolivia/559/2013, but its clinical effectiveness remains to be seen.

How effective is it?

Influenza vaccine effectiveness in the 2017–2018 influenza season was 36% overall, 67% against A(H1N1), 42% against influenza B, and 25% against A(H3N2).¹⁶ It is estimated that influenza vaccine prevents 300 to 4,000 deaths annually in the United States alone.¹⁷

A 2018 Cochrane review¹⁷ concluded that vaccination reduced the incidence of influenza by about half, with 2.3% of the population contracting the flu without vaccination compared with 0.9% with vaccination (risk ratio 0.41, 95% confidence interval 0.36–0.47). The same review found that 71 healthy adults need to be vaccinated to prevent 1 from experiencing influenza, and 29 to prevent 1 influenza-like illness.

Several recent studies showed that influenza vaccine effectiveness varied based on age and influenza serotype, with higher effectiveness in people ages 5 to 17 and ages 18 to 64 than in those age 65 and older.^18–20 A mathematical model of influenza transmission and vaccination in the United States determined that even relatively low-efficacy influenza vaccines can be very useful if optimally distributed across age groups.²¹

Vaccination rates are low, and ‘antivaxxers’ are on the rise

Although the influenza vaccine is recommended in the United States for all people age 6 months and older regardless of the state of their health, vaccination rates remain low. In 2016, only 37% of employed adults were vaccinated. The highest rate was for government employees (45%), followed by private employees (36%), followed by the self-employed (30%).²²

A national goal is to immunize 80% of all Americans and 90% of at-risk populations (which include children and the elderly).²³ The number of US hospitals that require their employees to be vaccinated increased from 37.1% in 2013 to 61.4% in 2017.²⁴ Regrettably, as of March 2018, 14 lawsuits addressing religious objections to hospital influenza vaccination mandates have been filed.²⁵

Despite hundreds of studies demonstrating the efficacy, safety, and cost savings of influenza vaccination, the antivaccine movement has been growing in the United States and worldwide.²⁶ All US states except West Virginia, Mississippi, and California allow nonmedical exemptions from vaccination based on religious or personal belief.²⁷ Several US metropolitan areas represent “hot spots” for these exemptions.²⁸ This may render such areas vulnerable to vaccine-preventable diseases, including influenza.

Herd immunity: We’re all in this together

Some argue that the potential adverse effects and the cost of vaccination outweigh the benefits, but the protective benefits of herd immunity are significant for those with comorbidities or compromised immunity.

Educating the public about herd immunity and local influenza vaccination uptake increases people’s willingness to be vaccinated.²⁹ A key educational point is that at least 70% of a community needs to be vaccinated to prevent community outbreaks; this protects everyone, including those who do not mount a protective antibody response to influenza vaccination and those who are not vaccinated.

DOES ANNUAL VACCINATION BLUNT ITS EFFECTIVENESS?

Some studies from the 1970s and 1980s raised concern over a possible negative effect of annual influenza vaccination on vaccine effectiveness. The “antigenic distance hypothesis” holds that vaccine effectiveness is influenced by antigenic similarity between the previous season’s vaccine serotypes and the epidemic serotypes, as well as the antigenic similarity between the serotypes of the current and previous seasons.

A meta-analysis of studies from 2010 through 2015 showed significant inconsistencies in repeat vaccination effects within and between seasons and serotypes. It also showed that vaccine effectiveness may be influenced by more than 1 previous season, particularly for influenza A(H3N2), in which repeated vaccination can blunt the hemagglutinin antibody response.³⁰

A study from Japan showed that people who needed medical attention for influenza in the previous season were at lower risk of a similar event in the current season.³¹ Prior-season influenza vaccination reduced current-season vaccine effectiveness only in those who did not have medically attended influenza in the prior season. This suggests that infection is more immunogenic than vaccination, but only against the serotype causing the infection and not the other serotypes included in the vaccine.

An Australian study showed that annual influenza vaccination did not decrease vaccine effectiveness against influenza-associated hospitalization. Rather, effectiveness increased by about 15% in those vaccinated in both current and previous seasons compared with those vaccinated in either season alone.³²

European investigators showed that repeated seasonal influenza vaccination in the elderly prevented the need for hospitalization due to influenza A(H3N2) and B, but not A(H1N1)pdm09.³³

High-dose vaccine for older adults

The high-dose influenza vaccine has been licensed since 2009 for use in the United States for people ages 65 and older.

Recent studies confirmed that high-dose vaccine is more effective than standard-dose vaccine in veterans³⁴ and US Medicare beneficiaries.³⁵

The high-dose vaccine is rapidly becoming the primary vaccine given to people ages 65 and older in retail pharmacies, where vaccination begins earlier in the season than in providers’ offices.³⁶ Some studies have shown that the standard-dose vaccine wanes in effectiveness toward the end of the influenza season (particularly if the season is long) if it is given very early. It remains to be seen whether the same applies to the high-dose influenza vaccine.

Some advocate twice-annual influenza vaccination, particularly for older adults living in tropical and subtropical areas, where influenza seasons are more prolonged. However, a recently published study observed reductions in influenza-specific hemagglutination inhibition and cell-mediated immunity after twice-annual vaccination.³⁷

Vaccination is beneficial during pregnancy

Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants.

One recently published study showed that 18% of infants who developed influenza required hospitalization.³⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively.

Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.³⁹

Some studies have shown that influenza virus infection can increase susceptibility to certain bacterial infections. A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.⁴⁰

Factors that make vaccination less effective

Several factors including age-related frailty and iatrogenic and disease-related immunosuppression can affect vaccine effectiveness.

Frailty. A recent study showed that vaccine effectiveness was 77.6% in nonfrail older adults but only 58.7% in frail older adults.⁴¹

Immunosuppression. Temporary discontinuation of methotrexate for 2 weeks after influenza vaccination in patients with rheumatoid arthritis improves vaccine immunogenicity without precipitating disease flare.⁴² Solid-organ and hematopoietic stem cell transplant recipients who received influenza vaccine were less likely to develop pneumonia and require intensive care unit admission.⁴³

The high-dose influenza vaccine is more immunogenic than the standard-dose vaccine in solid-organ transplant recipients.⁴⁴

Statins are widely prescribed and have recently been associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness, but their benefits in preventing cardiovascular events outweigh this risk.⁴⁵

FUTURE VACCINE CONSIDERATIONS

Moving away from eggs

During the annual egg-based production process, which takes several months, the influenza vaccine acquires antigenic changes that allow replication in eggs, particularly in the hemagglutinin protein, which mediates receptor binding. This process of egg adaptation may cause antigenic changes that decrease vaccine effectiveness against circulating viruses.

The cell-based baculovirus influenza vaccine grown in dog kidney cells has higher antigenic content and is not subject to the limitations of egg-based vaccine, although it still requires annual updates. A recombinant influenza vaccine reduces the probability of influenza-like illness by 30% compared with the egg-based influenza vaccine, but also still requires annual updates.⁴⁶ The market share of these non-egg-based vaccines is small, and thus their effectiveness has yet to be demonstrated.

The US Department of Defense administered the cell-based influenza vaccine to about one-third of Armed Forces personnel, their families, and retirees in the 2017–2018 influenza seasons, and data on its effectiveness are expected in the near future.⁴⁷

A universal vaccine would be ideal

The quest continues for a universal influenza vaccine, one that remains protective for several years and does not require annual updates.⁴⁸ Such a vaccine would protect against seasonal epidemic influenza drift variants and pandemic strains. More people could likely be persuaded to be vaccinated once rather than every year.

David Schumick, medical illustrator; adapted from reference 49; illustration of the influenza hemagglutinin created in part with data from reference 50.

An ideal universal vaccine would be suitable for all age groups, at least 75% effective against symptomatic influenza virus infection, protective against all influenza A viruses (influenza A, not B, causes pandemics and seasonal epidemics), and durable through multiple influenza seasons.⁵¹

Research and production of such a vaccine are expected to require funding of about $1 billion over the next 5 years.

Boosting effectiveness

Estimates of influenza vaccine effectiveness range from 40% to 60% in years when the vaccine viruses closely match the circulating viruses, and variably lower when they do not match. The efficacy of most other vaccines given to prevent other infections is much higher.

New technologies to improve influenza vaccine effectiveness are needed, particularly for influenza A(H3N2) viruses, which are rapidly evolving and are highly susceptible to egg-adaptive mutations in the manufacturing process.

In one study, a nanoparticle vaccine formulated with a saponin-based adjuvant induced hemagglutination inhibition responses that were even greater than those induced by the high-dose vaccine.⁵²

Immunoglobulin A (IgA) may be a more effective vaccine target than traditional influenza vaccines that target IgG, since different parts of IgA may engage the influenza virus simultaneously.⁵³

Vaccines can be developed more quickly than in the past. The timeline from viral sequencing to human studies with deoxyribonucleic acid plasmid vaccines decreased from 20 months in 2003 for the severe acquired respiratory syndrome coronavirus to 11 months in 2006 for influenza A/Indonesia/2006 (H5), to 4 months in 2009 for influenza A/California/2009 (H1), to 3.5 months in 2016 for Zika virus.⁵⁴ This is because it is possible today to sequence a virus and insert the genetic material into a vaccine platform without ever having to grow the virus.

Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.⁵⁵ Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza.⁵⁵

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.⁵⁶ Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients⁵⁷ and with a lower risk of otitis media in children.⁵⁸

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.⁵⁹

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.⁶⁰

Baloxavir marboxil

Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits cap-dependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.⁶¹

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation, and similar side effects.⁶² Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

CLOSING THE GAPS

Several gaps in the management of influenza persist since the 1918 pandemic.¹ These include gaps in epidemiology, prevention, diagnosis, treatment, and prognosis.

• Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
• Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
• Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
• Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
• In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread. In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
• A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.⁶³
• Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.

This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission, and treatment.

EPIDEMIOLOGY

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.²

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.² The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.²

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.³ Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.⁴

Influenza C exists but is rare

Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.⁵ Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains?

While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.⁶ With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza

Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.⁷

Influenza a cardiovascular risk factor

Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epi­demiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.^8,9

Which strain is the biggest threat?

Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.¹⁰

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.¹¹

TRANSMISSION

Humidity may not block transmission

Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.¹²

One sick passenger may not infect the whole plane

Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.¹³

WHAT’S IN THE NEW FLU SHOT?

The 2018–2019 quadrivalent vaccine for the Northern Hemisphere¹⁴ contains the following strains:

• A/Michigan/45/2015 A(H1N1)pdm09-like virus
• A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
• B/Colorado/06/2017-like virus (Victoria lineage)
• B/Phuket/3073/2013-like virus (Yamagata lineage).

The A(H3N2) (Singapore) and B/Victoria lineage components are new this year. The A(H3N2) strain was the main cause of the 2018 influenza epidemic in the Southern Hemisphere.

The quadrivalent live-attenuated vaccine, which was not recommended during the 2016–2017 and 2017–2018 influenza seasons, has made a comeback and is recommended for the 2018–2019 season in people for whom it is appropriate based on age and comorbidities.¹⁵ Although it was effective against influenza B and A(H3N2) viruses, it was less effective against the influenza A(H1N1)pdm09-like viruses during the 2013–2014 and 2015–2016 seasons.

A/Slovenia/2903/2015, the new A(H1N1)pdm09-like virus included in the 2018–2019 quadrivalent live-attenuated vaccine, is significantly more immunogenic than its predecessor, A/Bolivia/559/2013, but its clinical effectiveness remains to be seen.

How effective is it?

Influenza vaccine effectiveness in the 2017–2018 influenza season was 36% overall, 67% against A(H1N1), 42% against influenza B, and 25% against A(H3N2).¹⁶ It is estimated that influenza vaccine prevents 300 to 4,000 deaths annually in the United States alone.¹⁷

A 2018 Cochrane review¹⁷ concluded that vaccination reduced the incidence of influenza by about half, with 2.3% of the population contracting the flu without vaccination compared with 0.9% with vaccination (risk ratio 0.41, 95% confidence interval 0.36–0.47). The same review found that 71 healthy adults need to be vaccinated to prevent 1 from experiencing influenza, and 29 to prevent 1 influenza-like illness.

Several recent studies showed that influenza vaccine effectiveness varied based on age and influenza serotype, with higher effectiveness in people ages 5 to 17 and ages 18 to 64 than in those age 65 and older.^18–20 A mathematical model of influenza transmission and vaccination in the United States determined that even relatively low-efficacy influenza vaccines can be very useful if optimally distributed across age groups.²¹

Vaccination rates are low, and ‘antivaxxers’ are on the rise

Although the influenza vaccine is recommended in the United States for all people age 6 months and older regardless of the state of their health, vaccination rates remain low. In 2016, only 37% of employed adults were vaccinated. The highest rate was for government employees (45%), followed by private employees (36%), followed by the self-employed (30%).²²

A national goal is to immunize 80% of all Americans and 90% of at-risk populations (which include children and the elderly).²³ The number of US hospitals that require their employees to be vaccinated increased from 37.1% in 2013 to 61.4% in 2017.²⁴ Regrettably, as of March 2018, 14 lawsuits addressing religious objections to hospital influenza vaccination mandates have been filed.²⁵

Despite hundreds of studies demonstrating the efficacy, safety, and cost savings of influenza vaccination, the antivaccine movement has been growing in the United States and worldwide.²⁶ All US states except West Virginia, Mississippi, and California allow nonmedical exemptions from vaccination based on religious or personal belief.²⁷ Several US metropolitan areas represent “hot spots” for these exemptions.²⁸ This may render such areas vulnerable to vaccine-preventable diseases, including influenza.

Herd immunity: We’re all in this together

Some argue that the potential adverse effects and the cost of vaccination outweigh the benefits, but the protective benefits of herd immunity are significant for those with comorbidities or compromised immunity.

Educating the public about herd immunity and local influenza vaccination uptake increases people’s willingness to be vaccinated.²⁹ A key educational point is that at least 70% of a community needs to be vaccinated to prevent community outbreaks; this protects everyone, including those who do not mount a protective antibody response to influenza vaccination and those who are not vaccinated.

DOES ANNUAL VACCINATION BLUNT ITS EFFECTIVENESS?

Some studies from the 1970s and 1980s raised concern over a possible negative effect of annual influenza vaccination on vaccine effectiveness. The “antigenic distance hypothesis” holds that vaccine effectiveness is influenced by antigenic similarity between the previous season’s vaccine serotypes and the epidemic serotypes, as well as the antigenic similarity between the serotypes of the current and previous seasons.

A meta-analysis of studies from 2010 through 2015 showed significant inconsistencies in repeat vaccination effects within and between seasons and serotypes. It also showed that vaccine effectiveness may be influenced by more than 1 previous season, particularly for influenza A(H3N2), in which repeated vaccination can blunt the hemagglutinin antibody response.³⁰

A study from Japan showed that people who needed medical attention for influenza in the previous season were at lower risk of a similar event in the current season.³¹ Prior-season influenza vaccination reduced current-season vaccine effectiveness only in those who did not have medically attended influenza in the prior season. This suggests that infection is more immunogenic than vaccination, but only against the serotype causing the infection and not the other serotypes included in the vaccine.

An Australian study showed that annual influenza vaccination did not decrease vaccine effectiveness against influenza-associated hospitalization. Rather, effectiveness increased by about 15% in those vaccinated in both current and previous seasons compared with those vaccinated in either season alone.³²

European investigators showed that repeated seasonal influenza vaccination in the elderly prevented the need for hospitalization due to influenza A(H3N2) and B, but not A(H1N1)pdm09.³³

High-dose vaccine for older adults

The high-dose influenza vaccine has been licensed since 2009 for use in the United States for people ages 65 and older.

Recent studies confirmed that high-dose vaccine is more effective than standard-dose vaccine in veterans³⁴ and US Medicare beneficiaries.³⁵

The high-dose vaccine is rapidly becoming the primary vaccine given to people ages 65 and older in retail pharmacies, where vaccination begins earlier in the season than in providers’ offices.³⁶ Some studies have shown that the standard-dose vaccine wanes in effectiveness toward the end of the influenza season (particularly if the season is long) if it is given very early. It remains to be seen whether the same applies to the high-dose influenza vaccine.

Some advocate twice-annual influenza vaccination, particularly for older adults living in tropical and subtropical areas, where influenza seasons are more prolonged. However, a recently published study observed reductions in influenza-specific hemagglutination inhibition and cell-mediated immunity after twice-annual vaccination.³⁷

Vaccination is beneficial during pregnancy

Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants.

One recently published study showed that 18% of infants who developed influenza required hospitalization.³⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively.

Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.³⁹

Some studies have shown that influenza virus infection can increase susceptibility to certain bacterial infections. A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.⁴⁰

Factors that make vaccination less effective

Several factors including age-related frailty and iatrogenic and disease-related immunosuppression can affect vaccine effectiveness.

Frailty. A recent study showed that vaccine effectiveness was 77.6% in nonfrail older adults but only 58.7% in frail older adults.⁴¹

Immunosuppression. Temporary discontinuation of methotrexate for 2 weeks after influenza vaccination in patients with rheumatoid arthritis improves vaccine immunogenicity without precipitating disease flare.⁴² Solid-organ and hematopoietic stem cell transplant recipients who received influenza vaccine were less likely to develop pneumonia and require intensive care unit admission.⁴³

The high-dose influenza vaccine is more immunogenic than the standard-dose vaccine in solid-organ transplant recipients.⁴⁴

Statins are widely prescribed and have recently been associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness, but their benefits in preventing cardiovascular events outweigh this risk.⁴⁵

FUTURE VACCINE CONSIDERATIONS

Moving away from eggs

During the annual egg-based production process, which takes several months, the influenza vaccine acquires antigenic changes that allow replication in eggs, particularly in the hemagglutinin protein, which mediates receptor binding. This process of egg adaptation may cause antigenic changes that decrease vaccine effectiveness against circulating viruses.

The cell-based baculovirus influenza vaccine grown in dog kidney cells has higher antigenic content and is not subject to the limitations of egg-based vaccine, although it still requires annual updates. A recombinant influenza vaccine reduces the probability of influenza-like illness by 30% compared with the egg-based influenza vaccine, but also still requires annual updates.⁴⁶ The market share of these non-egg-based vaccines is small, and thus their effectiveness has yet to be demonstrated.

The US Department of Defense administered the cell-based influenza vaccine to about one-third of Armed Forces personnel, their families, and retirees in the 2017–2018 influenza seasons, and data on its effectiveness are expected in the near future.⁴⁷

A universal vaccine would be ideal

The quest continues for a universal influenza vaccine, one that remains protective for several years and does not require annual updates.⁴⁸ Such a vaccine would protect against seasonal epidemic influenza drift variants and pandemic strains. More people could likely be persuaded to be vaccinated once rather than every year.

David Schumick, medical illustrator; adapted from reference 49; illustration of the influenza hemagglutinin created in part with data from reference 50.

An ideal universal vaccine would be suitable for all age groups, at least 75% effective against symptomatic influenza virus infection, protective against all influenza A viruses (influenza A, not B, causes pandemics and seasonal epidemics), and durable through multiple influenza seasons.⁵¹

Research and production of such a vaccine are expected to require funding of about $1 billion over the next 5 years.

Boosting effectiveness

Estimates of influenza vaccine effectiveness range from 40% to 60% in years when the vaccine viruses closely match the circulating viruses, and variably lower when they do not match. The efficacy of most other vaccines given to prevent other infections is much higher.

New technologies to improve influenza vaccine effectiveness are needed, particularly for influenza A(H3N2) viruses, which are rapidly evolving and are highly susceptible to egg-adaptive mutations in the manufacturing process.

In one study, a nanoparticle vaccine formulated with a saponin-based adjuvant induced hemagglutination inhibition responses that were even greater than those induced by the high-dose vaccine.⁵²

Immunoglobulin A (IgA) may be a more effective vaccine target than traditional influenza vaccines that target IgG, since different parts of IgA may engage the influenza virus simultaneously.⁵³

Vaccines can be developed more quickly than in the past. The timeline from viral sequencing to human studies with deoxyribonucleic acid plasmid vaccines decreased from 20 months in 2003 for the severe acquired respiratory syndrome coronavirus to 11 months in 2006 for influenza A/Indonesia/2006 (H5), to 4 months in 2009 for influenza A/California/2009 (H1), to 3.5 months in 2016 for Zika virus.⁵⁴ This is because it is possible today to sequence a virus and insert the genetic material into a vaccine platform without ever having to grow the virus.

Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.⁵⁵ Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza.⁵⁵

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.⁵⁶ Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients⁵⁷ and with a lower risk of otitis media in children.⁵⁸

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.⁵⁹

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.⁶⁰

Baloxavir marboxil

Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits cap-dependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.⁶¹

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation, and similar side effects.⁶² Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

CLOSING THE GAPS

Several gaps in the management of influenza persist since the 1918 pandemic.¹ These include gaps in epidemiology, prevention, diagnosis, treatment, and prognosis.

• Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
• Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
• Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
• Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
• In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread. In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
• A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.⁶³
• Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.

Primary care physicians are tasked with a wide variety of issues affecting men. This article reviews the latest research in 4 areas of men’s health commonly addressed in primary care:

• Medical management of benign prostatic hyperplasia (BPH)
• Prostate cancer screening and treatment
• Medical management of erectile dysfunction
• Use of supplements.

See related commentary

MEDICAL MANAGEMENT OF BPH

An 84-year-old man with a history of hypertension, type 2 diabetes, hyperlipidemia, BPH, mild cognitive impairment, and osteoarthritis presents for a 6-month follow-up, accompanied by his son.

Two years ago he was started on a 5-alpha reductase inhibitor and an alpha-blocker for worsening BPH symptoms. His BPH symptoms are currently under control, with an American Urological Association (AUA) symptom index score of 7 of a possible 35 (higher scores being worse).

However, both the patient and son are concerned about the number of medications he is on and wonder if some could be eliminated.

Assessment tools

BPH is a common cause of lower urinary tract symptoms in older men. Evidence-based tools to help the clinician and patient decide on when to consider treatment for symptoms are:

• The AUA symptom index¹
• The International Prostate Symptom Score (IPSS).²

An AUA symptom index score or IPSS score of 8 through 19 of a possible 35 is consistent with moderate symptoms, while a score of 20 or higher indicates severe symptoms.

Combination therapy or monotherapy?

Monotherapy with an alpha-blocker or a 5-alpha reductase inhibitor is often the first-line treatment for BPH-related lower urinary tract symptoms.³ However, combination therapy with both an alpha-blocker and a 5-alpha reductase inhibitor is another evidence-based option.

The Medical Therapy of Prostatic Symptoms study,⁴ a randomized controlled trial, reported that long-term combination therapy reduced the risk of BPH clinical progression better than monotherapy. The same trial also found that either combination therapy or finasteride alone (a 5-alpha reductase inhibitor) reduced the risk of acute urinary retention and the future need for invasive therapy.

Monotherapy after a period of combination therapy?

There is also evidence to support switching from combination to monotherapy after an initial treatment period.

Matsukawa et al⁵ examined the effects of withdrawing the alpha-blocker from BPH combination therapy in a study in 140 patients. For 12 months, all patients received the alpha-blocker silodosin and the 5-alpha reductase inhibitor dutasteride. At 12 months, the remaining 132 patients (8 patients had been lost to follow-up) were randomized to continue combination therapy or to take dutasteride alone for another 12 months. They were evaluated at 0, 12, and 24 months by questionnaires (the IPSS and Overactive Bladder Symptom Score) and urodynamic testing (uroflowmetry, cystometrography, and pressure-flow studies).

There were no significant differen­ces in subjective symptoms and bladder outlet obstruction between patients who continued combination therapy and those who switched to dutasteride monotherapy. In the monotherapy group, those whose symptoms worsened weighed more (68.8 kg vs 62.6 kg, P =.002) and had a higher body mass index (BMI) (26.2 kg/m² vs 22.8 kg/m², P < .001) than those whose symptoms stayed the same or got better.

These findings of successful alpha-blocker withdrawal were consistent with those of other studies.

The Symptom Management After Reducing Therapy study⁶ showed that 80% of men with an IPSS score less than 20 who changed to dutasteride monotherapy did not have a noticeable worsening of their symptoms.

Baldwin et al⁷ noted similar success after withdrawing the alpha-blocker doxazosin in patients on finasteride.

Review all medications

The National Health and Nutrition Examination Survey noted that the estimated prevalence of polypharmacy increased from 8% in 1999 to 15% in 2011.⁸ Many commonly used medications, such as decongestants, antihistamines, and anticholinergic agents, can worsen BPH symptoms,⁹ so it is reasonable to consistently review the patient’s medications to weigh the risks and benefits and determine which ones align with the patient’s personal care goals.

BPH: Take-home points

• Combination therapy with an alpha-blocker and a 5-alpha reductase inhibitor is an effective regimen for BPH.
• Polypharmacy is a significant problem in the elderly.
• Withdrawing the alpha-blocker component from BPH combination therapy can be considered after 1 year of combination therapy in patients whose symptoms have been well controlled.

A 60-year-old patient calls you after receiving his laboratory testing report from his insurance physical. His prostate-specific antigen (PSA) level is 5.1 ng/mL, and he has several questions:

• Should he have agreed to the screening?
• How effective is the screening?
• What are the next steps?

Is PSA screening useful?

Over the last few years, there has been great debate as to the utility of screening for prostate cancer.

The US Centers for Disease Control and Prevention¹⁰ reported that in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it. These statistics support the notion that screening programs may be detecting what might otherwise be a silent disease.

The US Preventive Services Task Force (USPSTF)¹¹ recommends against blanket PSA screening, in view of the low probability that it reduces the risk of death from prostate cancer. For men ages 55 through 69, current guidelines give a grade C recommendation to PSA screening, meaning there is moderate agreement that the benefit is likely small, and screening should be selectively offered based on professional judgment and patient preference. In men ages 70 and older who are not at high risk, the guideline gives screening a grade D recommendation, meaning there is moderate evidence that there is no benefit from the practice. This is a change from the 2012 USPSTF guidelines,¹² which gave a grade D recommendation to PSA screening for all ages.

The American Urological Association¹³ recommends against PSA screening in men under age 40 or ages 70 and older. It does not recommend routine screening in those ages 40 to 54 at average risk, but it says the decision should be individualized in this age group in those at higher risk (eg, with a positive family history, African American). At ages 55 through 69, it recommends shared decision-making, taking into account cancer risk and life expectancy. In those who opt for screening, an interval of 2 years or more may be preferred over annual screening to reduce the risk of overdiagnosis.

The USPSTF recommendations rely heavily on data from 2 trials: the European Randomized Study of Screening for Prostate Cancer (ERSPC)¹⁴ and the Prostate, Lung, Colorectal, and Ovarian Screening (PLCO) trial.¹⁵

The ERSPC¹⁴ demonstrated that screening for prostate cancer reduced deaths from prostate cancer by 20%, with an absolute risk difference of 0.71 deaths per 1,000 men; 1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent 1 death from prostate cancer. Screening also decreased the risk of developing metastatic disease by 30%.¹⁶ On the negative side, screening increased the risk of overdiagnosis and other harms such as bleeding, sepsis, and incontinence.

The PLCO trial,¹⁵ in contrast, found no difference in death rates between men randomly assigned to annual screening and those assigned to usual care. Differences between the trial results were thought to be due to different practice settings as well as study implementation and compliance.

Tsodikov et al¹⁷ reanalyzed data from the ERSPC and the PLCO trial using 3 different mathematical models to estimate the effects of screening in both trials compared with no screening. The analysis found no evidence that the effects of screening vs not screening differed between the 2 trials, ultimately concluding that PSA screening reduced prostate cancer deaths by 25% to 32%, which the authors inferred was primarily a result of earlier detection of cancer.

The Cluster Randomized Trial of PSA Testing for Prostate Cancer,¹⁸ published in March 2018, explored the effect of single PSA screening vs no screening on prostate cancer mortality rates in 419,582 men ages 50 through 69. Although screening detected more cases of low-risk prostate cancer, there was no significant difference in prostate cancer mortality rates after a median follow-up of 10 years. However, 10% to 15% of the control group was estimated to have also been screened, and these results do not directly speak to the efficacy of serial PSA screening.

Extended follow-up of this trial is planned to report on long-term survival benefits and whether screening lowers the risk of metastasis.

Imaging-guided prostate biopsy

Once a patient is found to have an elevated PSA level, standard practice has been to perform transrectal ultrasonography to obtain 12 core biopsy samples. The results indicate whether the prostate contains cancer, how aggressive the cancer is (Gleason score), and whether there is extracapsular extension.

In the past, magnetic resonance imaging (MRI) of the prostate before biopsy was thought to be too costly, and many insurance plans do not currently cover it.

Pahwa et al,¹⁹ however, in a cost-effectiveness study using a decision-analysis model, found that using MRI to detect lesions and then guide biopsy by triaging patients into proper treatment pathways added health benefits in a cost-effective manner in 94.05% of simulations. These benefits were found across all age groups.

This study demonstrated that doctors could use MRI to better evaluate patients for potentially harmful lesions. If a focus of cancer is found, it can be biopsied; if no cancer is seen on MRI, the patient can avoid biopsy completely. Additionally, though MRI tended to miss low-risk cancers, these cancers are thought to disproportionately lead to higher healthcare costs through unnecessary treatment. Therefore, a negative MRI study was believed to be an excellent sign that the patient does not have aggressive prostate cancer. This approach led to a net gain of 0.251 additional quality-adjusted life years compared with the standard biopsy strategy.

The Prostate MRI Imaging Study²⁰ also found MRI to be effective in the prostate cancer workup. In this trial, 576 men who had never undergone biopsy underwent multiparametric MRI, transrectal ultrasonography-guided biopsy, and the reference standard, ie, transperineal template prostate mapping biopsy. Of those who underwent biopsy, 71% received a diagnosis of prostate cancer, and 40% had clinically significant disease. In patients with clinically significant disease, MRI was more sensitive than ultrasonography-guided biopsy (93% vs 48%, P < .0001) but less specific (41% vs 96%, P < .0001).

Based on these findings, if biopsy were performed only in those who had suspicious lesions on MRI, 27% of men with elevated PSA could avoid biopsy and its potential complications such as bleeding and sepsis, which occurred in 5.9% of the biopsy group.

The Prostate Evaluation for Clinically Important Disease: Sampling Using Image Guidance or Not? trial²¹ more recently studied MRI with or without targeted biopsy vs standard transrectal ultrasonography-guided biopsy in 500 men who had not undergone biopsy before, and reported similar results. MRI with or without biopsy led to fewer biopsies and less overdetection of clinically insignificant prostate cancers compared with the standard approach. Furthermore, those in the MRI-targeted biopsy group were 13% less likely to receive a diagnosis of clinically insignificant cancer than those who received the standard biopsy (adjusted difference −13 percentage points, 95% confidence interval [CI] −19 to −7, P < .001).

Together, these data provide another argument for adding multiparametric MRI to the workup of men with an elevated PSA level.

Surveillance vs treatment for prostate cancer

Once prostate cancer is diagnosed, surveillance is becoming an increasingly common management strategy.

The Prostate Cancer Intervention Versus Observation Trial (PIVOT),²² one of the largest and longest trials involving cancer patients, offered further evidence that active surveillance and less intervention for men with prostate cancer is a better approach in many cases. This trial compared prostatectomy and observation alone in a randomized fashion. Inclusion for the study required men to be medically fit for radical prostatectomy, along with having histologically confirmed localized prostate cancer (stage T1-T2NxM0 in the tumor-node-metastasis classification system) of any grade diagnosed within the last 12 months.

During 19.5 years of follow-up, 223 (61.3%) of the 364 men randomly assigned to radical prostatectomy died, compared with 245 (66.8%) of 367 men in the observation group; the difference was not statistically different (P = .06). Only 9.4% of the deaths were due to prostate cancer, 7.4% in the surgery group and 11.4% in the observation group (P = .06).

Surgery was associated with a lower all-cause mortality rate than observation in the subgroup of patients with intermediate-risk prostate cancer (defined as PSA 10–20 ng/mL and a Gleason score of 7). Surgery was also associated with less disease progression.²²

This finding is in line with previous data from the Scandinavian Prostate Cancer Group Study Number 4,²³ as well as the much larger Prostate Testing for Cancer and Treatment (ProtecT) trial,²⁴ both of which reported that metastasis was 1.5 and 2.6 times as common, respectively, in participants in the active surveillance groups. However, in the PIVOT trial, those in the surgery group were significantly more likely than those in the observation group to have erectile dysfunction and urinary incontinence at 10 years.

Therefore, in men with localized disease and in those with low-risk PSA levels, both the PIVOT and ProtecT trials suggest that death from prostate cancer is uncommon and that observation may be more appropriate.

Prostate cancer: Take-home points

• A new look at 2 large trials of PSA screening strengthened evidence that testing in the right patient population can reduce deaths from prostate cancer, but a third recently published trial that found no benefit from 1-time screening may reopen debate on the topic.
• MRI offers a better method than ultrasonography-guided biopsy to triage patients thought to be at high risk of prostate cancer and tends to limit costly overtreatment of disease that likely would not cause death.
• Surgery for prostate cancer may not prolong life but could reduce disease progression, at the risk of more adverse effects.
• Shared decision-making should be practiced when deciding whether to use active surveillance or active treatment of diagnosed prostate cancer.

A 62-year-old man with hypertension, hyperlipidemia, peripheral artery disease, and type 2 diabetes presents for a 6-month follow-up. His medications include aspirin, metformin, lisinopril, and atorvastatin, all of which he takes without problems. Over the past several months, he has noticed that his erections are not adequate for sexual intercourse. He recently heard that a generic version of sildenafil has just become available, and he wonders if it might benefit him.

Erectile dysfunction is common, associated with chronic diseases

Erectile dysfunction, ie, persistent inability to obtain and maintain an erection sufficient to permit satisfactory sexual intercourse,^25,26 is estimated to affect nearly 20% of men over the age of 20 and 75% of men over the age of 75.²⁷

In age-adjusted models, erectile dysfunction has been shown²⁸ to be associated with:

• History of cardiovascular disease (odds ratio [OR] 1.63, 95% CI 1.02–2.63)
• Diabetes (OR 3.90, 95% CI 2.16–7.04)
• Treated hypertension vs no hypertension (OR 2.22, 95% CI 1.30–3.80)
• Current smoking vs never smoking (OR 1.63, 95% CI 1.01–2.62)
• BMI greater than 30 kg/m² vs less than 25 kg/m² (OR 1.80, 95% CI 1.03–3.14).

Because of the strong association between cardiovascular disease and erectile dysfunction, the presence of one often suggests the need to screen for the other.²⁹ While tools such as the International Index of Erectile Function (IIEF-5) have been developed to evaluate erectile dysfunction, it is most often diagnosed on the basis of clinical impression, while validated assessment methods are reserved for clinical trials.²⁸

Multiple causes of erectile dysfunction

Erectile dysfunction arises from inadequate penile tissue response to a sexual signal. The response can be disrupted at several points. For example, damage to vascular smooth muscle cells (eg, from age or obesity) and endothelial cells (from smoking or diabetes) and narrowing of the vascular lumen (from atherosclerosis or hypertension) have all been shown to impair engorgement of the corpus cavernosum.³⁰ In addition, denervation from prostate surgery or spinal trauma and psychogenic causes should be recognized in discussions with patients.

Drugs for erectile dysfunction

Pharmacologic management of erectile dysfunction includes oral, sublingual, intracavernosal, and intraurethral therapies.³¹ Treatment in primary care settings usually includes addressing underlying chronic diseases³² and prescribing phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil, and avanafil). These drugs work by increasing local concentrations of cyclic guanosine monophosphate in the corpus cavernosum to induce vasodilation.³³

While these 4 drugs are still patent-protected, a manufacturer has been allowed to introduce a generic version of sildenafil into US markets, and a generic version of tadalafil is expected to be available soon.

Sildenafil, tadalafil, and vardenafil have been studied and found to have some degree of effectiveness in erectile dysfunction caused by damage to the penile vasculature, denervation, and spinal cord injury.³⁴ All drugs of this class have adverse effects including headache, facial flushing, and nasal congestion, but the drugs are generally well tolerated.³⁵

Sildenafil and tadalafil improve IIEF-5 scores by a similar margin, raising scores on the erectile domain subsection from approximately 14 of a possible 30 to approximately 24 of 30 in a trial of both drugs.³⁶ However, multiple crossover studies comparing the 2 drugs have shown that nearly 75% of patients prefer tadalafil to sildenafil,^36,37 perhaps because of tadalafil’s longer duration of action.³⁴

There is little evidence to suggest that vardenafil is more effective or more often preferred by patients than tadalafil or sidenafil.^34,38 And though data on the newest drug on the market, avanafil, are limited, a meta-analysis concluded that it may be less effective than tadalafil and without significant differences in terms of safety.³⁹

Other treatments

Lifestyle modifications, especially smoking cessation and exercise, have been shown to reduce the risk of erectile dysfunction with varying effect sizes across studies.^40–42 Moreover, factors such as obesity, alcohol use, and smoking may cause irreversible harm, and thus a healthy lifestyle should be encouraged.⁴¹

While there is only weak evidence for the use of psychological interventions alone for treating most types of erectile dysfunction, one meta-analysis found that the combination of psychological intervention and a phosphodiesterase-5 inhibitor improved sexual satisfaction more than drug therapy alone.⁴³

Erectile dysfunction: Take-home points

• Erectile dysfunction is common, affecting nearly 20% of men over the age of 20 and over 75% of men over the age of 75.
• Erectile dysfunction is often associated with chronic disease and may suggest the need to screen for cardiovascular disease.
• Treating underlying chronic diseases may help, and phosphodiesterase-5 inhibitors are effective; tadalafil may be most often preferred.

A 68-year-old man with a history of hypertension, BPH, and erectile dysfunction presents for a 6-month follow-up. His medication use includes lisinopril, which he takes without problems. He denies any new physical symptoms. His physical examination is unremarkable. He says he has heard about supplements that might help with his sexual performance and hopes to discuss recommendations during the visit.

A burgeoning, unregulated industry

Since the passage of the Dietary Supplement and Health Education Act in 1994, a law that decreased oversight of the supplement industry, spending on supplements has skyrocketed to over $41.1 billion each year.⁴⁴ Advertisements for these products typically claim that they improve general mental and physical health, sexual and romantic performance, leanness, and muscularity.⁴⁵ A national survey of men ages 57 and older reported that the most popular products were aimed at nutrition (such as multivitamins), cardiovascular health (such as omega-3 fatty acids), and chronic conditions (such as saw palmetto for BPH).⁴⁶

Little evidence of efficacy

There is little evidence to support the use of most supplements to improve men’s health. For example, a study in 82,405 men found no association between mortality rates and multivitamin use (hazard ratio [HR] 1.07, 95% CI 0.96–1.19).⁴⁷ Even for specific uses, such as cognitive performance, randomized trials exploring the effects of multivitamins in men have been largely negative.⁴⁸

The positive trials that have been reported are often of low quality and are funded by supplement manufacturers. For example, one of the few trials that reported a positive association between multivitamin supplementation and cognition in men was underpowered (N = 51) and found improvement in only 1 of 19 cognitive domains.⁴⁹ Despite the poor design and results to the contrary, this industry-funded study nevertheless concluded that multivitamins may play a role in improving elements of memory.

Evidence of possible harm from antioxidants

While not always specific to men, many meta-analyses have explored the effects of antioxidant supplements on cardiovascular and mortality risk. Most of them concluded that antioxidant supplements have no benefit and that some may actually be harmful.

For example, multiple meta-analyses of vitamin E supplementation found no cardiovascular benefit but possible increases in all-cause mortality rates in those taking high doses (risk ratio 1.04, 95% CI 1.01–1.07).^50,51

Another meta-analysis of 180,938 partici­pants in high-quality studies found an increased risk of all-cause mortality associated with independent intake of several antioxidant vitamins, including beta-carotene (risk ratio 1.07, 95% CI 1.02–1.11) and vitamin A (risk ratio 1.16, 95% CI 1.10–1.24), while intake of vitamin C and selenium had no impact on mortality.⁵²

Similarly, although nearly 10% of US adults report taking omega-3 fatty acid supplements, a review of 24 randomized controlled trials and meta-analyses published between 2005 and 2012 concluded that only 2 supported the use of these supplements for any health benefit.⁵³

Can supplements improve sexual function, prostate health?

To improve sexual function. A 2015 narrative review of the ingredients in General Nutrition Center’s top 30 best-selling products targeted at improving men’s sexual performance (including improving libido and erectile dysfunction) found only poor evidence for any efficacy.⁵⁴ The few studies that did support the use of select supplements, including B vitamins in people with diabetes, L-arginine, and yohimbine, were deemed to be of poor quality or showed a smaller effect size compared with standard medical therapy.

To prevent prostate cancer. Studies of supplement use to improve prostate health have had mixed results. For example, multiple large case-control studies have suggested that taking vitamin D^55,56 or vitamin C⁵⁷ is not associated with prostate cancer risk, while increased vitamin A^58,59 and E^60,61 intake is associated with inconsistent increases in prostate cancer risk.

In the Selenium and Vitamin E Cancer Prevention Trial,⁶² a randomized controlled trial in 35,533 men, those assigned to receive vitamin E supplementation were 17% more likely to get prostate cancer than were those assigned to placebo (HR 1.17, 99% CI 1.004–1.36, P = .008).

However, there are plausible biologic links between nutraceuticals and prostate cancer. For example, studies have linked genetic polymorphisms in vitamin D receptors⁶³ as well as intake of natural androgen receptor modulators, such as the most active polyphenol in green tea,⁶⁴ to prostate cancer risk and aggressiveness in certain populations. This led a recent review to conclude that there is some biologic plausibility, but at present little epidemiologic evidence, to support any dietary supplement’s ability to broadly affect prostate cancer risk.⁶⁵

Interest continues in exploring the targeted use of nutraceuticals as adjuvant therapy in specific populations at risk of prostate cancer.^66,67

To treat BPH. There is a similar dearth of clinical or population-based evidence that supplements can broadly affect BPH symptoms. For example, in a 2012 Cochrane review of Serenoa repens (saw palmetto) utilizing only high-quality evidence, there was no evidence that supplement use significantly reduced lower urinary tract symptoms, nocturia, or peak urine flow in BPH patients, and this was true even when the supplement was taken at triple-strength doses.⁶⁸

For other diseases. There is also limited evidence that supplements can affect other chronic diseases. For example, a meta-analysis of 3,803 patients found that glucosamine, chondroitin, and their combination had no impact on joint pain or joint space narrowing in patients with osteoarthritis of the knee or hip.⁶⁹

Even when there is some evidence to suggest benefit from supplementation, study heterogeneity and varying evidence quality limit confidence in the conclusions. For example, meta-analyses suggest garlic may improve blood pressure control in those with hypertension⁷⁰ and improve lipid and blood glucose control in type 2 diabetes.⁷¹ However, most of the trials included in those systematic reviews were underpowered, with samples as low as 10 patients, and many suffered from improper design, such as inadequate blinding of researchers. In addition, these meta-analyses often do not report adverse events, suggesting that higher quality studies would be needed to adequately measure event rates. As such, there is need for caution and a case-by-case review before recommending even a seemingly benign supplement like garlic to patients.

In total, there is only limited evidence to support the efficacy of supplements across many diseases and concerns common to men in primary care. This includes improving general health, cardiovascular health, sexual functioning, or other chronic diseases. While a supplement’s placebo effect may at times provide some benefit, supplements are much less strictly regulated since the passing of the 1994 act, and even vitamin supplementation has been shown to be associated with negative health outcomes. As such, a patient’s use of supplements requires careful consideration and shared decision-making.

Supplements: Take-home points

• Supplements are only loosely regulated by the federal government.
• There is some biologic but limited epidemiologic evidence for the use of multivitamins to improve cognition or mortality rates; for the use of antioxidant vitamins or omega-3 fatty acids to improve cardiovascular health; for the use of any of the top-selling sexual enhancement supplements to improve libido or erectile function; and for the use of vitamins or other supplements for improving BPH or reducing prostate cancer risk. Using supplements may in some cases be harmful.
• Given the heterogeneity of studies of supplements to manage chronic diseases and a lack of reporting of adverse events, careful consideration is needed when recommending supplements to patients.

Primary care physicians are tasked with a wide variety of issues affecting men. This article reviews the latest research in 4 areas of men’s health commonly addressed in primary care:

• Medical management of benign prostatic hyperplasia (BPH)
• Prostate cancer screening and treatment
• Medical management of erectile dysfunction
• Use of supplements.

See related commentary

MEDICAL MANAGEMENT OF BPH

An 84-year-old man with a history of hypertension, type 2 diabetes, hyperlipidemia, BPH, mild cognitive impairment, and osteoarthritis presents for a 6-month follow-up, accompanied by his son.

Two years ago he was started on a 5-alpha reductase inhibitor and an alpha-blocker for worsening BPH symptoms. His BPH symptoms are currently under control, with an American Urological Association (AUA) symptom index score of 7 of a possible 35 (higher scores being worse).

However, both the patient and son are concerned about the number of medications he is on and wonder if some could be eliminated.

Assessment tools

BPH is a common cause of lower urinary tract symptoms in older men. Evidence-based tools to help the clinician and patient decide on when to consider treatment for symptoms are:

• The AUA symptom index¹
• The International Prostate Symptom Score (IPSS).²

An AUA symptom index score or IPSS score of 8 through 19 of a possible 35 is consistent with moderate symptoms, while a score of 20 or higher indicates severe symptoms.

Combination therapy or monotherapy?

Monotherapy with an alpha-blocker or a 5-alpha reductase inhibitor is often the first-line treatment for BPH-related lower urinary tract symptoms.³ However, combination therapy with both an alpha-blocker and a 5-alpha reductase inhibitor is another evidence-based option.

The Medical Therapy of Prostatic Symptoms study,⁴ a randomized controlled trial, reported that long-term combination therapy reduced the risk of BPH clinical progression better than monotherapy. The same trial also found that either combination therapy or finasteride alone (a 5-alpha reductase inhibitor) reduced the risk of acute urinary retention and the future need for invasive therapy.

Monotherapy after a period of combination therapy?

There is also evidence to support switching from combination to monotherapy after an initial treatment period.

Matsukawa et al⁵ examined the effects of withdrawing the alpha-blocker from BPH combination therapy in a study in 140 patients. For 12 months, all patients received the alpha-blocker silodosin and the 5-alpha reductase inhibitor dutasteride. At 12 months, the remaining 132 patients (8 patients had been lost to follow-up) were randomized to continue combination therapy or to take dutasteride alone for another 12 months. They were evaluated at 0, 12, and 24 months by questionnaires (the IPSS and Overactive Bladder Symptom Score) and urodynamic testing (uroflowmetry, cystometrography, and pressure-flow studies).

There were no significant differen­ces in subjective symptoms and bladder outlet obstruction between patients who continued combination therapy and those who switched to dutasteride monotherapy. In the monotherapy group, those whose symptoms worsened weighed more (68.8 kg vs 62.6 kg, P =.002) and had a higher body mass index (BMI) (26.2 kg/m² vs 22.8 kg/m², P < .001) than those whose symptoms stayed the same or got better.

These findings of successful alpha-blocker withdrawal were consistent with those of other studies.

The Symptom Management After Reducing Therapy study⁶ showed that 80% of men with an IPSS score less than 20 who changed to dutasteride monotherapy did not have a noticeable worsening of their symptoms.

Baldwin et al⁷ noted similar success after withdrawing the alpha-blocker doxazosin in patients on finasteride.

Review all medications

The National Health and Nutrition Examination Survey noted that the estimated prevalence of polypharmacy increased from 8% in 1999 to 15% in 2011.⁸ Many commonly used medications, such as decongestants, antihistamines, and anticholinergic agents, can worsen BPH symptoms,⁹ so it is reasonable to consistently review the patient’s medications to weigh the risks and benefits and determine which ones align with the patient’s personal care goals.

BPH: Take-home points

• Combination therapy with an alpha-blocker and a 5-alpha reductase inhibitor is an effective regimen for BPH.
• Polypharmacy is a significant problem in the elderly.
• Withdrawing the alpha-blocker component from BPH combination therapy can be considered after 1 year of combination therapy in patients whose symptoms have been well controlled.

A 60-year-old patient calls you after receiving his laboratory testing report from his insurance physical. His prostate-specific antigen (PSA) level is 5.1 ng/mL, and he has several questions:

• Should he have agreed to the screening?
• How effective is the screening?
• What are the next steps?

Is PSA screening useful?

Over the last few years, there has been great debate as to the utility of screening for prostate cancer.

The US Centers for Disease Control and Prevention¹⁰ reported that in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it. These statistics support the notion that screening programs may be detecting what might otherwise be a silent disease.

The US Preventive Services Task Force (USPSTF)¹¹ recommends against blanket PSA screening, in view of the low probability that it reduces the risk of death from prostate cancer. For men ages 55 through 69, current guidelines give a grade C recommendation to PSA screening, meaning there is moderate agreement that the benefit is likely small, and screening should be selectively offered based on professional judgment and patient preference. In men ages 70 and older who are not at high risk, the guideline gives screening a grade D recommendation, meaning there is moderate evidence that there is no benefit from the practice. This is a change from the 2012 USPSTF guidelines,¹² which gave a grade D recommendation to PSA screening for all ages.

The American Urological Association¹³ recommends against PSA screening in men under age 40 or ages 70 and older. It does not recommend routine screening in those ages 40 to 54 at average risk, but it says the decision should be individualized in this age group in those at higher risk (eg, with a positive family history, African American). At ages 55 through 69, it recommends shared decision-making, taking into account cancer risk and life expectancy. In those who opt for screening, an interval of 2 years or more may be preferred over annual screening to reduce the risk of overdiagnosis.

The USPSTF recommendations rely heavily on data from 2 trials: the European Randomized Study of Screening for Prostate Cancer (ERSPC)¹⁴ and the Prostate, Lung, Colorectal, and Ovarian Screening (PLCO) trial.¹⁵

The ERSPC¹⁴ demonstrated that screening for prostate cancer reduced deaths from prostate cancer by 20%, with an absolute risk difference of 0.71 deaths per 1,000 men; 1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent 1 death from prostate cancer. Screening also decreased the risk of developing metastatic disease by 30%.¹⁶ On the negative side, screening increased the risk of overdiagnosis and other harms such as bleeding, sepsis, and incontinence.

The PLCO trial,¹⁵ in contrast, found no difference in death rates between men randomly assigned to annual screening and those assigned to usual care. Differences between the trial results were thought to be due to different practice settings as well as study implementation and compliance.

Tsodikov et al¹⁷ reanalyzed data from the ERSPC and the PLCO trial using 3 different mathematical models to estimate the effects of screening in both trials compared with no screening. The analysis found no evidence that the effects of screening vs not screening differed between the 2 trials, ultimately concluding that PSA screening reduced prostate cancer deaths by 25% to 32%, which the authors inferred was primarily a result of earlier detection of cancer.

The Cluster Randomized Trial of PSA Testing for Prostate Cancer,¹⁸ published in March 2018, explored the effect of single PSA screening vs no screening on prostate cancer mortality rates in 419,582 men ages 50 through 69. Although screening detected more cases of low-risk prostate cancer, there was no significant difference in prostate cancer mortality rates after a median follow-up of 10 years. However, 10% to 15% of the control group was estimated to have also been screened, and these results do not directly speak to the efficacy of serial PSA screening.

Extended follow-up of this trial is planned to report on long-term survival benefits and whether screening lowers the risk of metastasis.

Imaging-guided prostate biopsy

Once a patient is found to have an elevated PSA level, standard practice has been to perform transrectal ultrasonography to obtain 12 core biopsy samples. The results indicate whether the prostate contains cancer, how aggressive the cancer is (Gleason score), and whether there is extracapsular extension.

In the past, magnetic resonance imaging (MRI) of the prostate before biopsy was thought to be too costly, and many insurance plans do not currently cover it.

Pahwa et al,¹⁹ however, in a cost-effectiveness study using a decision-analysis model, found that using MRI to detect lesions and then guide biopsy by triaging patients into proper treatment pathways added health benefits in a cost-effective manner in 94.05% of simulations. These benefits were found across all age groups.

This study demonstrated that doctors could use MRI to better evaluate patients for potentially harmful lesions. If a focus of cancer is found, it can be biopsied; if no cancer is seen on MRI, the patient can avoid biopsy completely. Additionally, though MRI tended to miss low-risk cancers, these cancers are thought to disproportionately lead to higher healthcare costs through unnecessary treatment. Therefore, a negative MRI study was believed to be an excellent sign that the patient does not have aggressive prostate cancer. This approach led to a net gain of 0.251 additional quality-adjusted life years compared with the standard biopsy strategy.

The Prostate MRI Imaging Study²⁰ also found MRI to be effective in the prostate cancer workup. In this trial, 576 men who had never undergone biopsy underwent multiparametric MRI, transrectal ultrasonography-guided biopsy, and the reference standard, ie, transperineal template prostate mapping biopsy. Of those who underwent biopsy, 71% received a diagnosis of prostate cancer, and 40% had clinically significant disease. In patients with clinically significant disease, MRI was more sensitive than ultrasonography-guided biopsy (93% vs 48%, P < .0001) but less specific (41% vs 96%, P < .0001).

Based on these findings, if biopsy were performed only in those who had suspicious lesions on MRI, 27% of men with elevated PSA could avoid biopsy and its potential complications such as bleeding and sepsis, which occurred in 5.9% of the biopsy group.

The Prostate Evaluation for Clinically Important Disease: Sampling Using Image Guidance or Not? trial²¹ more recently studied MRI with or without targeted biopsy vs standard transrectal ultrasonography-guided biopsy in 500 men who had not undergone biopsy before, and reported similar results. MRI with or without biopsy led to fewer biopsies and less overdetection of clinically insignificant prostate cancers compared with the standard approach. Furthermore, those in the MRI-targeted biopsy group were 13% less likely to receive a diagnosis of clinically insignificant cancer than those who received the standard biopsy (adjusted difference −13 percentage points, 95% confidence interval [CI] −19 to −7, P < .001).

Together, these data provide another argument for adding multiparametric MRI to the workup of men with an elevated PSA level.

Surveillance vs treatment for prostate cancer

Once prostate cancer is diagnosed, surveillance is becoming an increasingly common management strategy.

The Prostate Cancer Intervention Versus Observation Trial (PIVOT),²² one of the largest and longest trials involving cancer patients, offered further evidence that active surveillance and less intervention for men with prostate cancer is a better approach in many cases. This trial compared prostatectomy and observation alone in a randomized fashion. Inclusion for the study required men to be medically fit for radical prostatectomy, along with having histologically confirmed localized prostate cancer (stage T1-T2NxM0 in the tumor-node-metastasis classification system) of any grade diagnosed within the last 12 months.

During 19.5 years of follow-up, 223 (61.3%) of the 364 men randomly assigned to radical prostatectomy died, compared with 245 (66.8%) of 367 men in the observation group; the difference was not statistically different (P = .06). Only 9.4% of the deaths were due to prostate cancer, 7.4% in the surgery group and 11.4% in the observation group (P = .06).

Surgery was associated with a lower all-cause mortality rate than observation in the subgroup of patients with intermediate-risk prostate cancer (defined as PSA 10–20 ng/mL and a Gleason score of 7). Surgery was also associated with less disease progression.²²

This finding is in line with previous data from the Scandinavian Prostate Cancer Group Study Number 4,²³ as well as the much larger Prostate Testing for Cancer and Treatment (ProtecT) trial,²⁴ both of which reported that metastasis was 1.5 and 2.6 times as common, respectively, in participants in the active surveillance groups. However, in the PIVOT trial, those in the surgery group were significantly more likely than those in the observation group to have erectile dysfunction and urinary incontinence at 10 years.

Therefore, in men with localized disease and in those with low-risk PSA levels, both the PIVOT and ProtecT trials suggest that death from prostate cancer is uncommon and that observation may be more appropriate.

Prostate cancer: Take-home points

• A new look at 2 large trials of PSA screening strengthened evidence that testing in the right patient population can reduce deaths from prostate cancer, but a third recently published trial that found no benefit from 1-time screening may reopen debate on the topic.
• MRI offers a better method than ultrasonography-guided biopsy to triage patients thought to be at high risk of prostate cancer and tends to limit costly overtreatment of disease that likely would not cause death.
• Surgery for prostate cancer may not prolong life but could reduce disease progression, at the risk of more adverse effects.
• Shared decision-making should be practiced when deciding whether to use active surveillance or active treatment of diagnosed prostate cancer.

A 62-year-old man with hypertension, hyperlipidemia, peripheral artery disease, and type 2 diabetes presents for a 6-month follow-up. His medications include aspirin, metformin, lisinopril, and atorvastatin, all of which he takes without problems. Over the past several months, he has noticed that his erections are not adequate for sexual intercourse. He recently heard that a generic version of sildenafil has just become available, and he wonders if it might benefit him.

Erectile dysfunction is common, associated with chronic diseases

Erectile dysfunction, ie, persistent inability to obtain and maintain an erection sufficient to permit satisfactory sexual intercourse,^25,26 is estimated to affect nearly 20% of men over the age of 20 and 75% of men over the age of 75.²⁷

In age-adjusted models, erectile dysfunction has been shown²⁸ to be associated with:

• History of cardiovascular disease (odds ratio [OR] 1.63, 95% CI 1.02–2.63)
• Diabetes (OR 3.90, 95% CI 2.16–7.04)
• Treated hypertension vs no hypertension (OR 2.22, 95% CI 1.30–3.80)
• Current smoking vs never smoking (OR 1.63, 95% CI 1.01–2.62)
• BMI greater than 30 kg/m² vs less than 25 kg/m² (OR 1.80, 95% CI 1.03–3.14).

Because of the strong association between cardiovascular disease and erectile dysfunction, the presence of one often suggests the need to screen for the other.²⁹ While tools such as the International Index of Erectile Function (IIEF-5) have been developed to evaluate erectile dysfunction, it is most often diagnosed on the basis of clinical impression, while validated assessment methods are reserved for clinical trials.²⁸

Multiple causes of erectile dysfunction

Erectile dysfunction arises from inadequate penile tissue response to a sexual signal. The response can be disrupted at several points. For example, damage to vascular smooth muscle cells (eg, from age or obesity) and endothelial cells (from smoking or diabetes) and narrowing of the vascular lumen (from atherosclerosis or hypertension) have all been shown to impair engorgement of the corpus cavernosum.³⁰ In addition, denervation from prostate surgery or spinal trauma and psychogenic causes should be recognized in discussions with patients.

Drugs for erectile dysfunction

Pharmacologic management of erectile dysfunction includes oral, sublingual, intracavernosal, and intraurethral therapies.³¹ Treatment in primary care settings usually includes addressing underlying chronic diseases³² and prescribing phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil, and avanafil). These drugs work by increasing local concentrations of cyclic guanosine monophosphate in the corpus cavernosum to induce vasodilation.³³

While these 4 drugs are still patent-protected, a manufacturer has been allowed to introduce a generic version of sildenafil into US markets, and a generic version of tadalafil is expected to be available soon.

Sildenafil, tadalafil, and vardenafil have been studied and found to have some degree of effectiveness in erectile dysfunction caused by damage to the penile vasculature, denervation, and spinal cord injury.³⁴ All drugs of this class have adverse effects including headache, facial flushing, and nasal congestion, but the drugs are generally well tolerated.³⁵

Sildenafil and tadalafil improve IIEF-5 scores by a similar margin, raising scores on the erectile domain subsection from approximately 14 of a possible 30 to approximately 24 of 30 in a trial of both drugs.³⁶ However, multiple crossover studies comparing the 2 drugs have shown that nearly 75% of patients prefer tadalafil to sildenafil,^36,37 perhaps because of tadalafil’s longer duration of action.³⁴

There is little evidence to suggest that vardenafil is more effective or more often preferred by patients than tadalafil or sidenafil.^34,38 And though data on the newest drug on the market, avanafil, are limited, a meta-analysis concluded that it may be less effective than tadalafil and without significant differences in terms of safety.³⁹

Other treatments

Lifestyle modifications, especially smoking cessation and exercise, have been shown to reduce the risk of erectile dysfunction with varying effect sizes across studies.^40–42 Moreover, factors such as obesity, alcohol use, and smoking may cause irreversible harm, and thus a healthy lifestyle should be encouraged.⁴¹

While there is only weak evidence for the use of psychological interventions alone for treating most types of erectile dysfunction, one meta-analysis found that the combination of psychological intervention and a phosphodiesterase-5 inhibitor improved sexual satisfaction more than drug therapy alone.⁴³

Erectile dysfunction: Take-home points

• Erectile dysfunction is common, affecting nearly 20% of men over the age of 20 and over 75% of men over the age of 75.
• Erectile dysfunction is often associated with chronic disease and may suggest the need to screen for cardiovascular disease.
• Treating underlying chronic diseases may help, and phosphodiesterase-5 inhibitors are effective; tadalafil may be most often preferred.

A 68-year-old man with a history of hypertension, BPH, and erectile dysfunction presents for a 6-month follow-up. His medication use includes lisinopril, which he takes without problems. He denies any new physical symptoms. His physical examination is unremarkable. He says he has heard about supplements that might help with his sexual performance and hopes to discuss recommendations during the visit.

A burgeoning, unregulated industry

Since the passage of the Dietary Supplement and Health Education Act in 1994, a law that decreased oversight of the supplement industry, spending on supplements has skyrocketed to over $41.1 billion each year.⁴⁴ Advertisements for these products typically claim that they improve general mental and physical health, sexual and romantic performance, leanness, and muscularity.⁴⁵ A national survey of men ages 57 and older reported that the most popular products were aimed at nutrition (such as multivitamins), cardiovascular health (such as omega-3 fatty acids), and chronic conditions (such as saw palmetto for BPH).⁴⁶

Little evidence of efficacy

There is little evidence to support the use of most supplements to improve men’s health. For example, a study in 82,405 men found no association between mortality rates and multivitamin use (hazard ratio [HR] 1.07, 95% CI 0.96–1.19).⁴⁷ Even for specific uses, such as cognitive performance, randomized trials exploring the effects of multivitamins in men have been largely negative.⁴⁸

The positive trials that have been reported are often of low quality and are funded by supplement manufacturers. For example, one of the few trials that reported a positive association between multivitamin supplementation and cognition in men was underpowered (N = 51) and found improvement in only 1 of 19 cognitive domains.⁴⁹ Despite the poor design and results to the contrary, this industry-funded study nevertheless concluded that multivitamins may play a role in improving elements of memory.

Evidence of possible harm from antioxidants

While not always specific to men, many meta-analyses have explored the effects of antioxidant supplements on cardiovascular and mortality risk. Most of them concluded that antioxidant supplements have no benefit and that some may actually be harmful.

For example, multiple meta-analyses of vitamin E supplementation found no cardiovascular benefit but possible increases in all-cause mortality rates in those taking high doses (risk ratio 1.04, 95% CI 1.01–1.07).^50,51

Another meta-analysis of 180,938 partici­pants in high-quality studies found an increased risk of all-cause mortality associated with independent intake of several antioxidant vitamins, including beta-carotene (risk ratio 1.07, 95% CI 1.02–1.11) and vitamin A (risk ratio 1.16, 95% CI 1.10–1.24), while intake of vitamin C and selenium had no impact on mortality.⁵²

Similarly, although nearly 10% of US adults report taking omega-3 fatty acid supplements, a review of 24 randomized controlled trials and meta-analyses published between 2005 and 2012 concluded that only 2 supported the use of these supplements for any health benefit.⁵³

Can supplements improve sexual function, prostate health?

To improve sexual function. A 2015 narrative review of the ingredients in General Nutrition Center’s top 30 best-selling products targeted at improving men’s sexual performance (including improving libido and erectile dysfunction) found only poor evidence for any efficacy.⁵⁴ The few studies that did support the use of select supplements, including B vitamins in people with diabetes, L-arginine, and yohimbine, were deemed to be of poor quality or showed a smaller effect size compared with standard medical therapy.

To prevent prostate cancer. Studies of supplement use to improve prostate health have had mixed results. For example, multiple large case-control studies have suggested that taking vitamin D^55,56 or vitamin C⁵⁷ is not associated with prostate cancer risk, while increased vitamin A^58,59 and E^60,61 intake is associated with inconsistent increases in prostate cancer risk.

In the Selenium and Vitamin E Cancer Prevention Trial,⁶² a randomized controlled trial in 35,533 men, those assigned to receive vitamin E supplementation were 17% more likely to get prostate cancer than were those assigned to placebo (HR 1.17, 99% CI 1.004–1.36, P = .008).

However, there are plausible biologic links between nutraceuticals and prostate cancer. For example, studies have linked genetic polymorphisms in vitamin D receptors⁶³ as well as intake of natural androgen receptor modulators, such as the most active polyphenol in green tea,⁶⁴ to prostate cancer risk and aggressiveness in certain populations. This led a recent review to conclude that there is some biologic plausibility, but at present little epidemiologic evidence, to support any dietary supplement’s ability to broadly affect prostate cancer risk.⁶⁵

Interest continues in exploring the targeted use of nutraceuticals as adjuvant therapy in specific populations at risk of prostate cancer.^66,67

To treat BPH. There is a similar dearth of clinical or population-based evidence that supplements can broadly affect BPH symptoms. For example, in a 2012 Cochrane review of Serenoa repens (saw palmetto) utilizing only high-quality evidence, there was no evidence that supplement use significantly reduced lower urinary tract symptoms, nocturia, or peak urine flow in BPH patients, and this was true even when the supplement was taken at triple-strength doses.⁶⁸

For other diseases. There is also limited evidence that supplements can affect other chronic diseases. For example, a meta-analysis of 3,803 patients found that glucosamine, chondroitin, and their combination had no impact on joint pain or joint space narrowing in patients with osteoarthritis of the knee or hip.⁶⁹

Even when there is some evidence to suggest benefit from supplementation, study heterogeneity and varying evidence quality limit confidence in the conclusions. For example, meta-analyses suggest garlic may improve blood pressure control in those with hypertension⁷⁰ and improve lipid and blood glucose control in type 2 diabetes.⁷¹ However, most of the trials included in those systematic reviews were underpowered, with samples as low as 10 patients, and many suffered from improper design, such as inadequate blinding of researchers. In addition, these meta-analyses often do not report adverse events, suggesting that higher quality studies would be needed to adequately measure event rates. As such, there is need for caution and a case-by-case review before recommending even a seemingly benign supplement like garlic to patients.

In total, there is only limited evidence to support the efficacy of supplements across many diseases and concerns common to men in primary care. This includes improving general health, cardiovascular health, sexual functioning, or other chronic diseases. While a supplement’s placebo effect may at times provide some benefit, supplements are much less strictly regulated since the passing of the 1994 act, and even vitamin supplementation has been shown to be associated with negative health outcomes. As such, a patient’s use of supplements requires careful consideration and shared decision-making.

Supplements: Take-home points

• Supplements are only loosely regulated by the federal government.
• There is some biologic but limited epidemiologic evidence for the use of multivitamins to improve cognition or mortality rates; for the use of antioxidant vitamins or omega-3 fatty acids to improve cardiovascular health; for the use of any of the top-selling sexual enhancement supplements to improve libido or erectile function; and for the use of vitamins or other supplements for improving BPH or reducing prostate cancer risk. Using supplements may in some cases be harmful.
• Given the heterogeneity of studies of supplements to manage chronic diseases and a lack of reporting of adverse events, careful consideration is needed when recommending supplements to patients.

Primary care physicians are tasked with a wide variety of issues affecting men. This article reviews the latest research in 4 areas of men’s health commonly addressed in primary care:

• Medical management of benign prostatic hyperplasia (BPH)
• Prostate cancer screening and treatment
• Medical management of erectile dysfunction
• Use of supplements.

See related commentary

MEDICAL MANAGEMENT OF BPH

An 84-year-old man with a history of hypertension, type 2 diabetes, hyperlipidemia, BPH, mild cognitive impairment, and osteoarthritis presents for a 6-month follow-up, accompanied by his son.

Two years ago he was started on a 5-alpha reductase inhibitor and an alpha-blocker for worsening BPH symptoms. His BPH symptoms are currently under control, with an American Urological Association (AUA) symptom index score of 7 of a possible 35 (higher scores being worse).

However, both the patient and son are concerned about the number of medications he is on and wonder if some could be eliminated.

Assessment tools

BPH is a common cause of lower urinary tract symptoms in older men. Evidence-based tools to help the clinician and patient decide on when to consider treatment for symptoms are:

• The AUA symptom index¹
• The International Prostate Symptom Score (IPSS).²

An AUA symptom index score or IPSS score of 8 through 19 of a possible 35 is consistent with moderate symptoms, while a score of 20 or higher indicates severe symptoms.

Combination therapy or monotherapy?

Monotherapy with an alpha-blocker or a 5-alpha reductase inhibitor is often the first-line treatment for BPH-related lower urinary tract symptoms.³ However, combination therapy with both an alpha-blocker and a 5-alpha reductase inhibitor is another evidence-based option.

The Medical Therapy of Prostatic Symptoms study,⁴ a randomized controlled trial, reported that long-term combination therapy reduced the risk of BPH clinical progression better than monotherapy. The same trial also found that either combination therapy or finasteride alone (a 5-alpha reductase inhibitor) reduced the risk of acute urinary retention and the future need for invasive therapy.

Monotherapy after a period of combination therapy?

There is also evidence to support switching from combination to monotherapy after an initial treatment period.

Matsukawa et al⁵ examined the effects of withdrawing the alpha-blocker from BPH combination therapy in a study in 140 patients. For 12 months, all patients received the alpha-blocker silodosin and the 5-alpha reductase inhibitor dutasteride. At 12 months, the remaining 132 patients (8 patients had been lost to follow-up) were randomized to continue combination therapy or to take dutasteride alone for another 12 months. They were evaluated at 0, 12, and 24 months by questionnaires (the IPSS and Overactive Bladder Symptom Score) and urodynamic testing (uroflowmetry, cystometrography, and pressure-flow studies).

There were no significant differen­ces in subjective symptoms and bladder outlet obstruction between patients who continued combination therapy and those who switched to dutasteride monotherapy. In the monotherapy group, those whose symptoms worsened weighed more (68.8 kg vs 62.6 kg, P =.002) and had a higher body mass index (BMI) (26.2 kg/m² vs 22.8 kg/m², P < .001) than those whose symptoms stayed the same or got better.

These findings of successful alpha-blocker withdrawal were consistent with those of other studies.

The Symptom Management After Reducing Therapy study⁶ showed that 80% of men with an IPSS score less than 20 who changed to dutasteride monotherapy did not have a noticeable worsening of their symptoms.

Baldwin et al⁷ noted similar success after withdrawing the alpha-blocker doxazosin in patients on finasteride.

Review all medications

The National Health and Nutrition Examination Survey noted that the estimated prevalence of polypharmacy increased from 8% in 1999 to 15% in 2011.⁸ Many commonly used medications, such as decongestants, antihistamines, and anticholinergic agents, can worsen BPH symptoms,⁹ so it is reasonable to consistently review the patient’s medications to weigh the risks and benefits and determine which ones align with the patient’s personal care goals.

BPH: Take-home points

• Combination therapy with an alpha-blocker and a 5-alpha reductase inhibitor is an effective regimen for BPH.
• Polypharmacy is a significant problem in the elderly.
• Withdrawing the alpha-blocker component from BPH combination therapy can be considered after 1 year of combination therapy in patients whose symptoms have been well controlled.

A 60-year-old patient calls you after receiving his laboratory testing report from his insurance physical. His prostate-specific antigen (PSA) level is 5.1 ng/mL, and he has several questions:

• Should he have agreed to the screening?
• How effective is the screening?
• What are the next steps?

Is PSA screening useful?

Over the last few years, there has been great debate as to the utility of screening for prostate cancer.

The US Centers for Disease Control and Prevention¹⁰ reported that in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it. These statistics support the notion that screening programs may be detecting what might otherwise be a silent disease.

The US Preventive Services Task Force (USPSTF)¹¹ recommends against blanket PSA screening, in view of the low probability that it reduces the risk of death from prostate cancer. For men ages 55 through 69, current guidelines give a grade C recommendation to PSA screening, meaning there is moderate agreement that the benefit is likely small, and screening should be selectively offered based on professional judgment and patient preference. In men ages 70 and older who are not at high risk, the guideline gives screening a grade D recommendation, meaning there is moderate evidence that there is no benefit from the practice. This is a change from the 2012 USPSTF guidelines,¹² which gave a grade D recommendation to PSA screening for all ages.

The American Urological Association¹³ recommends against PSA screening in men under age 40 or ages 70 and older. It does not recommend routine screening in those ages 40 to 54 at average risk, but it says the decision should be individualized in this age group in those at higher risk (eg, with a positive family history, African American). At ages 55 through 69, it recommends shared decision-making, taking into account cancer risk and life expectancy. In those who opt for screening, an interval of 2 years or more may be preferred over annual screening to reduce the risk of overdiagnosis.

The USPSTF recommendations rely heavily on data from 2 trials: the European Randomized Study of Screening for Prostate Cancer (ERSPC)¹⁴ and the Prostate, Lung, Colorectal, and Ovarian Screening (PLCO) trial.¹⁵

The ERSPC¹⁴ demonstrated that screening for prostate cancer reduced deaths from prostate cancer by 20%, with an absolute risk difference of 0.71 deaths per 1,000 men; 1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent 1 death from prostate cancer. Screening also decreased the risk of developing metastatic disease by 30%.¹⁶ On the negative side, screening increased the risk of overdiagnosis and other harms such as bleeding, sepsis, and incontinence.

The PLCO trial,¹⁵ in contrast, found no difference in death rates between men randomly assigned to annual screening and those assigned to usual care. Differences between the trial results were thought to be due to different practice settings as well as study implementation and compliance.

Tsodikov et al¹⁷ reanalyzed data from the ERSPC and the PLCO trial using 3 different mathematical models to estimate the effects of screening in both trials compared with no screening. The analysis found no evidence that the effects of screening vs not screening differed between the 2 trials, ultimately concluding that PSA screening reduced prostate cancer deaths by 25% to 32%, which the authors inferred was primarily a result of earlier detection of cancer.

The Cluster Randomized Trial of PSA Testing for Prostate Cancer,¹⁸ published in March 2018, explored the effect of single PSA screening vs no screening on prostate cancer mortality rates in 419,582 men ages 50 through 69. Although screening detected more cases of low-risk prostate cancer, there was no significant difference in prostate cancer mortality rates after a median follow-up of 10 years. However, 10% to 15% of the control group was estimated to have also been screened, and these results do not directly speak to the efficacy of serial PSA screening.

Extended follow-up of this trial is planned to report on long-term survival benefits and whether screening lowers the risk of metastasis.

Imaging-guided prostate biopsy

Once a patient is found to have an elevated PSA level, standard practice has been to perform transrectal ultrasonography to obtain 12 core biopsy samples. The results indicate whether the prostate contains cancer, how aggressive the cancer is (Gleason score), and whether there is extracapsular extension.

In the past, magnetic resonance imaging (MRI) of the prostate before biopsy was thought to be too costly, and many insurance plans do not currently cover it.

Pahwa et al,¹⁹ however, in a cost-effectiveness study using a decision-analysis model, found that using MRI to detect lesions and then guide biopsy by triaging patients into proper treatment pathways added health benefits in a cost-effective manner in 94.05% of simulations. These benefits were found across all age groups.

This study demonstrated that doctors could use MRI to better evaluate patients for potentially harmful lesions. If a focus of cancer is found, it can be biopsied; if no cancer is seen on MRI, the patient can avoid biopsy completely. Additionally, though MRI tended to miss low-risk cancers, these cancers are thought to disproportionately lead to higher healthcare costs through unnecessary treatment. Therefore, a negative MRI study was believed to be an excellent sign that the patient does not have aggressive prostate cancer. This approach led to a net gain of 0.251 additional quality-adjusted life years compared with the standard biopsy strategy.

The Prostate MRI Imaging Study²⁰ also found MRI to be effective in the prostate cancer workup. In this trial, 576 men who had never undergone biopsy underwent multiparametric MRI, transrectal ultrasonography-guided biopsy, and the reference standard, ie, transperineal template prostate mapping biopsy. Of those who underwent biopsy, 71% received a diagnosis of prostate cancer, and 40% had clinically significant disease. In patients with clinically significant disease, MRI was more sensitive than ultrasonography-guided biopsy (93% vs 48%, P < .0001) but less specific (41% vs 96%, P < .0001).

Based on these findings, if biopsy were performed only in those who had suspicious lesions on MRI, 27% of men with elevated PSA could avoid biopsy and its potential complications such as bleeding and sepsis, which occurred in 5.9% of the biopsy group.

The Prostate Evaluation for Clinically Important Disease: Sampling Using Image Guidance or Not? trial²¹ more recently studied MRI with or without targeted biopsy vs standard transrectal ultrasonography-guided biopsy in 500 men who had not undergone biopsy before, and reported similar results. MRI with or without biopsy led to fewer biopsies and less overdetection of clinically insignificant prostate cancers compared with the standard approach. Furthermore, those in the MRI-targeted biopsy group were 13% less likely to receive a diagnosis of clinically insignificant cancer than those who received the standard biopsy (adjusted difference −13 percentage points, 95% confidence interval [CI] −19 to −7, P < .001).

Together, these data provide another argument for adding multiparametric MRI to the workup of men with an elevated PSA level.

Surveillance vs treatment for prostate cancer

Once prostate cancer is diagnosed, surveillance is becoming an increasingly common management strategy.

The Prostate Cancer Intervention Versus Observation Trial (PIVOT),²² one of the largest and longest trials involving cancer patients, offered further evidence that active surveillance and less intervention for men with prostate cancer is a better approach in many cases. This trial compared prostatectomy and observation alone in a randomized fashion. Inclusion for the study required men to be medically fit for radical prostatectomy, along with having histologically confirmed localized prostate cancer (stage T1-T2NxM0 in the tumor-node-metastasis classification system) of any grade diagnosed within the last 12 months.

During 19.5 years of follow-up, 223 (61.3%) of the 364 men randomly assigned to radical prostatectomy died, compared with 245 (66.8%) of 367 men in the observation group; the difference was not statistically different (P = .06). Only 9.4% of the deaths were due to prostate cancer, 7.4% in the surgery group and 11.4% in the observation group (P = .06).

Surgery was associated with a lower all-cause mortality rate than observation in the subgroup of patients with intermediate-risk prostate cancer (defined as PSA 10–20 ng/mL and a Gleason score of 7). Surgery was also associated with less disease progression.²²

This finding is in line with previous data from the Scandinavian Prostate Cancer Group Study Number 4,²³ as well as the much larger Prostate Testing for Cancer and Treatment (ProtecT) trial,²⁴ both of which reported that metastasis was 1.5 and 2.6 times as common, respectively, in participants in the active surveillance groups. However, in the PIVOT trial, those in the surgery group were significantly more likely than those in the observation group to have erectile dysfunction and urinary incontinence at 10 years.

Therefore, in men with localized disease and in those with low-risk PSA levels, both the PIVOT and ProtecT trials suggest that death from prostate cancer is uncommon and that observation may be more appropriate.

Prostate cancer: Take-home points

• A new look at 2 large trials of PSA screening strengthened evidence that testing in the right patient population can reduce deaths from prostate cancer, but a third recently published trial that found no benefit from 1-time screening may reopen debate on the topic.
• MRI offers a better method than ultrasonography-guided biopsy to triage patients thought to be at high risk of prostate cancer and tends to limit costly overtreatment of disease that likely would not cause death.
• Surgery for prostate cancer may not prolong life but could reduce disease progression, at the risk of more adverse effects.
• Shared decision-making should be practiced when deciding whether to use active surveillance or active treatment of diagnosed prostate cancer.

A 62-year-old man with hypertension, hyperlipidemia, peripheral artery disease, and type 2 diabetes presents for a 6-month follow-up. His medications include aspirin, metformin, lisinopril, and atorvastatin, all of which he takes without problems. Over the past several months, he has noticed that his erections are not adequate for sexual intercourse. He recently heard that a generic version of sildenafil has just become available, and he wonders if it might benefit him.

Erectile dysfunction is common, associated with chronic diseases

Erectile dysfunction, ie, persistent inability to obtain and maintain an erection sufficient to permit satisfactory sexual intercourse,^25,26 is estimated to affect nearly 20% of men over the age of 20 and 75% of men over the age of 75.²⁷

In age-adjusted models, erectile dysfunction has been shown²⁸ to be associated with:

• History of cardiovascular disease (odds ratio [OR] 1.63, 95% CI 1.02–2.63)
• Diabetes (OR 3.90, 95% CI 2.16–7.04)
• Treated hypertension vs no hypertension (OR 2.22, 95% CI 1.30–3.80)
• Current smoking vs never smoking (OR 1.63, 95% CI 1.01–2.62)
• BMI greater than 30 kg/m² vs less than 25 kg/m² (OR 1.80, 95% CI 1.03–3.14).

Because of the strong association between cardiovascular disease and erectile dysfunction, the presence of one often suggests the need to screen for the other.²⁹ While tools such as the International Index of Erectile Function (IIEF-5) have been developed to evaluate erectile dysfunction, it is most often diagnosed on the basis of clinical impression, while validated assessment methods are reserved for clinical trials.²⁸

Multiple causes of erectile dysfunction

Erectile dysfunction arises from inadequate penile tissue response to a sexual signal. The response can be disrupted at several points. For example, damage to vascular smooth muscle cells (eg, from age or obesity) and endothelial cells (from smoking or diabetes) and narrowing of the vascular lumen (from atherosclerosis or hypertension) have all been shown to impair engorgement of the corpus cavernosum.³⁰ In addition, denervation from prostate surgery or spinal trauma and psychogenic causes should be recognized in discussions with patients.

Drugs for erectile dysfunction

Pharmacologic management of erectile dysfunction includes oral, sublingual, intracavernosal, and intraurethral therapies.³¹ Treatment in primary care settings usually includes addressing underlying chronic diseases³² and prescribing phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil, and avanafil). These drugs work by increasing local concentrations of cyclic guanosine monophosphate in the corpus cavernosum to induce vasodilation.³³

While these 4 drugs are still patent-protected, a manufacturer has been allowed to introduce a generic version of sildenafil into US markets, and a generic version of tadalafil is expected to be available soon.

Sildenafil, tadalafil, and vardenafil have been studied and found to have some degree of effectiveness in erectile dysfunction caused by damage to the penile vasculature, denervation, and spinal cord injury.³⁴ All drugs of this class have adverse effects including headache, facial flushing, and nasal congestion, but the drugs are generally well tolerated.³⁵

Sildenafil and tadalafil improve IIEF-5 scores by a similar margin, raising scores on the erectile domain subsection from approximately 14 of a possible 30 to approximately 24 of 30 in a trial of both drugs.³⁶ However, multiple crossover studies comparing the 2 drugs have shown that nearly 75% of patients prefer tadalafil to sildenafil,^36,37 perhaps because of tadalafil’s longer duration of action.³⁴

There is little evidence to suggest that vardenafil is more effective or more often preferred by patients than tadalafil or sidenafil.^34,38 And though data on the newest drug on the market, avanafil, are limited, a meta-analysis concluded that it may be less effective than tadalafil and without significant differences in terms of safety.³⁹

Other treatments

Lifestyle modifications, especially smoking cessation and exercise, have been shown to reduce the risk of erectile dysfunction with varying effect sizes across studies.^40–42 Moreover, factors such as obesity, alcohol use, and smoking may cause irreversible harm, and thus a healthy lifestyle should be encouraged.⁴¹

While there is only weak evidence for the use of psychological interventions alone for treating most types of erectile dysfunction, one meta-analysis found that the combination of psychological intervention and a phosphodiesterase-5 inhibitor improved sexual satisfaction more than drug therapy alone.⁴³

Erectile dysfunction: Take-home points

• Erectile dysfunction is common, affecting nearly 20% of men over the age of 20 and over 75% of men over the age of 75.
• Erectile dysfunction is often associated with chronic disease and may suggest the need to screen for cardiovascular disease.
• Treating underlying chronic diseases may help, and phosphodiesterase-5 inhibitors are effective; tadalafil may be most often preferred.

A 68-year-old man with a history of hypertension, BPH, and erectile dysfunction presents for a 6-month follow-up. His medication use includes lisinopril, which he takes without problems. He denies any new physical symptoms. His physical examination is unremarkable. He says he has heard about supplements that might help with his sexual performance and hopes to discuss recommendations during the visit.

A burgeoning, unregulated industry

Since the passage of the Dietary Supplement and Health Education Act in 1994, a law that decreased oversight of the supplement industry, spending on supplements has skyrocketed to over $41.1 billion each year.⁴⁴ Advertisements for these products typically claim that they improve general mental and physical health, sexual and romantic performance, leanness, and muscularity.⁴⁵ A national survey of men ages 57 and older reported that the most popular products were aimed at nutrition (such as multivitamins), cardiovascular health (such as omega-3 fatty acids), and chronic conditions (such as saw palmetto for BPH).⁴⁶

Little evidence of efficacy

There is little evidence to support the use of most supplements to improve men’s health. For example, a study in 82,405 men found no association between mortality rates and multivitamin use (hazard ratio [HR] 1.07, 95% CI 0.96–1.19).⁴⁷ Even for specific uses, such as cognitive performance, randomized trials exploring the effects of multivitamins in men have been largely negative.⁴⁸

The positive trials that have been reported are often of low quality and are funded by supplement manufacturers. For example, one of the few trials that reported a positive association between multivitamin supplementation and cognition in men was underpowered (N = 51) and found improvement in only 1 of 19 cognitive domains.⁴⁹ Despite the poor design and results to the contrary, this industry-funded study nevertheless concluded that multivitamins may play a role in improving elements of memory.

Evidence of possible harm from antioxidants

While not always specific to men, many meta-analyses have explored the effects of antioxidant supplements on cardiovascular and mortality risk. Most of them concluded that antioxidant supplements have no benefit and that some may actually be harmful.

For example, multiple meta-analyses of vitamin E supplementation found no cardiovascular benefit but possible increases in all-cause mortality rates in those taking high doses (risk ratio 1.04, 95% CI 1.01–1.07).^50,51

Another meta-analysis of 180,938 partici­pants in high-quality studies found an increased risk of all-cause mortality associated with independent intake of several antioxidant vitamins, including beta-carotene (risk ratio 1.07, 95% CI 1.02–1.11) and vitamin A (risk ratio 1.16, 95% CI 1.10–1.24), while intake of vitamin C and selenium had no impact on mortality.⁵²

Similarly, although nearly 10% of US adults report taking omega-3 fatty acid supplements, a review of 24 randomized controlled trials and meta-analyses published between 2005 and 2012 concluded that only 2 supported the use of these supplements for any health benefit.⁵³

Can supplements improve sexual function, prostate health?

To improve sexual function. A 2015 narrative review of the ingredients in General Nutrition Center’s top 30 best-selling products targeted at improving men’s sexual performance (including improving libido and erectile dysfunction) found only poor evidence for any efficacy.⁵⁴ The few studies that did support the use of select supplements, including B vitamins in people with diabetes, L-arginine, and yohimbine, were deemed to be of poor quality or showed a smaller effect size compared with standard medical therapy.

To prevent prostate cancer. Studies of supplement use to improve prostate health have had mixed results. For example, multiple large case-control studies have suggested that taking vitamin D^55,56 or vitamin C⁵⁷ is not associated with prostate cancer risk, while increased vitamin A^58,59 and E^60,61 intake is associated with inconsistent increases in prostate cancer risk.

In the Selenium and Vitamin E Cancer Prevention Trial,⁶² a randomized controlled trial in 35,533 men, those assigned to receive vitamin E supplementation were 17% more likely to get prostate cancer than were those assigned to placebo (HR 1.17, 99% CI 1.004–1.36, P = .008).

However, there are plausible biologic links between nutraceuticals and prostate cancer. For example, studies have linked genetic polymorphisms in vitamin D receptors⁶³ as well as intake of natural androgen receptor modulators, such as the most active polyphenol in green tea,⁶⁴ to prostate cancer risk and aggressiveness in certain populations. This led a recent review to conclude that there is some biologic plausibility, but at present little epidemiologic evidence, to support any dietary supplement’s ability to broadly affect prostate cancer risk.⁶⁵

Interest continues in exploring the targeted use of nutraceuticals as adjuvant therapy in specific populations at risk of prostate cancer.^66,67

To treat BPH. There is a similar dearth of clinical or population-based evidence that supplements can broadly affect BPH symptoms. For example, in a 2012 Cochrane review of Serenoa repens (saw palmetto) utilizing only high-quality evidence, there was no evidence that supplement use significantly reduced lower urinary tract symptoms, nocturia, or peak urine flow in BPH patients, and this was true even when the supplement was taken at triple-strength doses.⁶⁸

For other diseases. There is also limited evidence that supplements can affect other chronic diseases. For example, a meta-analysis of 3,803 patients found that glucosamine, chondroitin, and their combination had no impact on joint pain or joint space narrowing in patients with osteoarthritis of the knee or hip.⁶⁹

Even when there is some evidence to suggest benefit from supplementation, study heterogeneity and varying evidence quality limit confidence in the conclusions. For example, meta-analyses suggest garlic may improve blood pressure control in those with hypertension⁷⁰ and improve lipid and blood glucose control in type 2 diabetes.⁷¹ However, most of the trials included in those systematic reviews were underpowered, with samples as low as 10 patients, and many suffered from improper design, such as inadequate blinding of researchers. In addition, these meta-analyses often do not report adverse events, suggesting that higher quality studies would be needed to adequately measure event rates. As such, there is need for caution and a case-by-case review before recommending even a seemingly benign supplement like garlic to patients.

In total, there is only limited evidence to support the efficacy of supplements across many diseases and concerns common to men in primary care. This includes improving general health, cardiovascular health, sexual functioning, or other chronic diseases. While a supplement’s placebo effect may at times provide some benefit, supplements are much less strictly regulated since the passing of the 1994 act, and even vitamin supplementation has been shown to be associated with negative health outcomes. As such, a patient’s use of supplements requires careful consideration and shared decision-making.

Supplements: Take-home points

• Supplements are only loosely regulated by the federal government.
• There is some biologic but limited epidemiologic evidence for the use of multivitamins to improve cognition or mortality rates; for the use of antioxidant vitamins or omega-3 fatty acids to improve cardiovascular health; for the use of any of the top-selling sexual enhancement supplements to improve libido or erectile function; and for the use of vitamins or other supplements for improving BPH or reducing prostate cancer risk. Using supplements may in some cases be harmful.
• Given the heterogeneity of studies of supplements to manage chronic diseases and a lack of reporting of adverse events, careful consideration is needed when recommending supplements to patients.

Bisphosphonate therapy minimizes bone loss and reduces fracture risk by up to 50% in patients with osteoporosis,¹ but it is also associated with increased risks of osteonecrosis of the jaw and atypical femoral fracture. Although atypical femoral fractures are rare, they can have a devastating effect. Patient concern about this complication has contributed to a decrease in bisphosphonate use by about half in the last decade or so,^2,3 and we fear this could result in an increase in hip fracture rates.

In this article, we examine the evidence on bisphosphonate-associated atypical femoral fractures, including risks, pathogenesis, treatment, and prevention.

ATYPICAL FRACTURES INVOLVE THE FEMORAL SHAFT, NOT THE HEAD

An atypical femoral fracture is a transverse fracture of the femoral shaft (diaphysis), defined by both clinical criteria and radiographic appearance.

To be defined as atypical, a femoral fracture must meet 4 of the following 5 criteria⁴:

• Occurs with minimal or no trauma
• Has a predominantly transverse fracture line, originating at the lateral cortex and sometimes becoming oblique as it progresses medially across the femur
• Extends through both cortices and may be associated with a medial spike (complete fractures); or involves only the lateral cortex (incomplete fractures)
• Is noncomminuted or minimally comminuted
• Shows localized periosteal or endosteal thickening (termed “beaking” or “flaring”) of the lateral cortex at the fracture site.

Several minor features are also important but are not required, eg:

• Cortical thickening of the femoral shaft
• Unilateral or bilateral prodromal pain preceding the fracture
• Bilateral incomplete or complete femoral diaphysis fractures
• Delayed fracture healing.

Atypical femoral fracture can occur anywhere along the shaft, from just distal to the lesser trochanter to just proximal to the supracondylar flare. However, most occur in 2 areas, with 1 cluster centered at about 41 mm from the lesser trochanter (more common in relatively younger patients) and the other at 187 mm.⁵

ABSOLUTE RISK IS LOW BUT INCREASES WITH LONGER USE

Atypical femoral fractures are rare. Schilcher et al⁶ reviewed radiographs of 1,234 women who had a subtrochanteric or shaft fracture and found 59 (4.6%) of fractures were atypical. In a systematic review of 14 studies,⁷ the incidence ranged from 3.0 to 9.8 cases per 100,000 patient-years.

Furthermore, not all atypical femoral fractures are in bisphosphonate users: 7.4% were in nonusers in 1 series⁸ and 22% in another.⁹

Nevertheless, most studies show that bis­phosphonate use increases the incidence of atypical femoral fracture, and the incidence increases with duration of use, especially after 3 years.⁷

An international task force of the American Society for Bone and Mineral Research listed the absolute risk as between 3.2 and 50 cases per 100,000 patient-years, with longer use (> 5 years) increasing the risk to about 100 per 100,000 patient-years.⁴ After stopping bis­phosphonate therapy, the risk diminished by 70% per year.⁹

In another study, for 0.1 to 1.9 years of therapy, the age-adjusted atypical fracture rates were 1.78 per 100,000 per year (95% confidence interval [CI] 1.5–2.0), increasing to 113.1 per 100,000 per year (95% CI 69.3–156.8) with exposure from 8 to 9.9 years.¹⁰

A case-control study found that more than 5 years of bisphosphonate use increased the fracture risk by an odds ratio of 2.74 (95% CI 1.25–6.02).¹¹

The incidence of typical femoral fracture was higher in those who adhered better to their oral bisphosphonate regimen in some studies,¹² but the opposite was true in others.¹³

The benefits of bisphosphonate therapy in reducing fracture risk, however, outweigh the risk of atypical fracture.⁴

We do not know whether the rate of atypical femoral fracture is increasing. A review of Kaiser Permanente Northwest records found that the rates of atypical femoral shaft fracture had remained stable from 1996 to 2009. However, 61.9% of patients who met the strict radiographic criteria had taken oral bisphosphonates.¹⁴ These data suggest that bisphosphonate use has not increased the overall population-based risk for subtrochanteric and femoral shaft fractures, but that bisphosphonates and other risk factors may have increased the likelihood that such fractures will exhibit atypical radiographic features.

A population-based study in Denmark¹³ found that alendronate use longer than 10 years was associated with an adjusted 30% lower risk of hip fracture and no increase in the risk of subtrochanteric and femoral shaft fracture. In addition, the risk of subtrochanteric and femoral shaft fracture was lower with high adherence to alendronate treatment (based on medication possession ratio > 80%) compared with low adherence (ratio < 50%) (odds ratio 0.88, 95% CI 0.77–0.99). The risk was not increased in current vs past users.

The Danish study¹³ used the coding of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) to identify subtrochanteric and femoral shaft fractures without radiologic review for atypical radiographic features. The lack of specific ICD-10 coding for subtrochanteric and femoral shaft fractures with atypical radiographic features has limited our knowledge of their incidence.

After an atypical femoral fracture, patients have a significant risk of fracture on the contralateral side. In a case-control study, 28% of patients with atypical femoral fracture suffered a contralateral fracture, compared with 0.9% of patients presenting with a typical fracture pattern (odds ratio 42.6, 95% CI 12.8–142.4).¹⁵

Contralateral fracture occurs from 1 month to 4 years after the index atypical femoral fracture.¹⁶

There are reports of bisphosphonate-related low-impact fractures in other sites such as the tibia¹⁷ and forearm.¹⁸ However, they may be too rare to warrant screening.

Mortality rates

A Swedish database study found that patients with atypical femoral fractures, whether bisphosphonate users or nonusers, do not have higher mortality rates than patients with ordinary subtrochanteric or femoral shaft fractures.¹⁹ Furthermore, the mortality rates for those with atypical femoral fracture were similar to rates in the general population. In contrast, patients with an ordinary femoral fracture had a higher mortality risk than the general population.¹⁹

Other studies suggest that atypical femoral fracture may be associated with a less favorable prognosis in older patients,²⁰ but this could be due to differences in demographics, treatment adherence, or postfracture care.²¹

In addition, functional outcomes as measured by independent mobility at discharge and at 3 months were comparable between patients with atypical fracture and those with typical fracture.²²

IMAGING STUDIES

If a long-term bisphosphonate user presents with hip, thigh, or groin pain, imaging studies are recommended.

Plain radiography

Radiography is usually the first step and should include a frontal view of the pelvis (Figure 1) and 2 views of the full length of each femur. If radiography is not conclusive, bone scan or magnetic resonance imaging (MRI) should be considered.

A linear cortex transverse fracture pattern and focal lateral cortical thickening are the most sensitive and specific radiographic features.^23,24 Because of the risk of fracture on the contralateral side, radiographic study of that side is recommended as well.

Computed tomography

Computed tomography (CT) is not sensitive for early stress fractures and, given the radiation burden, is not recommended in the workup of atypical fracture.

Bone scanning

Bone scanning using technetium 99m-labeled methylene diphosphonate with a gamma camera shows active bone turnover. Stress fractures and atypical femoral fractures are most easily identified in the third (delayed) phase of the bone scan. Although bone scanning is highly sensitive, the specificity is limited by lack of spatial resolution. Atypical femoral fracture appears as increased activity in the subtrochanteric region with a predilection for the lateral cortex.

Dual-energy x-ray absorptiometry

Conventional dual-energy x-ray absorptiometry (DXA) extends only to 1 to 2 cm below the lesser trochanter and can therefore miss atypical fractures, which usually occur farther down. The overall detection rate for DXA was 61% in a sample of 33 patients.²⁵

Newer scanners can look at the entire femoral shaft.²⁶ In addition, newer software can quantify focal thickening (beaking) of the lateral cortex and screen patients who have no symptoms. The results of serial measurements can be graphed so that the practitioner can view trends to help assess or rule out potential asymptomatic atypical femoral fracture.

A localized reaction (periosteal thickening of the lateral cortex or beaking) often precedes atypical femoral fracture. A 2017 study reported that patients with high localized reaction (mean height 3.3 mm) that was of the pointed type and was accompanied by prodromal pain had an increased risk of complete or incomplete atypical femoral fracture at that site.²⁷ This finding is used by the newer DXA software. The predictive value of beaking on extended femoral DXA may be as high as 83%.²⁶

Magnetic resonance imaging

The MRI characteristics of atypical femoral fracture are similar to those of other stress fractures except that there is a lateral-to-medial pattern rather than a medial pattern. The earliest findings include periosteal reaction about the lateral cortex with a normal marrow signal.

MRI may be of particular benefit in patients with known atypical femoral fracture to screen the contralateral leg. It should image the entire length of both femurs. Contrast enhancement is not needed.

Regardless of whether initial findings were discovered on conventional radiographs or DXA, MRI confirmation is needed. Radio­nuclide bone scanning is currently not recommended because it lacks specificity. Combination imaging is recommended, with either radiography plus MRI or DXA plus MRI.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of atypical femoral fracture includes stress fracture, pathologic fracture, hypophosphatasia, and osteogenesis imperfecta.²⁸ Hypophosphatemic osteomalacia can cause Looser zones, which can be confused with atypical femoral fractures but usually occur on the medial side.⁴ Stress fracture of the femur can occur below the lesser trochanter but usually begins in the medial, not the lateral, cortex.

Pathologic fractures from underlying osseous lesions can mimic the cortical beaking of bisphosphonate-related fracture, but they usually show the associated underlying lucent lesion and poorly defined margins. A sinus tract along the region of a chronic osteomyelitis may also appear similar.

Hypophosphatasia is an inborn error of metabolism caused by a loss-of-function mutation in the gene encoding alkaline phosphatase, resulting in pyrophosphate accumulation and causing osteomalacia from impaired mineralization. This can result in femoral pseudofracture that is often bilateral and occurs in the subtrochanteric region.²⁹

Patients with atypical femoral fracture are generally a heterogeneous group, but there are risk factors to note other than bisphosphonate exposure.

Asian women had a risk 8 times higher than white women in 1 study.³⁰

Bone geometry. Mahjoub et al⁸ reported that compared with controls, patients with atypical femoral fracture had greater offset of the femoral shaft from the center of rotation of the femoral head, a more acute angle between the femoral neck and shaft, and greater proximal cortical thickness.

Medications. In addition to bisphosphonates, other drugs associated with atypical femoral fracture include RANK-ligand inhibitors such as denosumab (another drug for osteoporosis),³¹ glucocorticoids,^32,33 and proton pump inhibitors.^32,33

Genetics. Three sisters with atypical femoral fracture were found to have 37 rare mutations in 34 genes, including one in the GGPS1 gene, which codes for geranylgeranyl pyrophosphate synthase—an enzyme that bisphosphonates inhibit.³⁴

Medical conditions other than osteoporosis include collagen diseases, chronic pulmonary disease, asthma, rheumatoid arthritis, and diabetes.³⁵

Clinical recommendations

Current recommendations are to reevaluate bisphosphonate use in patients with osteoporosis after 5 or more years of therapy.³⁶

Given that patients with osteoporosis are at increased risk of typical fracture, those at higher risk should be considered for continued bisphosphonate therapy. Factors for high risk include the following:

• History of fracture on therapy
• Hip T score –2.5 or lower
• Older age (≥ 70)
• Other strong risk factors for fracture such as smoking, alcohol use, corticosteroid use, rheumatoid arthritis, and family history
• World Health Organization FRAX fracture risk score above the country-specific threshold.

Those at lower risk should be considered for a 2- to 3-year bisphosphonate holiday with periodic reevaluation of bone density and, possibly, bone markers.³⁶

WHAT IS THE UNDERLYING PATHOPHYSIOLOGY?

The mechanism by which bisphosphonates increase the risk of atypical femoral fracture is not clear. These drugs work by suppressing bone turnover; however, in theory, prolonged use could suppress it too much and increase bone fragility.

One hypothesis is that bisphosphonates impair the toughening of cortical bone, an important barrier to clinical fracture. This is supported by a study that found bisphosphonate users with atypical femoral fracture had deficits in intrinsic and extrinsic bone toughness, perhaps due to treatment-related increases in matrix mineralization.³⁷ Although this study and others showed an increase in matrix mineralization and reduced mineralization heterogeneity with bisphosphonate use,^38,39 it is unclear whether such changes contributed to reduced toughness or to atypical femoral fracture.

Changes in the skeletal geometry of the lower limb such as femoral neck-shaft angle and femoral curvature alter the stresses and strains experienced by the femoral diaphysis with loading. Because the incidence of incomplete atypical femoral fracture is much greater than that of complete fracture, most incomplete atypical femoral fractures heal before the fracture progresses.

Ultimately, all fractures, including atypical femoral fractures, occur when mechanical stress and strain exceed bone strength.

Antiresorptive drugs such as bisphosphonates, estrogen, calcitonin, and RANK ligand inhibitors prevent hip fracture by increasing the strength of the proximal femur—perhaps at the expense of the strength (or toughness) of the subtrochanteric shaft. It is also possible that treatment-related increases in hip strength (and reduced hip fracture rates) promote or sustain the transfer of stress and strain to femoral regions that experience lesser or no increases in strength from treatment, which likely includes the shaft.^40,41

CT studies in Japanese women with osteoporosis have shown that 2 years of zoledronate therapy had greater effects in the hip than in the femoral shaft, with significant increases in cortical thickness and volumetric bone mineral density at the femoral neck and intertrochanteric region compared with baseline.⁴² But zoledronate did not increase femoral shaft cortical thickness and caused only a minor increase in femoral shaft volumetric bone mineral density. Fracture patterns may have depended on damage and effects of bone turnover on mass and structure.

This hypothetical scenario portrays a possible “hip survival bias” mechanism for atypical femoral fracture, with the association with antiresorptive drugs arising from greater stress and strain in cortical regions where these fractures occur rather than from treatment-related reductions in cortical bone strength or toughness.

PRODROMAL PAIN IS COMMON

From 32% to 76% of patients who have incomplete or developing atypical femoral fracture present with a prodrome of groin or hip pain.^4,43 Prodromal pain occurs any time from 2 weeks to several years before the fracture, presenting as pain in the anterior or lateral thigh or in the groin.

Prodromal pain in a patient on antiresorptive therapy should be a signal for the clinician to obtain a radiograph of the hip and to look for contralateral symptoms and fractures. The most common mechanism of injury appears to be a ground-level fall or even a nontraumatic activity such as walking or stepping off a curb.

MEDICAL MANAGEMENT

In bisphosphonate users with radiographic evidence of atypical femoral fracture, the bis­phosphonate should be discontinued and the patient assessed for calcium and vitamin D deficiency, with supplements prescribed if needed.⁴

For patients with incomplete fracture and persistent pain after 3 months of medical management, prophylactic surgical nail fixation is recommended to prevent complete fracture.

Teriparatide, which has been associated with enhanced bone fracture healing, is a possible treatment to promote healing of atypical femoral fracture, either alone or as an adjunct to surgical fixation. A systematic review published in 2015 supported the use of teriparatide for enhancing fracture healing in atypical femoral fracture.⁴⁴ In addition, a 10-patient series⁴⁵ showed that incomplete fractures without radiolucent lines responded to teriparatide alone, whereas those with radiolucent lines needed intramedullary nailing.

These results suggest that teriparatide works best when the fracture site is stable, either inherently or with surgical fixation.

ORTHOPEDIC CARE

Orthopedic care for atypical femoral fracture differs depending on whether the patient experiences pain and whether the fracture is incomplete or complete. Figure 2 shows a treatment algorithm for atypical femoral fracture.

These are difficult fractures to manage, complicated by delayed healing in the elderly, complex displacement patterns, altered bone geometry, and risk of fracture in the opposite limb, all of which raise questions about recommending protected weight-bearing exercise.

Furthermore, atypical femoral fracture is often associated with increased anterolateral bowing of the femur, making it difficult to insert an intramedullary nail: the radius of curvature of the bone is shorter than that of a standard femoral nail. This mismatch can lead to intraoperative complications such as iatrogenic fracture during prophylactic nailing, malunion from excess straightening of the femur (which can itself lead to leg length discrepancy), and gapping of the fracture site, particularly on the medial side.

Intramedullary nailing is the first-line treatment for complete atypical femoral fracture, although the risk of delayed healing and revision surgery may be somewhat higher than with typical femoral fracture.⁴⁶ Prophylactic intramedullary nailing should be considered for a patient with intractable pain.²

A radiograph of the opposite leg should be obtained routinely, looking for an asymptomatic fracture. Bisphosphonates should be discontinued and calcium and vitamin D continued. Teriparatide therapy can be considered as an alternative treatment.

Conservative management for incomplete fracture without pain

Incomplete atypical femoral fracture unaccompanied by pain can be followed conservatively.⁴⁷ In addition to stopping antiresorptive therapy, patients need to avoid high-impact and repetitive-impact activities such as jumping or running. If pain occurs, patients should begin protected weight-bearing exercise.

Treatment is uncertain for incomplete fracture with pain

For patients with incomplete atypical femoral fracture and pain, treatment is controversial. Regimens that include 2 to 3 months of protected weight-bearing exercise, a full metabolic bone workup, calcium and vitamin D supplementation, and anabolic bone agents have produced some success. Some authors have reported poor results from conservative care, with few patients achieving pain relief or signs of complete healing.^48,49 Additionally, if an incomplete fracture is found in the opposite femur, protected weight-bearing of both legs may not be possible.

Patients with incomplete fracture should be monitored regularly with radiography and physical examination. If there is progression of the fracture, escalation of pain, or failure to heal within 2 to 3 months, then surgical treatment is necessary.

Prophylactic placement of an intramedullary nail to prevent completion of the fracture and allow a return to full weight-bearing is generally advised.⁵⁰ A long locking plate can be used if bone deformities make it difficult to place an intramedullary nail; however, nails are preferred because they allow formation of endochondral callus, which can be helpful in these difficult-to-heal fractures.

Results from retrospective reviews have shown that surgically treated patients with bis­phosphonate-associated incomplete atypical femoral fracture were more likely than those treated nonsurgically to be pain-free (81% vs 64%) and have radiographic healing (100% vs 18% at final follow-up).⁴⁶ Results have also been positive for those with complete atypical femoral fracture. At 6 months, 64% of surgically treated patients were pain-free and 98% were radiographically healed.⁵¹

The unusual geometry of the femur in patients with atypical femoral fracture and the presence of intramedullary cortical callus makes the placement of an intramedullary femoral rod more complex than in typical femoral fracture.⁸

Intramedullary nailing of atypical femoral fracture is a challenge for even the most experienced surgeon, and vigilance is imperative to avoid iatrogenic fracture and malunion.

MANY QUESTIONS REMAIN

We need more studies on the pathophysiology of bisphosphonate-associated atypical femoral fracture, the value of periodic screening with DXA, and which factors predict high risk (eg, Asian ethnicity, use of certain medications, femoral geometry). In addition, we need more data on the success of conservative management of incomplete fracture, including use of teriparatide.

Bisphosphonate therapy minimizes bone loss and reduces fracture risk by up to 50% in patients with osteoporosis,¹ but it is also associated with increased risks of osteonecrosis of the jaw and atypical femoral fracture. Although atypical femoral fractures are rare, they can have a devastating effect. Patient concern about this complication has contributed to a decrease in bisphosphonate use by about half in the last decade or so,^2,3 and we fear this could result in an increase in hip fracture rates.

In this article, we examine the evidence on bisphosphonate-associated atypical femoral fractures, including risks, pathogenesis, treatment, and prevention.

ATYPICAL FRACTURES INVOLVE THE FEMORAL SHAFT, NOT THE HEAD

An atypical femoral fracture is a transverse fracture of the femoral shaft (diaphysis), defined by both clinical criteria and radiographic appearance.

To be defined as atypical, a femoral fracture must meet 4 of the following 5 criteria⁴:

• Occurs with minimal or no trauma
• Has a predominantly transverse fracture line, originating at the lateral cortex and sometimes becoming oblique as it progresses medially across the femur
• Extends through both cortices and may be associated with a medial spike (complete fractures); or involves only the lateral cortex (incomplete fractures)
• Is noncomminuted or minimally comminuted
• Shows localized periosteal or endosteal thickening (termed “beaking” or “flaring”) of the lateral cortex at the fracture site.

Several minor features are also important but are not required, eg:

• Cortical thickening of the femoral shaft
• Unilateral or bilateral prodromal pain preceding the fracture
• Bilateral incomplete or complete femoral diaphysis fractures
• Delayed fracture healing.

Atypical femoral fracture can occur anywhere along the shaft, from just distal to the lesser trochanter to just proximal to the supracondylar flare. However, most occur in 2 areas, with 1 cluster centered at about 41 mm from the lesser trochanter (more common in relatively younger patients) and the other at 187 mm.⁵

ABSOLUTE RISK IS LOW BUT INCREASES WITH LONGER USE

Atypical femoral fractures are rare. Schilcher et al⁶ reviewed radiographs of 1,234 women who had a subtrochanteric or shaft fracture and found 59 (4.6%) of fractures were atypical. In a systematic review of 14 studies,⁷ the incidence ranged from 3.0 to 9.8 cases per 100,000 patient-years.

Furthermore, not all atypical femoral fractures are in bisphosphonate users: 7.4% were in nonusers in 1 series⁸ and 22% in another.⁹

Nevertheless, most studies show that bis­phosphonate use increases the incidence of atypical femoral fracture, and the incidence increases with duration of use, especially after 3 years.⁷

An international task force of the American Society for Bone and Mineral Research listed the absolute risk as between 3.2 and 50 cases per 100,000 patient-years, with longer use (> 5 years) increasing the risk to about 100 per 100,000 patient-years.⁴ After stopping bis­phosphonate therapy, the risk diminished by 70% per year.⁹

In another study, for 0.1 to 1.9 years of therapy, the age-adjusted atypical fracture rates were 1.78 per 100,000 per year (95% confidence interval [CI] 1.5–2.0), increasing to 113.1 per 100,000 per year (95% CI 69.3–156.8) with exposure from 8 to 9.9 years.¹⁰

A case-control study found that more than 5 years of bisphosphonate use increased the fracture risk by an odds ratio of 2.74 (95% CI 1.25–6.02).¹¹

The incidence of typical femoral fracture was higher in those who adhered better to their oral bisphosphonate regimen in some studies,¹² but the opposite was true in others.¹³

The benefits of bisphosphonate therapy in reducing fracture risk, however, outweigh the risk of atypical fracture.⁴

We do not know whether the rate of atypical femoral fracture is increasing. A review of Kaiser Permanente Northwest records found that the rates of atypical femoral shaft fracture had remained stable from 1996 to 2009. However, 61.9% of patients who met the strict radiographic criteria had taken oral bisphosphonates.¹⁴ These data suggest that bisphosphonate use has not increased the overall population-based risk for subtrochanteric and femoral shaft fractures, but that bisphosphonates and other risk factors may have increased the likelihood that such fractures will exhibit atypical radiographic features.

A population-based study in Denmark¹³ found that alendronate use longer than 10 years was associated with an adjusted 30% lower risk of hip fracture and no increase in the risk of subtrochanteric and femoral shaft fracture. In addition, the risk of subtrochanteric and femoral shaft fracture was lower with high adherence to alendronate treatment (based on medication possession ratio > 80%) compared with low adherence (ratio < 50%) (odds ratio 0.88, 95% CI 0.77–0.99). The risk was not increased in current vs past users.

The Danish study¹³ used the coding of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) to identify subtrochanteric and femoral shaft fractures without radiologic review for atypical radiographic features. The lack of specific ICD-10 coding for subtrochanteric and femoral shaft fractures with atypical radiographic features has limited our knowledge of their incidence.

After an atypical femoral fracture, patients have a significant risk of fracture on the contralateral side. In a case-control study, 28% of patients with atypical femoral fracture suffered a contralateral fracture, compared with 0.9% of patients presenting with a typical fracture pattern (odds ratio 42.6, 95% CI 12.8–142.4).¹⁵

Contralateral fracture occurs from 1 month to 4 years after the index atypical femoral fracture.¹⁶

There are reports of bisphosphonate-related low-impact fractures in other sites such as the tibia¹⁷ and forearm.¹⁸ However, they may be too rare to warrant screening.

Mortality rates

A Swedish database study found that patients with atypical femoral fractures, whether bisphosphonate users or nonusers, do not have higher mortality rates than patients with ordinary subtrochanteric or femoral shaft fractures.¹⁹ Furthermore, the mortality rates for those with atypical femoral fracture were similar to rates in the general population. In contrast, patients with an ordinary femoral fracture had a higher mortality risk than the general population.¹⁹

Other studies suggest that atypical femoral fracture may be associated with a less favorable prognosis in older patients,²⁰ but this could be due to differences in demographics, treatment adherence, or postfracture care.²¹

In addition, functional outcomes as measured by independent mobility at discharge and at 3 months were comparable between patients with atypical fracture and those with typical fracture.²²

IMAGING STUDIES

If a long-term bisphosphonate user presents with hip, thigh, or groin pain, imaging studies are recommended.

Plain radiography

Radiography is usually the first step and should include a frontal view of the pelvis (Figure 1) and 2 views of the full length of each femur. If radiography is not conclusive, bone scan or magnetic resonance imaging (MRI) should be considered.

A linear cortex transverse fracture pattern and focal lateral cortical thickening are the most sensitive and specific radiographic features.^23,24 Because of the risk of fracture on the contralateral side, radiographic study of that side is recommended as well.

Computed tomography

Computed tomography (CT) is not sensitive for early stress fractures and, given the radiation burden, is not recommended in the workup of atypical fracture.

Bone scanning

Bone scanning using technetium 99m-labeled methylene diphosphonate with a gamma camera shows active bone turnover. Stress fractures and atypical femoral fractures are most easily identified in the third (delayed) phase of the bone scan. Although bone scanning is highly sensitive, the specificity is limited by lack of spatial resolution. Atypical femoral fracture appears as increased activity in the subtrochanteric region with a predilection for the lateral cortex.

Dual-energy x-ray absorptiometry

Conventional dual-energy x-ray absorptiometry (DXA) extends only to 1 to 2 cm below the lesser trochanter and can therefore miss atypical fractures, which usually occur farther down. The overall detection rate for DXA was 61% in a sample of 33 patients.²⁵

Newer scanners can look at the entire femoral shaft.²⁶ In addition, newer software can quantify focal thickening (beaking) of the lateral cortex and screen patients who have no symptoms. The results of serial measurements can be graphed so that the practitioner can view trends to help assess or rule out potential asymptomatic atypical femoral fracture.

A localized reaction (periosteal thickening of the lateral cortex or beaking) often precedes atypical femoral fracture. A 2017 study reported that patients with high localized reaction (mean height 3.3 mm) that was of the pointed type and was accompanied by prodromal pain had an increased risk of complete or incomplete atypical femoral fracture at that site.²⁷ This finding is used by the newer DXA software. The predictive value of beaking on extended femoral DXA may be as high as 83%.²⁶

Magnetic resonance imaging

The MRI characteristics of atypical femoral fracture are similar to those of other stress fractures except that there is a lateral-to-medial pattern rather than a medial pattern. The earliest findings include periosteal reaction about the lateral cortex with a normal marrow signal.

MRI may be of particular benefit in patients with known atypical femoral fracture to screen the contralateral leg. It should image the entire length of both femurs. Contrast enhancement is not needed.

Regardless of whether initial findings were discovered on conventional radiographs or DXA, MRI confirmation is needed. Radio­nuclide bone scanning is currently not recommended because it lacks specificity. Combination imaging is recommended, with either radiography plus MRI or DXA plus MRI.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of atypical femoral fracture includes stress fracture, pathologic fracture, hypophosphatasia, and osteogenesis imperfecta.²⁸ Hypophosphatemic osteomalacia can cause Looser zones, which can be confused with atypical femoral fractures but usually occur on the medial side.⁴ Stress fracture of the femur can occur below the lesser trochanter but usually begins in the medial, not the lateral, cortex.

Pathologic fractures from underlying osseous lesions can mimic the cortical beaking of bisphosphonate-related fracture, but they usually show the associated underlying lucent lesion and poorly defined margins. A sinus tract along the region of a chronic osteomyelitis may also appear similar.

Hypophosphatasia is an inborn error of metabolism caused by a loss-of-function mutation in the gene encoding alkaline phosphatase, resulting in pyrophosphate accumulation and causing osteomalacia from impaired mineralization. This can result in femoral pseudofracture that is often bilateral and occurs in the subtrochanteric region.²⁹

Patients with atypical femoral fracture are generally a heterogeneous group, but there are risk factors to note other than bisphosphonate exposure.

Asian women had a risk 8 times higher than white women in 1 study.³⁰

Bone geometry. Mahjoub et al⁸ reported that compared with controls, patients with atypical femoral fracture had greater offset of the femoral shaft from the center of rotation of the femoral head, a more acute angle between the femoral neck and shaft, and greater proximal cortical thickness.

Medications. In addition to bisphosphonates, other drugs associated with atypical femoral fracture include RANK-ligand inhibitors such as denosumab (another drug for osteoporosis),³¹ glucocorticoids,^32,33 and proton pump inhibitors.^32,33

Genetics. Three sisters with atypical femoral fracture were found to have 37 rare mutations in 34 genes, including one in the GGPS1 gene, which codes for geranylgeranyl pyrophosphate synthase—an enzyme that bisphosphonates inhibit.³⁴

Medical conditions other than osteoporosis include collagen diseases, chronic pulmonary disease, asthma, rheumatoid arthritis, and diabetes.³⁵

Clinical recommendations

Current recommendations are to reevaluate bisphosphonate use in patients with osteoporosis after 5 or more years of therapy.³⁶

Given that patients with osteoporosis are at increased risk of typical fracture, those at higher risk should be considered for continued bisphosphonate therapy. Factors for high risk include the following:

• History of fracture on therapy
• Hip T score –2.5 or lower
• Older age (≥ 70)
• Other strong risk factors for fracture such as smoking, alcohol use, corticosteroid use, rheumatoid arthritis, and family history
• World Health Organization FRAX fracture risk score above the country-specific threshold.

Those at lower risk should be considered for a 2- to 3-year bisphosphonate holiday with periodic reevaluation of bone density and, possibly, bone markers.³⁶

WHAT IS THE UNDERLYING PATHOPHYSIOLOGY?

The mechanism by which bisphosphonates increase the risk of atypical femoral fracture is not clear. These drugs work by suppressing bone turnover; however, in theory, prolonged use could suppress it too much and increase bone fragility.

One hypothesis is that bisphosphonates impair the toughening of cortical bone, an important barrier to clinical fracture. This is supported by a study that found bisphosphonate users with atypical femoral fracture had deficits in intrinsic and extrinsic bone toughness, perhaps due to treatment-related increases in matrix mineralization.³⁷ Although this study and others showed an increase in matrix mineralization and reduced mineralization heterogeneity with bisphosphonate use,^38,39 it is unclear whether such changes contributed to reduced toughness or to atypical femoral fracture.

Changes in the skeletal geometry of the lower limb such as femoral neck-shaft angle and femoral curvature alter the stresses and strains experienced by the femoral diaphysis with loading. Because the incidence of incomplete atypical femoral fracture is much greater than that of complete fracture, most incomplete atypical femoral fractures heal before the fracture progresses.

Ultimately, all fractures, including atypical femoral fractures, occur when mechanical stress and strain exceed bone strength.

Antiresorptive drugs such as bisphosphonates, estrogen, calcitonin, and RANK ligand inhibitors prevent hip fracture by increasing the strength of the proximal femur—perhaps at the expense of the strength (or toughness) of the subtrochanteric shaft. It is also possible that treatment-related increases in hip strength (and reduced hip fracture rates) promote or sustain the transfer of stress and strain to femoral regions that experience lesser or no increases in strength from treatment, which likely includes the shaft.^40,41

CT studies in Japanese women with osteoporosis have shown that 2 years of zoledronate therapy had greater effects in the hip than in the femoral shaft, with significant increases in cortical thickness and volumetric bone mineral density at the femoral neck and intertrochanteric region compared with baseline.⁴² But zoledronate did not increase femoral shaft cortical thickness and caused only a minor increase in femoral shaft volumetric bone mineral density. Fracture patterns may have depended on damage and effects of bone turnover on mass and structure.

This hypothetical scenario portrays a possible “hip survival bias” mechanism for atypical femoral fracture, with the association with antiresorptive drugs arising from greater stress and strain in cortical regions where these fractures occur rather than from treatment-related reductions in cortical bone strength or toughness.

PRODROMAL PAIN IS COMMON

From 32% to 76% of patients who have incomplete or developing atypical femoral fracture present with a prodrome of groin or hip pain.^4,43 Prodromal pain occurs any time from 2 weeks to several years before the fracture, presenting as pain in the anterior or lateral thigh or in the groin.

Prodromal pain in a patient on antiresorptive therapy should be a signal for the clinician to obtain a radiograph of the hip and to look for contralateral symptoms and fractures. The most common mechanism of injury appears to be a ground-level fall or even a nontraumatic activity such as walking or stepping off a curb.

MEDICAL MANAGEMENT

In bisphosphonate users with radiographic evidence of atypical femoral fracture, the bis­phosphonate should be discontinued and the patient assessed for calcium and vitamin D deficiency, with supplements prescribed if needed.⁴

For patients with incomplete fracture and persistent pain after 3 months of medical management, prophylactic surgical nail fixation is recommended to prevent complete fracture.

Teriparatide, which has been associated with enhanced bone fracture healing, is a possible treatment to promote healing of atypical femoral fracture, either alone or as an adjunct to surgical fixation. A systematic review published in 2015 supported the use of teriparatide for enhancing fracture healing in atypical femoral fracture.⁴⁴ In addition, a 10-patient series⁴⁵ showed that incomplete fractures without radiolucent lines responded to teriparatide alone, whereas those with radiolucent lines needed intramedullary nailing.

These results suggest that teriparatide works best when the fracture site is stable, either inherently or with surgical fixation.

ORTHOPEDIC CARE

Orthopedic care for atypical femoral fracture differs depending on whether the patient experiences pain and whether the fracture is incomplete or complete. Figure 2 shows a treatment algorithm for atypical femoral fracture.

These are difficult fractures to manage, complicated by delayed healing in the elderly, complex displacement patterns, altered bone geometry, and risk of fracture in the opposite limb, all of which raise questions about recommending protected weight-bearing exercise.

Furthermore, atypical femoral fracture is often associated with increased anterolateral bowing of the femur, making it difficult to insert an intramedullary nail: the radius of curvature of the bone is shorter than that of a standard femoral nail. This mismatch can lead to intraoperative complications such as iatrogenic fracture during prophylactic nailing, malunion from excess straightening of the femur (which can itself lead to leg length discrepancy), and gapping of the fracture site, particularly on the medial side.

Intramedullary nailing is the first-line treatment for complete atypical femoral fracture, although the risk of delayed healing and revision surgery may be somewhat higher than with typical femoral fracture.⁴⁶ Prophylactic intramedullary nailing should be considered for a patient with intractable pain.²

A radiograph of the opposite leg should be obtained routinely, looking for an asymptomatic fracture. Bisphosphonates should be discontinued and calcium and vitamin D continued. Teriparatide therapy can be considered as an alternative treatment.

Conservative management for incomplete fracture without pain

Incomplete atypical femoral fracture unaccompanied by pain can be followed conservatively.⁴⁷ In addition to stopping antiresorptive therapy, patients need to avoid high-impact and repetitive-impact activities such as jumping or running. If pain occurs, patients should begin protected weight-bearing exercise.

Treatment is uncertain for incomplete fracture with pain

For patients with incomplete atypical femoral fracture and pain, treatment is controversial. Regimens that include 2 to 3 months of protected weight-bearing exercise, a full metabolic bone workup, calcium and vitamin D supplementation, and anabolic bone agents have produced some success. Some authors have reported poor results from conservative care, with few patients achieving pain relief or signs of complete healing.^48,49 Additionally, if an incomplete fracture is found in the opposite femur, protected weight-bearing of both legs may not be possible.

Patients with incomplete fracture should be monitored regularly with radiography and physical examination. If there is progression of the fracture, escalation of pain, or failure to heal within 2 to 3 months, then surgical treatment is necessary.

Prophylactic placement of an intramedullary nail to prevent completion of the fracture and allow a return to full weight-bearing is generally advised.⁵⁰ A long locking plate can be used if bone deformities make it difficult to place an intramedullary nail; however, nails are preferred because they allow formation of endochondral callus, which can be helpful in these difficult-to-heal fractures.

Results from retrospective reviews have shown that surgically treated patients with bis­phosphonate-associated incomplete atypical femoral fracture were more likely than those treated nonsurgically to be pain-free (81% vs 64%) and have radiographic healing (100% vs 18% at final follow-up).⁴⁶ Results have also been positive for those with complete atypical femoral fracture. At 6 months, 64% of surgically treated patients were pain-free and 98% were radiographically healed.⁵¹

The unusual geometry of the femur in patients with atypical femoral fracture and the presence of intramedullary cortical callus makes the placement of an intramedullary femoral rod more complex than in typical femoral fracture.⁸

Intramedullary nailing of atypical femoral fracture is a challenge for even the most experienced surgeon, and vigilance is imperative to avoid iatrogenic fracture and malunion.

MANY QUESTIONS REMAIN

We need more studies on the pathophysiology of bisphosphonate-associated atypical femoral fracture, the value of periodic screening with DXA, and which factors predict high risk (eg, Asian ethnicity, use of certain medications, femoral geometry). In addition, we need more data on the success of conservative management of incomplete fracture, including use of teriparatide.

Bisphosphonate therapy minimizes bone loss and reduces fracture risk by up to 50% in patients with osteoporosis,¹ but it is also associated with increased risks of osteonecrosis of the jaw and atypical femoral fracture. Although atypical femoral fractures are rare, they can have a devastating effect. Patient concern about this complication has contributed to a decrease in bisphosphonate use by about half in the last decade or so,^2,3 and we fear this could result in an increase in hip fracture rates.

In this article, we examine the evidence on bisphosphonate-associated atypical femoral fractures, including risks, pathogenesis, treatment, and prevention.

ATYPICAL FRACTURES INVOLVE THE FEMORAL SHAFT, NOT THE HEAD

An atypical femoral fracture is a transverse fracture of the femoral shaft (diaphysis), defined by both clinical criteria and radiographic appearance.

To be defined as atypical, a femoral fracture must meet 4 of the following 5 criteria⁴:

• Occurs with minimal or no trauma
• Has a predominantly transverse fracture line, originating at the lateral cortex and sometimes becoming oblique as it progresses medially across the femur
• Extends through both cortices and may be associated with a medial spike (complete fractures); or involves only the lateral cortex (incomplete fractures)
• Is noncomminuted or minimally comminuted
• Shows localized periosteal or endosteal thickening (termed “beaking” or “flaring”) of the lateral cortex at the fracture site.

Several minor features are also important but are not required, eg:

• Cortical thickening of the femoral shaft
• Unilateral or bilateral prodromal pain preceding the fracture
• Bilateral incomplete or complete femoral diaphysis fractures
• Delayed fracture healing.

Atypical femoral fracture can occur anywhere along the shaft, from just distal to the lesser trochanter to just proximal to the supracondylar flare. However, most occur in 2 areas, with 1 cluster centered at about 41 mm from the lesser trochanter (more common in relatively younger patients) and the other at 187 mm.⁵

ABSOLUTE RISK IS LOW BUT INCREASES WITH LONGER USE

Atypical femoral fractures are rare. Schilcher et al⁶ reviewed radiographs of 1,234 women who had a subtrochanteric or shaft fracture and found 59 (4.6%) of fractures were atypical. In a systematic review of 14 studies,⁷ the incidence ranged from 3.0 to 9.8 cases per 100,000 patient-years.

Furthermore, not all atypical femoral fractures are in bisphosphonate users: 7.4% were in nonusers in 1 series⁸ and 22% in another.⁹

Nevertheless, most studies show that bis­phosphonate use increases the incidence of atypical femoral fracture, and the incidence increases with duration of use, especially after 3 years.⁷

An international task force of the American Society for Bone and Mineral Research listed the absolute risk as between 3.2 and 50 cases per 100,000 patient-years, with longer use (> 5 years) increasing the risk to about 100 per 100,000 patient-years.⁴ After stopping bis­phosphonate therapy, the risk diminished by 70% per year.⁹

In another study, for 0.1 to 1.9 years of therapy, the age-adjusted atypical fracture rates were 1.78 per 100,000 per year (95% confidence interval [CI] 1.5–2.0), increasing to 113.1 per 100,000 per year (95% CI 69.3–156.8) with exposure from 8 to 9.9 years.¹⁰

A case-control study found that more than 5 years of bisphosphonate use increased the fracture risk by an odds ratio of 2.74 (95% CI 1.25–6.02).¹¹

The incidence of typical femoral fracture was higher in those who adhered better to their oral bisphosphonate regimen in some studies,¹² but the opposite was true in others.¹³

The benefits of bisphosphonate therapy in reducing fracture risk, however, outweigh the risk of atypical fracture.⁴

We do not know whether the rate of atypical femoral fracture is increasing. A review of Kaiser Permanente Northwest records found that the rates of atypical femoral shaft fracture had remained stable from 1996 to 2009. However, 61.9% of patients who met the strict radiographic criteria had taken oral bisphosphonates.¹⁴ These data suggest that bisphosphonate use has not increased the overall population-based risk for subtrochanteric and femoral shaft fractures, but that bisphosphonates and other risk factors may have increased the likelihood that such fractures will exhibit atypical radiographic features.

A population-based study in Denmark¹³ found that alendronate use longer than 10 years was associated with an adjusted 30% lower risk of hip fracture and no increase in the risk of subtrochanteric and femoral shaft fracture. In addition, the risk of subtrochanteric and femoral shaft fracture was lower with high adherence to alendronate treatment (based on medication possession ratio > 80%) compared with low adherence (ratio < 50%) (odds ratio 0.88, 95% CI 0.77–0.99). The risk was not increased in current vs past users.

The Danish study¹³ used the coding of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) to identify subtrochanteric and femoral shaft fractures without radiologic review for atypical radiographic features. The lack of specific ICD-10 coding for subtrochanteric and femoral shaft fractures with atypical radiographic features has limited our knowledge of their incidence.

After an atypical femoral fracture, patients have a significant risk of fracture on the contralateral side. In a case-control study, 28% of patients with atypical femoral fracture suffered a contralateral fracture, compared with 0.9% of patients presenting with a typical fracture pattern (odds ratio 42.6, 95% CI 12.8–142.4).¹⁵

Contralateral fracture occurs from 1 month to 4 years after the index atypical femoral fracture.¹⁶

There are reports of bisphosphonate-related low-impact fractures in other sites such as the tibia¹⁷ and forearm.¹⁸ However, they may be too rare to warrant screening.

Mortality rates

A Swedish database study found that patients with atypical femoral fractures, whether bisphosphonate users or nonusers, do not have higher mortality rates than patients with ordinary subtrochanteric or femoral shaft fractures.¹⁹ Furthermore, the mortality rates for those with atypical femoral fracture were similar to rates in the general population. In contrast, patients with an ordinary femoral fracture had a higher mortality risk than the general population.¹⁹

Other studies suggest that atypical femoral fracture may be associated with a less favorable prognosis in older patients,²⁰ but this could be due to differences in demographics, treatment adherence, or postfracture care.²¹

In addition, functional outcomes as measured by independent mobility at discharge and at 3 months were comparable between patients with atypical fracture and those with typical fracture.²²

IMAGING STUDIES

If a long-term bisphosphonate user presents with hip, thigh, or groin pain, imaging studies are recommended.

Plain radiography

Radiography is usually the first step and should include a frontal view of the pelvis (Figure 1) and 2 views of the full length of each femur. If radiography is not conclusive, bone scan or magnetic resonance imaging (MRI) should be considered.

A linear cortex transverse fracture pattern and focal lateral cortical thickening are the most sensitive and specific radiographic features.^23,24 Because of the risk of fracture on the contralateral side, radiographic study of that side is recommended as well.

Computed tomography

Computed tomography (CT) is not sensitive for early stress fractures and, given the radiation burden, is not recommended in the workup of atypical fracture.

Bone scanning

Bone scanning using technetium 99m-labeled methylene diphosphonate with a gamma camera shows active bone turnover. Stress fractures and atypical femoral fractures are most easily identified in the third (delayed) phase of the bone scan. Although bone scanning is highly sensitive, the specificity is limited by lack of spatial resolution. Atypical femoral fracture appears as increased activity in the subtrochanteric region with a predilection for the lateral cortex.

Dual-energy x-ray absorptiometry

Conventional dual-energy x-ray absorptiometry (DXA) extends only to 1 to 2 cm below the lesser trochanter and can therefore miss atypical fractures, which usually occur farther down. The overall detection rate for DXA was 61% in a sample of 33 patients.²⁵

Newer scanners can look at the entire femoral shaft.²⁶ In addition, newer software can quantify focal thickening (beaking) of the lateral cortex and screen patients who have no symptoms. The results of serial measurements can be graphed so that the practitioner can view trends to help assess or rule out potential asymptomatic atypical femoral fracture.

A localized reaction (periosteal thickening of the lateral cortex or beaking) often precedes atypical femoral fracture. A 2017 study reported that patients with high localized reaction (mean height 3.3 mm) that was of the pointed type and was accompanied by prodromal pain had an increased risk of complete or incomplete atypical femoral fracture at that site.²⁷ This finding is used by the newer DXA software. The predictive value of beaking on extended femoral DXA may be as high as 83%.²⁶

Magnetic resonance imaging

The MRI characteristics of atypical femoral fracture are similar to those of other stress fractures except that there is a lateral-to-medial pattern rather than a medial pattern. The earliest findings include periosteal reaction about the lateral cortex with a normal marrow signal.

MRI may be of particular benefit in patients with known atypical femoral fracture to screen the contralateral leg. It should image the entire length of both femurs. Contrast enhancement is not needed.

Regardless of whether initial findings were discovered on conventional radiographs or DXA, MRI confirmation is needed. Radio­nuclide bone scanning is currently not recommended because it lacks specificity. Combination imaging is recommended, with either radiography plus MRI or DXA plus MRI.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of atypical femoral fracture includes stress fracture, pathologic fracture, hypophosphatasia, and osteogenesis imperfecta.²⁸ Hypophosphatemic osteomalacia can cause Looser zones, which can be confused with atypical femoral fractures but usually occur on the medial side.⁴ Stress fracture of the femur can occur below the lesser trochanter but usually begins in the medial, not the lateral, cortex.

Pathologic fractures from underlying osseous lesions can mimic the cortical beaking of bisphosphonate-related fracture, but they usually show the associated underlying lucent lesion and poorly defined margins. A sinus tract along the region of a chronic osteomyelitis may also appear similar.

Hypophosphatasia is an inborn error of metabolism caused by a loss-of-function mutation in the gene encoding alkaline phosphatase, resulting in pyrophosphate accumulation and causing osteomalacia from impaired mineralization. This can result in femoral pseudofracture that is often bilateral and occurs in the subtrochanteric region.²⁹

Patients with atypical femoral fracture are generally a heterogeneous group, but there are risk factors to note other than bisphosphonate exposure.

Asian women had a risk 8 times higher than white women in 1 study.³⁰

Bone geometry. Mahjoub et al⁸ reported that compared with controls, patients with atypical femoral fracture had greater offset of the femoral shaft from the center of rotation of the femoral head, a more acute angle between the femoral neck and shaft, and greater proximal cortical thickness.

Medications. In addition to bisphosphonates, other drugs associated with atypical femoral fracture include RANK-ligand inhibitors such as denosumab (another drug for osteoporosis),³¹ glucocorticoids,^32,33 and proton pump inhibitors.^32,33

Genetics. Three sisters with atypical femoral fracture were found to have 37 rare mutations in 34 genes, including one in the GGPS1 gene, which codes for geranylgeranyl pyrophosphate synthase—an enzyme that bisphosphonates inhibit.³⁴

Medical conditions other than osteoporosis include collagen diseases, chronic pulmonary disease, asthma, rheumatoid arthritis, and diabetes.³⁵

Clinical recommendations

Current recommendations are to reevaluate bisphosphonate use in patients with osteoporosis after 5 or more years of therapy.³⁶

Given that patients with osteoporosis are at increased risk of typical fracture, those at higher risk should be considered for continued bisphosphonate therapy. Factors for high risk include the following:

• History of fracture on therapy
• Hip T score –2.5 or lower
• Older age (≥ 70)
• Other strong risk factors for fracture such as smoking, alcohol use, corticosteroid use, rheumatoid arthritis, and family history
• World Health Organization FRAX fracture risk score above the country-specific threshold.

Those at lower risk should be considered for a 2- to 3-year bisphosphonate holiday with periodic reevaluation of bone density and, possibly, bone markers.³⁶

WHAT IS THE UNDERLYING PATHOPHYSIOLOGY?

The mechanism by which bisphosphonates increase the risk of atypical femoral fracture is not clear. These drugs work by suppressing bone turnover; however, in theory, prolonged use could suppress it too much and increase bone fragility.

One hypothesis is that bisphosphonates impair the toughening of cortical bone, an important barrier to clinical fracture. This is supported by a study that found bisphosphonate users with atypical femoral fracture had deficits in intrinsic and extrinsic bone toughness, perhaps due to treatment-related increases in matrix mineralization.³⁷ Although this study and others showed an increase in matrix mineralization and reduced mineralization heterogeneity with bisphosphonate use,^38,39 it is unclear whether such changes contributed to reduced toughness or to atypical femoral fracture.

Changes in the skeletal geometry of the lower limb such as femoral neck-shaft angle and femoral curvature alter the stresses and strains experienced by the femoral diaphysis with loading. Because the incidence of incomplete atypical femoral fracture is much greater than that of complete fracture, most incomplete atypical femoral fractures heal before the fracture progresses.

Ultimately, all fractures, including atypical femoral fractures, occur when mechanical stress and strain exceed bone strength.

Antiresorptive drugs such as bisphosphonates, estrogen, calcitonin, and RANK ligand inhibitors prevent hip fracture by increasing the strength of the proximal femur—perhaps at the expense of the strength (or toughness) of the subtrochanteric shaft. It is also possible that treatment-related increases in hip strength (and reduced hip fracture rates) promote or sustain the transfer of stress and strain to femoral regions that experience lesser or no increases in strength from treatment, which likely includes the shaft.^40,41

CT studies in Japanese women with osteoporosis have shown that 2 years of zoledronate therapy had greater effects in the hip than in the femoral shaft, with significant increases in cortical thickness and volumetric bone mineral density at the femoral neck and intertrochanteric region compared with baseline.⁴² But zoledronate did not increase femoral shaft cortical thickness and caused only a minor increase in femoral shaft volumetric bone mineral density. Fracture patterns may have depended on damage and effects of bone turnover on mass and structure.

This hypothetical scenario portrays a possible “hip survival bias” mechanism for atypical femoral fracture, with the association with antiresorptive drugs arising from greater stress and strain in cortical regions where these fractures occur rather than from treatment-related reductions in cortical bone strength or toughness.

PRODROMAL PAIN IS COMMON

From 32% to 76% of patients who have incomplete or developing atypical femoral fracture present with a prodrome of groin or hip pain.^4,43 Prodromal pain occurs any time from 2 weeks to several years before the fracture, presenting as pain in the anterior or lateral thigh or in the groin.

Prodromal pain in a patient on antiresorptive therapy should be a signal for the clinician to obtain a radiograph of the hip and to look for contralateral symptoms and fractures. The most common mechanism of injury appears to be a ground-level fall or even a nontraumatic activity such as walking or stepping off a curb.

MEDICAL MANAGEMENT

In bisphosphonate users with radiographic evidence of atypical femoral fracture, the bis­phosphonate should be discontinued and the patient assessed for calcium and vitamin D deficiency, with supplements prescribed if needed.⁴

For patients with incomplete fracture and persistent pain after 3 months of medical management, prophylactic surgical nail fixation is recommended to prevent complete fracture.

Teriparatide, which has been associated with enhanced bone fracture healing, is a possible treatment to promote healing of atypical femoral fracture, either alone or as an adjunct to surgical fixation. A systematic review published in 2015 supported the use of teriparatide for enhancing fracture healing in atypical femoral fracture.⁴⁴ In addition, a 10-patient series⁴⁵ showed that incomplete fractures without radiolucent lines responded to teriparatide alone, whereas those with radiolucent lines needed intramedullary nailing.

These results suggest that teriparatide works best when the fracture site is stable, either inherently or with surgical fixation.

ORTHOPEDIC CARE

Orthopedic care for atypical femoral fracture differs depending on whether the patient experiences pain and whether the fracture is incomplete or complete. Figure 2 shows a treatment algorithm for atypical femoral fracture.

These are difficult fractures to manage, complicated by delayed healing in the elderly, complex displacement patterns, altered bone geometry, and risk of fracture in the opposite limb, all of which raise questions about recommending protected weight-bearing exercise.

Furthermore, atypical femoral fracture is often associated with increased anterolateral bowing of the femur, making it difficult to insert an intramedullary nail: the radius of curvature of the bone is shorter than that of a standard femoral nail. This mismatch can lead to intraoperative complications such as iatrogenic fracture during prophylactic nailing, malunion from excess straightening of the femur (which can itself lead to leg length discrepancy), and gapping of the fracture site, particularly on the medial side.

Intramedullary nailing is the first-line treatment for complete atypical femoral fracture, although the risk of delayed healing and revision surgery may be somewhat higher than with typical femoral fracture.⁴⁶ Prophylactic intramedullary nailing should be considered for a patient with intractable pain.²

A radiograph of the opposite leg should be obtained routinely, looking for an asymptomatic fracture. Bisphosphonates should be discontinued and calcium and vitamin D continued. Teriparatide therapy can be considered as an alternative treatment.

Conservative management for incomplete fracture without pain

Incomplete atypical femoral fracture unaccompanied by pain can be followed conservatively.⁴⁷ In addition to stopping antiresorptive therapy, patients need to avoid high-impact and repetitive-impact activities such as jumping or running. If pain occurs, patients should begin protected weight-bearing exercise.

Treatment is uncertain for incomplete fracture with pain

For patients with incomplete atypical femoral fracture and pain, treatment is controversial. Regimens that include 2 to 3 months of protected weight-bearing exercise, a full metabolic bone workup, calcium and vitamin D supplementation, and anabolic bone agents have produced some success. Some authors have reported poor results from conservative care, with few patients achieving pain relief or signs of complete healing.^48,49 Additionally, if an incomplete fracture is found in the opposite femur, protected weight-bearing of both legs may not be possible.

Patients with incomplete fracture should be monitored regularly with radiography and physical examination. If there is progression of the fracture, escalation of pain, or failure to heal within 2 to 3 months, then surgical treatment is necessary.

Prophylactic placement of an intramedullary nail to prevent completion of the fracture and allow a return to full weight-bearing is generally advised.⁵⁰ A long locking plate can be used if bone deformities make it difficult to place an intramedullary nail; however, nails are preferred because they allow formation of endochondral callus, which can be helpful in these difficult-to-heal fractures.

Results from retrospective reviews have shown that surgically treated patients with bis­phosphonate-associated incomplete atypical femoral fracture were more likely than those treated nonsurgically to be pain-free (81% vs 64%) and have radiographic healing (100% vs 18% at final follow-up).⁴⁶ Results have also been positive for those with complete atypical femoral fracture. At 6 months, 64% of surgically treated patients were pain-free and 98% were radiographically healed.⁵¹

The unusual geometry of the femur in patients with atypical femoral fracture and the presence of intramedullary cortical callus makes the placement of an intramedullary femoral rod more complex than in typical femoral fracture.⁸

Intramedullary nailing of atypical femoral fracture is a challenge for even the most experienced surgeon, and vigilance is imperative to avoid iatrogenic fracture and malunion.

MANY QUESTIONS REMAIN

We need more studies on the pathophysiology of bisphosphonate-associated atypical femoral fracture, the value of periodic screening with DXA, and which factors predict high risk (eg, Asian ethnicity, use of certain medications, femoral geometry). In addition, we need more data on the success of conservative management of incomplete fracture, including use of teriparatide.