Drug Therapy

Plaque rupture and thrombosis play central roles in the genesis of acute coronary syndrome. Aspirin has long been the preventive agent of choice. But dual antiplatelet therapy with aspirin plus clopidogrel (Plavix) is warranted in many patients to further reduce their risk of future cardiovascular events.

Although dual antiplatelet therapy is usually started by a subspecialist, the primary care physician is often the one who ensures that the patient remains compliant with it in the long term. A review of the seminal published data is helpful in understanding the rationale behind dual antiplatelet therapy and its risks and benefits.

In the mid-1990s, the thienopyridine ticlopidine (Ticlid) was found to significantly decrease the number of deaths, target-lesion revascularizations, and myocardial infarctions (MIs) in the 30 days following stent placement. ¹ However, 2% to 3% of patients experienced neutropenia² and thrombotic thrombocytopenic purpura with this drug,³ leading to the use of clopidogrel, another agent in the same class. Over the past decade, a large body of evidence has established the usefulness of clopidogrel in a number of clinical settings.

In this paper we review the current use of clopidogrel in ST-elevation MI, non-ST-elevation acute coronary syndromes, and percutaneous coronary intervention, and discuss the landmark trials that are the basis for the treatment guidelines published jointly by the American College of Cardiology (ACC) and the American Heart Association (AHA).^4–6 We also briefly discuss the use of prasugrel (Effient), the newest antiplatelet agent to gain approval from the US Food and Drug Administration (FDA).

CLOPIDOGREL AS AN ALTERNATIVE TO ASPIRIN

Clopidogrel, a prodrug, is converted into its active form in the liver.⁷ It then irreversibly binds to the platelet P2Y12 receptor and inhibits adenosine diphosphate-induced platelet aggregation.

Those treated with clopidogrel had an annual risk of ischemic stroke, MI, or vascular death of 5.32%, compared with 5.83% in the aspirin group, for a statistically significant 8.7% relative risk reduction (P = .043). The observed frequency of neutropenia (neutrophils < 1.2 × 10⁹/L) was 0.10% with clopidogrel vs 0.17% with aspirin. This study showed clopidogrel to be an effective alternative in patients who cannot tolerate aspirin.

CASE 1: ST-ELEVATION MI

A 57-year-old farmer in rural Ohio with a history of hypertension and hyperlipidemia presents to the local emergency department 45 minutes after the onset, while he was chopping wood, of dull, aching, substernal chest pain that radiates to his jaw. Electrocardiography reveals 2-mm ST-segment elevation in leads V₁ through V₆. He is treated with aspirin 162 mg, low-molecular-weight heparin, and tenecteplase.

What would be the value of starting dual antiplatelet therapy with clopidogrel in this patient?

Clopidogrel, aspirin, and fibrinolysis in ST-elevation MI

The CLARITY-TIMI 28 trial (Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction)⁹ included 3,491 patients (ages 18 to 75) from 319 international sites. All patients received a fibrinolytic agent, aspirin (162 mg to 325 mg on the first day and 75 mg to 162 mg thereafter), and heparin as part of standard care for acute ST-elevation MI (Table 1). Patients were randomized to receive a 300-mg loading dose of clopidogrel followed by 75 mg daily or placebo within 12 hours of onset of ST-elevation MI. The status of the infarct-related artery was ascertained by protocol-mandated coronary angiography 48 to 192 hours after starting the study medication. The primary end point was the composite of an occluded infarct-related artery on angiography, death from any cause prior to angiography, or recurrent MI prior to angiography.

Significantly fewer patients had an end point event in the clopidogrel group than in the placebo group, 15% vs 21.7% (P < .001), for a relative risk reduction of 31%. There was no significant increase in major or minor bleeding events.

Of note, the CLARITY-TIMI 28 patients were relatively young (average age 57 years) and at low cardiovascular risk (30-day mortality risk < 5%).

The COMMIT trial (Clopidogrel and Metoprolol in Myocardial Infarction)¹⁰ consisted of 45,852 patients with suspected acute MI admitted to 1,250 hospitals in China. Each patient received aspirin 162 mg daily plus either clopidogrel 75 mg daily (n = 22,961) or placebo (n = 22,891) for the duration of hospitalization (average 16 days) or 28 days, whichever came first.

The incidence of the primary composite end point of death, reinfarction, or stroke was significantly lower with clopidogrel than with placebo (9.2% vs 10.1%, P = .002). This was regardless of age (the average age was 61, and 26% of patients were older than 70), sex, time to presentation (67% presented within 12 hours), or reperfusion strategy (49% underwent fibrinolysis). The clopidogrel group did not have a significantly higher incidence of bleeding, but patients in this trial did not receive a loading dose of clopidogrel.

Comment. In view of the results of these trials, our 57-year-old patient should start clopidogrel early.

CASE 2: NON-ST-ELEVATION ACUTE CORONARY SYNDROME

A 65-year-old woman living independently with no significant medical history presents to the emergency room with 2 hours of waxing and waning substernal chest pain. Her blood pressure is 145/90 mm Hg, her heart rate is 95 beats per minute, and the results of her physical examination are unremarkable. Resting electrocardiography reveals 1.5-mm ST-segment depression in the inferior leads, and her troponin T level on admission is two times the upper limit of normal. She is given aspirin and is started on low-molecular-weight heparin and intravenous nitroglycerin.

What would be the value of starting clopidogrel in this patient?

Clopidogrel in non-ST-elevation acute coronary syndromes

The ACC/AHA guidelines strongly support starting clopidogrel in patients with non-ST-elevation acute coronary syndromes (Table 2).⁵

The CURE trial (Clopidogrel in Unstable Angina to Prevent Recurrent Events)¹¹ provided the evidence for this recommendation. In this trial, 12,562 patients from 482 centers in 28 countries who presented within 24 hours of coronary symptoms, without ST elevation, were randomized to receive either clopidogrel (a 300-mg loading dose, followed by 75 mg daily) or placebo for 3 to 12 months (mean 9 months).

Significantly fewer patients in the clopidogrel group reached one of the end points of the composite primary outcome (cardiovascular death, nonfatal MI, or stroke): 9.3% vs 11.4%, 95% confidence interval (CI) 0.72–0.90, P < .001. Significantly fewer of them also suffered one of the secondary outcomes, ie, severe ischemia, heart failure, or need for revascularization.

Of concern was a higher rate of major bleeding in the clopidogrel group (3.7%) than in the placebo group (2.7%) without an excess of fatal bleeding. For every 1,000 patients treated with clopidogrel, 6 required a blood transfusion. Nevertheless, CURE proved that patients with non-ST-elevation acute coronary syndromes benefited from clopidogrel, regardless of whether they underwent percutaneous coronary intervention.

Comment. Our patient should receive clopidogrel and, if she has no significant bleeding, she should continue to take it for at least 12 months after discharge. It is important for the primary care physician to ensure compliance with this agent and not discontinue it on routine clinical follow-up.

CASE 3: BARE-METAL STENT PLACEMENT

A 62-year-old man with a history of hypertension, diabetes, and hyperlipidemia presents to his primary care physician’s office with stable-effort angina that is not responding to an excellent anti-ischemic regimen and is affecting his quality of life. He is referred for coronary angiography, which reveals 80% stenosis of the proximal left circumflex artery. He undergoes a percutaneous coronary intervention with placement of a bare-metal stent.

How long should he be on clopidogrel? And what if a drug-eluting stent had been placed instead of a bare-metal stent?

Dual therapy after bare-metal stent placement

Dual antiplatelet therapy with clopidogrel and aspirin is recommended in all patients receiving a stent (Table 2). The better safety and efficacy of clopidogrel compared with ticlopidine has been established in patients receiving a coronary artery stent,^12,13 and clopidogrel’s favorable safety profile soon made it the thienopyridine of choice.

The CREDO trial (Clopidogrel for the Reduction of Events During Observation)¹⁴ randomized 2,116 patients undergoing an elective percutaneous coronary intervention (bare-metal stent placement only) to receive a 300-mg loading dose of clopidogrel 3 to 24 hours before the procedure, or placebo. All patients received 325 mg of aspirin. After the intervention, all patients received clopidogrel 75 mg daily and aspirin 325 mg daily through day 28. For day 29 through 12 months, those who had received the 300-mg preprocedural loading dose of clopidogrel continued with 75 mg daily, and those who had not received clopidogrel before the procedure received placebo.

No significant difference was seen in the primary outcome for those who received pretreatment with clopidogrel; however, in a subgroup analysis, those who received clopidogrel at least 6 hours before the percutaneous coronary intervention had a 38.6% relative risk reduction (Table 1). Long-term use of clopidogrel (ie, for 12 months) was associated with an overall relative reduction of 26.9% in the combined risk of death, MI, or stroke.

PCI-CURE, an analysis of 2,658 patients in the CURE trial with non-ST-elevation acute coronary syndrome who underwent PCI,¹⁵ yielded results similar to those of CREDO, with a 31% reduction in the rate of cardiovascular death or MI at 30 days and at 9 months. Of note, however, clopidogrel was given for a median of 6 days prior to the procedure.

Comment. The minimum suggested duration of clopidogrel treatment after placement of a bare-metal stent is 1 month. However, these trial results indicate that patients who are not at high risk of bleeding should take clopidogrel for at least 12 months.

Dual antiplatelet therapy with drug-eluting stents

Although rates of in-stent restenosis are clearly lower with drug-eluting stents than with bare-metal stents, the antiproliferative effect of drug-eluting stents may delay complete endothelialization of every strut. This may contribute to late (> 1 month after placement) or very late (> 1 year) thrombosis of the stent after clopidogrel is discontinued.^16–18

In 2006, the FDA indicated that dual antiplatelet therapy was needed for 6 months with paclitaxel-eluting (Taxus) stents and 3 months with sirolimus-eluting (Cipher) stents. As reports of very late stent thrombosis began to appear in 2007, concern arose over the need to extend the duration of clopidogrel treatment.

Bavry et al¹⁹ quantified the incidence of late and very late stent thrombosis in a meta-analysis of 14 clinical trials that randomized patients to receive either a drug-eluting stent (paclitaxel or sirolimus) or a bare-metal stent.¹⁹ The incidence of stent thrombosis within 30 days in this analysis was similar for both groups—4.4 per 1,000 patients vs 5 per 1,000 (relative risk 0.89; 95% CI 0.46–1.75; P = .74). However, the rate of very late stent thrombosis was significantly higher in those receiving a drug-eluting stent vs a bare-metal stent—5 per 1,000 patients treated (relative risk 5.02, 95% CI 1.29–19.52; P = .02).

The results of this and other studies led the ACC and AHA to revise their joint guidelines to recommend thienopyridine treatment for at least 1 year for patients who receive a drug-eluting stent.^6,20–22 In fact, many cardiologists consider indefinite dual antiplatelet therapy in patients with a drug-eluting stent to avoid very late in-stent thrombosis, especially in patients undergoing high-risk interventions such as placement of multiple stents, bifurcation lesions, and unprotected left main trunk interventions.

Thus, when faced with a patient with a recent coronary stent implantation, the primary care physician should be aware of the type of stent and the duration of therapy recommended by the interventional cardiologist. Also, in the absence of a pressing indication, elective surgery should be deferred for 1 year after placement of a drug-eluting stent, as this would necessitate stopping clopidogrel and would increase the risk of perioperative stent thrombosis, which is associated with high rates of morbidity and death.

CASE 4: HIGH-RISK CORONARY ARTERY DISEASE

A 67-year-old woman presents to your office to establish care. She has a history of diabetes and established coronary artery disease with two bare-metal stents placed 2 years ago. She is taking aspirin 81 mg.

What would be the value of adding clopidogrel to her regimen?

No indication for clopidogrel in chronic coronary artery disease

The CHARISMA trial (Clopidogrel for High Atherothrombotic and Ischemic Stabilization, Management, and Avoidance)²³ randomized 15,603 patients with stable cardiovascular disease or multiple risk factors to receive either clopidogrel plus low-dose aspirin or placebo plus low-dose aspirin and followed them for a median of 28 months (Table 1).

The primary end point (a composite of MI, stroke, or death) was 6.8% with clopidogrel plus aspirin and 7.3% with aspirin alone, indicating no significant benefit with clopidogrel plus aspirin compared with aspirin alone in reducing the rate of MI, stroke, or cardiovascular death in patients with high-risk but stable atherothrombotic disease. A marginal statistical benefit with dual antiplatelet therapy was noted in the subgroup of patients with previously documented coronary, cerebrovascular, or peripheral vascular disease—6.9% with aspirin plus clopidogrel vs 7.9% with aspirin alone (relative risk 0.88; 95% CI 0.77–0.998; P = .046).

Consequently, there is no compelling reason to start clopidogrel in this patient.

PRASUGREL, THE NEWEST THIENOPYRIDINE

Prasugrel was recently approved by the FDA as antiplatelet treatment for patients with acute coronary syndromes planning to undergo a percutaneous coronary intervention.²⁴ It has been shown to inhibit adenosine-diphosphate-induced platelet activation in a more consistent and effective manner than clopidogrel.^25,26

Although both clopidogrel and prasugrel are prodrugs, 80% of absorbed clopidogrel is metabolized by esterases into inactive metabolites, and the availability of active metabolite can vary, as it is significantly influenced by polymorphisms in the cytochrome P450 system. ²⁷ In contrast, prasugrel is not degraded by esterases, and its conversion to active metabolite by the cytochrome P450 system is not influenced by common genetic polymorphisms, particularly CYP2C19*2.

TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction) provided most of the evidence for the approval of prasugrel for clinical use.^28,29 In this trial, a 60-mg loading dose of prasugrel followed by a daily maintenance dose of 10 mg was significantly superior to the current clopidogrel regimen in preventing death from cardiovascular causes, nonfatal MI, or nonfatal stroke during a study period of 15 months.²⁸ Also observed was a 24% lower rate of MI, a 34% lower rate of urgent target-vessel revascularization, and a 52% lower rate of stent thrombosis.

These benefits, however, came at the cost of a significantly higher risk of major bleeding, including the potential for three excess fatal bleeding events for every 1,000 patients treated. Patients at highest risk at the dosages evaluated included the elderly (age 75 and older), patients who weigh less than 60 kg, and patients with a history of stroke or transient ischemic attack. Based on these results, we recommend caution with the use of prasugrel in these patient subsets.

Clinical use of prasugrel is likely to be highest in patients presenting with ST-elevation MI who are undergoing a primary percutaneous coronary intervention. There is currently no evidence from any randomized clinical trial to support the safety of prasugrel given in the emergency room or “upstream” in the setting of non-ST-elevation acute coronary syndromes.

Of note, patients with non-ST-elevation acute coronary syndromes in the TRITON trial were randomized only after angiographic definition. As a result, only 179 patients exposed to prasugrel were referred for coronary artery bypass surgery, but the rate of surgery-related major bleeding in this group was 13.4% (vs 3.2% in the clopidogrel group). Based on these data, prasugrel should be withheld for at least 1 week prior to any surgery.

Plaque rupture and thrombosis play central roles in the genesis of acute coronary syndrome. Aspirin has long been the preventive agent of choice. But dual antiplatelet therapy with aspirin plus clopidogrel (Plavix) is warranted in many patients to further reduce their risk of future cardiovascular events.

Although dual antiplatelet therapy is usually started by a subspecialist, the primary care physician is often the one who ensures that the patient remains compliant with it in the long term. A review of the seminal published data is helpful in understanding the rationale behind dual antiplatelet therapy and its risks and benefits.

In the mid-1990s, the thienopyridine ticlopidine (Ticlid) was found to significantly decrease the number of deaths, target-lesion revascularizations, and myocardial infarctions (MIs) in the 30 days following stent placement. ¹ However, 2% to 3% of patients experienced neutropenia² and thrombotic thrombocytopenic purpura with this drug,³ leading to the use of clopidogrel, another agent in the same class. Over the past decade, a large body of evidence has established the usefulness of clopidogrel in a number of clinical settings.

In this paper we review the current use of clopidogrel in ST-elevation MI, non-ST-elevation acute coronary syndromes, and percutaneous coronary intervention, and discuss the landmark trials that are the basis for the treatment guidelines published jointly by the American College of Cardiology (ACC) and the American Heart Association (AHA).^4–6 We also briefly discuss the use of prasugrel (Effient), the newest antiplatelet agent to gain approval from the US Food and Drug Administration (FDA).

CLOPIDOGREL AS AN ALTERNATIVE TO ASPIRIN

Clopidogrel, a prodrug, is converted into its active form in the liver.⁷ It then irreversibly binds to the platelet P2Y12 receptor and inhibits adenosine diphosphate-induced platelet aggregation.

Those treated with clopidogrel had an annual risk of ischemic stroke, MI, or vascular death of 5.32%, compared with 5.83% in the aspirin group, for a statistically significant 8.7% relative risk reduction (P = .043). The observed frequency of neutropenia (neutrophils < 1.2 × 10⁹/L) was 0.10% with clopidogrel vs 0.17% with aspirin. This study showed clopidogrel to be an effective alternative in patients who cannot tolerate aspirin.

CASE 1: ST-ELEVATION MI

A 57-year-old farmer in rural Ohio with a history of hypertension and hyperlipidemia presents to the local emergency department 45 minutes after the onset, while he was chopping wood, of dull, aching, substernal chest pain that radiates to his jaw. Electrocardiography reveals 2-mm ST-segment elevation in leads V₁ through V₆. He is treated with aspirin 162 mg, low-molecular-weight heparin, and tenecteplase.

What would be the value of starting dual antiplatelet therapy with clopidogrel in this patient?

Clopidogrel, aspirin, and fibrinolysis in ST-elevation MI

The CLARITY-TIMI 28 trial (Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction)⁹ included 3,491 patients (ages 18 to 75) from 319 international sites. All patients received a fibrinolytic agent, aspirin (162 mg to 325 mg on the first day and 75 mg to 162 mg thereafter), and heparin as part of standard care for acute ST-elevation MI (Table 1). Patients were randomized to receive a 300-mg loading dose of clopidogrel followed by 75 mg daily or placebo within 12 hours of onset of ST-elevation MI. The status of the infarct-related artery was ascertained by protocol-mandated coronary angiography 48 to 192 hours after starting the study medication. The primary end point was the composite of an occluded infarct-related artery on angiography, death from any cause prior to angiography, or recurrent MI prior to angiography.

Significantly fewer patients had an end point event in the clopidogrel group than in the placebo group, 15% vs 21.7% (P < .001), for a relative risk reduction of 31%. There was no significant increase in major or minor bleeding events.

Of note, the CLARITY-TIMI 28 patients were relatively young (average age 57 years) and at low cardiovascular risk (30-day mortality risk < 5%).

The COMMIT trial (Clopidogrel and Metoprolol in Myocardial Infarction)¹⁰ consisted of 45,852 patients with suspected acute MI admitted to 1,250 hospitals in China. Each patient received aspirin 162 mg daily plus either clopidogrel 75 mg daily (n = 22,961) or placebo (n = 22,891) for the duration of hospitalization (average 16 days) or 28 days, whichever came first.

The incidence of the primary composite end point of death, reinfarction, or stroke was significantly lower with clopidogrel than with placebo (9.2% vs 10.1%, P = .002). This was regardless of age (the average age was 61, and 26% of patients were older than 70), sex, time to presentation (67% presented within 12 hours), or reperfusion strategy (49% underwent fibrinolysis). The clopidogrel group did not have a significantly higher incidence of bleeding, but patients in this trial did not receive a loading dose of clopidogrel.

Comment. In view of the results of these trials, our 57-year-old patient should start clopidogrel early.

CASE 2: NON-ST-ELEVATION ACUTE CORONARY SYNDROME

A 65-year-old woman living independently with no significant medical history presents to the emergency room with 2 hours of waxing and waning substernal chest pain. Her blood pressure is 145/90 mm Hg, her heart rate is 95 beats per minute, and the results of her physical examination are unremarkable. Resting electrocardiography reveals 1.5-mm ST-segment depression in the inferior leads, and her troponin T level on admission is two times the upper limit of normal. She is given aspirin and is started on low-molecular-weight heparin and intravenous nitroglycerin.

What would be the value of starting clopidogrel in this patient?

Clopidogrel in non-ST-elevation acute coronary syndromes

The ACC/AHA guidelines strongly support starting clopidogrel in patients with non-ST-elevation acute coronary syndromes (Table 2).⁵

The CURE trial (Clopidogrel in Unstable Angina to Prevent Recurrent Events)¹¹ provided the evidence for this recommendation. In this trial, 12,562 patients from 482 centers in 28 countries who presented within 24 hours of coronary symptoms, without ST elevation, were randomized to receive either clopidogrel (a 300-mg loading dose, followed by 75 mg daily) or placebo for 3 to 12 months (mean 9 months).

Significantly fewer patients in the clopidogrel group reached one of the end points of the composite primary outcome (cardiovascular death, nonfatal MI, or stroke): 9.3% vs 11.4%, 95% confidence interval (CI) 0.72–0.90, P < .001. Significantly fewer of them also suffered one of the secondary outcomes, ie, severe ischemia, heart failure, or need for revascularization.

Of concern was a higher rate of major bleeding in the clopidogrel group (3.7%) than in the placebo group (2.7%) without an excess of fatal bleeding. For every 1,000 patients treated with clopidogrel, 6 required a blood transfusion. Nevertheless, CURE proved that patients with non-ST-elevation acute coronary syndromes benefited from clopidogrel, regardless of whether they underwent percutaneous coronary intervention.

Comment. Our patient should receive clopidogrel and, if she has no significant bleeding, she should continue to take it for at least 12 months after discharge. It is important for the primary care physician to ensure compliance with this agent and not discontinue it on routine clinical follow-up.

CASE 3: BARE-METAL STENT PLACEMENT

A 62-year-old man with a history of hypertension, diabetes, and hyperlipidemia presents to his primary care physician’s office with stable-effort angina that is not responding to an excellent anti-ischemic regimen and is affecting his quality of life. He is referred for coronary angiography, which reveals 80% stenosis of the proximal left circumflex artery. He undergoes a percutaneous coronary intervention with placement of a bare-metal stent.

How long should he be on clopidogrel? And what if a drug-eluting stent had been placed instead of a bare-metal stent?

Dual therapy after bare-metal stent placement

Dual antiplatelet therapy with clopidogrel and aspirin is recommended in all patients receiving a stent (Table 2). The better safety and efficacy of clopidogrel compared with ticlopidine has been established in patients receiving a coronary artery stent,^12,13 and clopidogrel’s favorable safety profile soon made it the thienopyridine of choice.

The CREDO trial (Clopidogrel for the Reduction of Events During Observation)¹⁴ randomized 2,116 patients undergoing an elective percutaneous coronary intervention (bare-metal stent placement only) to receive a 300-mg loading dose of clopidogrel 3 to 24 hours before the procedure, or placebo. All patients received 325 mg of aspirin. After the intervention, all patients received clopidogrel 75 mg daily and aspirin 325 mg daily through day 28. For day 29 through 12 months, those who had received the 300-mg preprocedural loading dose of clopidogrel continued with 75 mg daily, and those who had not received clopidogrel before the procedure received placebo.

No significant difference was seen in the primary outcome for those who received pretreatment with clopidogrel; however, in a subgroup analysis, those who received clopidogrel at least 6 hours before the percutaneous coronary intervention had a 38.6% relative risk reduction (Table 1). Long-term use of clopidogrel (ie, for 12 months) was associated with an overall relative reduction of 26.9% in the combined risk of death, MI, or stroke.

PCI-CURE, an analysis of 2,658 patients in the CURE trial with non-ST-elevation acute coronary syndrome who underwent PCI,¹⁵ yielded results similar to those of CREDO, with a 31% reduction in the rate of cardiovascular death or MI at 30 days and at 9 months. Of note, however, clopidogrel was given for a median of 6 days prior to the procedure.

Comment. The minimum suggested duration of clopidogrel treatment after placement of a bare-metal stent is 1 month. However, these trial results indicate that patients who are not at high risk of bleeding should take clopidogrel for at least 12 months.

Dual antiplatelet therapy with drug-eluting stents

Although rates of in-stent restenosis are clearly lower with drug-eluting stents than with bare-metal stents, the antiproliferative effect of drug-eluting stents may delay complete endothelialization of every strut. This may contribute to late (> 1 month after placement) or very late (> 1 year) thrombosis of the stent after clopidogrel is discontinued.^16–18

In 2006, the FDA indicated that dual antiplatelet therapy was needed for 6 months with paclitaxel-eluting (Taxus) stents and 3 months with sirolimus-eluting (Cipher) stents. As reports of very late stent thrombosis began to appear in 2007, concern arose over the need to extend the duration of clopidogrel treatment.

Bavry et al¹⁹ quantified the incidence of late and very late stent thrombosis in a meta-analysis of 14 clinical trials that randomized patients to receive either a drug-eluting stent (paclitaxel or sirolimus) or a bare-metal stent.¹⁹ The incidence of stent thrombosis within 30 days in this analysis was similar for both groups—4.4 per 1,000 patients vs 5 per 1,000 (relative risk 0.89; 95% CI 0.46–1.75; P = .74). However, the rate of very late stent thrombosis was significantly higher in those receiving a drug-eluting stent vs a bare-metal stent—5 per 1,000 patients treated (relative risk 5.02, 95% CI 1.29–19.52; P = .02).

The results of this and other studies led the ACC and AHA to revise their joint guidelines to recommend thienopyridine treatment for at least 1 year for patients who receive a drug-eluting stent.^6,20–22 In fact, many cardiologists consider indefinite dual antiplatelet therapy in patients with a drug-eluting stent to avoid very late in-stent thrombosis, especially in patients undergoing high-risk interventions such as placement of multiple stents, bifurcation lesions, and unprotected left main trunk interventions.

Thus, when faced with a patient with a recent coronary stent implantation, the primary care physician should be aware of the type of stent and the duration of therapy recommended by the interventional cardiologist. Also, in the absence of a pressing indication, elective surgery should be deferred for 1 year after placement of a drug-eluting stent, as this would necessitate stopping clopidogrel and would increase the risk of perioperative stent thrombosis, which is associated with high rates of morbidity and death.

CASE 4: HIGH-RISK CORONARY ARTERY DISEASE

A 67-year-old woman presents to your office to establish care. She has a history of diabetes and established coronary artery disease with two bare-metal stents placed 2 years ago. She is taking aspirin 81 mg.

What would be the value of adding clopidogrel to her regimen?

No indication for clopidogrel in chronic coronary artery disease

The CHARISMA trial (Clopidogrel for High Atherothrombotic and Ischemic Stabilization, Management, and Avoidance)²³ randomized 15,603 patients with stable cardiovascular disease or multiple risk factors to receive either clopidogrel plus low-dose aspirin or placebo plus low-dose aspirin and followed them for a median of 28 months (Table 1).

The primary end point (a composite of MI, stroke, or death) was 6.8% with clopidogrel plus aspirin and 7.3% with aspirin alone, indicating no significant benefit with clopidogrel plus aspirin compared with aspirin alone in reducing the rate of MI, stroke, or cardiovascular death in patients with high-risk but stable atherothrombotic disease. A marginal statistical benefit with dual antiplatelet therapy was noted in the subgroup of patients with previously documented coronary, cerebrovascular, or peripheral vascular disease—6.9% with aspirin plus clopidogrel vs 7.9% with aspirin alone (relative risk 0.88; 95% CI 0.77–0.998; P = .046).

Consequently, there is no compelling reason to start clopidogrel in this patient.

PRASUGREL, THE NEWEST THIENOPYRIDINE

Prasugrel was recently approved by the FDA as antiplatelet treatment for patients with acute coronary syndromes planning to undergo a percutaneous coronary intervention.²⁴ It has been shown to inhibit adenosine-diphosphate-induced platelet activation in a more consistent and effective manner than clopidogrel.^25,26

Although both clopidogrel and prasugrel are prodrugs, 80% of absorbed clopidogrel is metabolized by esterases into inactive metabolites, and the availability of active metabolite can vary, as it is significantly influenced by polymorphisms in the cytochrome P450 system. ²⁷ In contrast, prasugrel is not degraded by esterases, and its conversion to active metabolite by the cytochrome P450 system is not influenced by common genetic polymorphisms, particularly CYP2C19*2.

TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction) provided most of the evidence for the approval of prasugrel for clinical use.^28,29 In this trial, a 60-mg loading dose of prasugrel followed by a daily maintenance dose of 10 mg was significantly superior to the current clopidogrel regimen in preventing death from cardiovascular causes, nonfatal MI, or nonfatal stroke during a study period of 15 months.²⁸ Also observed was a 24% lower rate of MI, a 34% lower rate of urgent target-vessel revascularization, and a 52% lower rate of stent thrombosis.

These benefits, however, came at the cost of a significantly higher risk of major bleeding, including the potential for three excess fatal bleeding events for every 1,000 patients treated. Patients at highest risk at the dosages evaluated included the elderly (age 75 and older), patients who weigh less than 60 kg, and patients with a history of stroke or transient ischemic attack. Based on these results, we recommend caution with the use of prasugrel in these patient subsets.

Clinical use of prasugrel is likely to be highest in patients presenting with ST-elevation MI who are undergoing a primary percutaneous coronary intervention. There is currently no evidence from any randomized clinical trial to support the safety of prasugrel given in the emergency room or “upstream” in the setting of non-ST-elevation acute coronary syndromes.

Of note, patients with non-ST-elevation acute coronary syndromes in the TRITON trial were randomized only after angiographic definition. As a result, only 179 patients exposed to prasugrel were referred for coronary artery bypass surgery, but the rate of surgery-related major bleeding in this group was 13.4% (vs 3.2% in the clopidogrel group). Based on these data, prasugrel should be withheld for at least 1 week prior to any surgery.

Plaque rupture and thrombosis play central roles in the genesis of acute coronary syndrome. Aspirin has long been the preventive agent of choice. But dual antiplatelet therapy with aspirin plus clopidogrel (Plavix) is warranted in many patients to further reduce their risk of future cardiovascular events.

Although dual antiplatelet therapy is usually started by a subspecialist, the primary care physician is often the one who ensures that the patient remains compliant with it in the long term. A review of the seminal published data is helpful in understanding the rationale behind dual antiplatelet therapy and its risks and benefits.

In the mid-1990s, the thienopyridine ticlopidine (Ticlid) was found to significantly decrease the number of deaths, target-lesion revascularizations, and myocardial infarctions (MIs) in the 30 days following stent placement. ¹ However, 2% to 3% of patients experienced neutropenia² and thrombotic thrombocytopenic purpura with this drug,³ leading to the use of clopidogrel, another agent in the same class. Over the past decade, a large body of evidence has established the usefulness of clopidogrel in a number of clinical settings.

In this paper we review the current use of clopidogrel in ST-elevation MI, non-ST-elevation acute coronary syndromes, and percutaneous coronary intervention, and discuss the landmark trials that are the basis for the treatment guidelines published jointly by the American College of Cardiology (ACC) and the American Heart Association (AHA).^4–6 We also briefly discuss the use of prasugrel (Effient), the newest antiplatelet agent to gain approval from the US Food and Drug Administration (FDA).

CLOPIDOGREL AS AN ALTERNATIVE TO ASPIRIN

Clopidogrel, a prodrug, is converted into its active form in the liver.⁷ It then irreversibly binds to the platelet P2Y12 receptor and inhibits adenosine diphosphate-induced platelet aggregation.

Those treated with clopidogrel had an annual risk of ischemic stroke, MI, or vascular death of 5.32%, compared with 5.83% in the aspirin group, for a statistically significant 8.7% relative risk reduction (P = .043). The observed frequency of neutropenia (neutrophils < 1.2 × 10⁹/L) was 0.10% with clopidogrel vs 0.17% with aspirin. This study showed clopidogrel to be an effective alternative in patients who cannot tolerate aspirin.

CASE 1: ST-ELEVATION MI

A 57-year-old farmer in rural Ohio with a history of hypertension and hyperlipidemia presents to the local emergency department 45 minutes after the onset, while he was chopping wood, of dull, aching, substernal chest pain that radiates to his jaw. Electrocardiography reveals 2-mm ST-segment elevation in leads V₁ through V₆. He is treated with aspirin 162 mg, low-molecular-weight heparin, and tenecteplase.

What would be the value of starting dual antiplatelet therapy with clopidogrel in this patient?

Clopidogrel, aspirin, and fibrinolysis in ST-elevation MI

The CLARITY-TIMI 28 trial (Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction)⁹ included 3,491 patients (ages 18 to 75) from 319 international sites. All patients received a fibrinolytic agent, aspirin (162 mg to 325 mg on the first day and 75 mg to 162 mg thereafter), and heparin as part of standard care for acute ST-elevation MI (Table 1). Patients were randomized to receive a 300-mg loading dose of clopidogrel followed by 75 mg daily or placebo within 12 hours of onset of ST-elevation MI. The status of the infarct-related artery was ascertained by protocol-mandated coronary angiography 48 to 192 hours after starting the study medication. The primary end point was the composite of an occluded infarct-related artery on angiography, death from any cause prior to angiography, or recurrent MI prior to angiography.

Significantly fewer patients had an end point event in the clopidogrel group than in the placebo group, 15% vs 21.7% (P < .001), for a relative risk reduction of 31%. There was no significant increase in major or minor bleeding events.

Of note, the CLARITY-TIMI 28 patients were relatively young (average age 57 years) and at low cardiovascular risk (30-day mortality risk < 5%).

The COMMIT trial (Clopidogrel and Metoprolol in Myocardial Infarction)¹⁰ consisted of 45,852 patients with suspected acute MI admitted to 1,250 hospitals in China. Each patient received aspirin 162 mg daily plus either clopidogrel 75 mg daily (n = 22,961) or placebo (n = 22,891) for the duration of hospitalization (average 16 days) or 28 days, whichever came first.

The incidence of the primary composite end point of death, reinfarction, or stroke was significantly lower with clopidogrel than with placebo (9.2% vs 10.1%, P = .002). This was regardless of age (the average age was 61, and 26% of patients were older than 70), sex, time to presentation (67% presented within 12 hours), or reperfusion strategy (49% underwent fibrinolysis). The clopidogrel group did not have a significantly higher incidence of bleeding, but patients in this trial did not receive a loading dose of clopidogrel.

Comment. In view of the results of these trials, our 57-year-old patient should start clopidogrel early.

CASE 2: NON-ST-ELEVATION ACUTE CORONARY SYNDROME

A 65-year-old woman living independently with no significant medical history presents to the emergency room with 2 hours of waxing and waning substernal chest pain. Her blood pressure is 145/90 mm Hg, her heart rate is 95 beats per minute, and the results of her physical examination are unremarkable. Resting electrocardiography reveals 1.5-mm ST-segment depression in the inferior leads, and her troponin T level on admission is two times the upper limit of normal. She is given aspirin and is started on low-molecular-weight heparin and intravenous nitroglycerin.

What would be the value of starting clopidogrel in this patient?

Clopidogrel in non-ST-elevation acute coronary syndromes

The ACC/AHA guidelines strongly support starting clopidogrel in patients with non-ST-elevation acute coronary syndromes (Table 2).⁵

The CURE trial (Clopidogrel in Unstable Angina to Prevent Recurrent Events)¹¹ provided the evidence for this recommendation. In this trial, 12,562 patients from 482 centers in 28 countries who presented within 24 hours of coronary symptoms, without ST elevation, were randomized to receive either clopidogrel (a 300-mg loading dose, followed by 75 mg daily) or placebo for 3 to 12 months (mean 9 months).

Significantly fewer patients in the clopidogrel group reached one of the end points of the composite primary outcome (cardiovascular death, nonfatal MI, or stroke): 9.3% vs 11.4%, 95% confidence interval (CI) 0.72–0.90, P < .001. Significantly fewer of them also suffered one of the secondary outcomes, ie, severe ischemia, heart failure, or need for revascularization.

Of concern was a higher rate of major bleeding in the clopidogrel group (3.7%) than in the placebo group (2.7%) without an excess of fatal bleeding. For every 1,000 patients treated with clopidogrel, 6 required a blood transfusion. Nevertheless, CURE proved that patients with non-ST-elevation acute coronary syndromes benefited from clopidogrel, regardless of whether they underwent percutaneous coronary intervention.

Comment. Our patient should receive clopidogrel and, if she has no significant bleeding, she should continue to take it for at least 12 months after discharge. It is important for the primary care physician to ensure compliance with this agent and not discontinue it on routine clinical follow-up.

CASE 3: BARE-METAL STENT PLACEMENT

A 62-year-old man with a history of hypertension, diabetes, and hyperlipidemia presents to his primary care physician’s office with stable-effort angina that is not responding to an excellent anti-ischemic regimen and is affecting his quality of life. He is referred for coronary angiography, which reveals 80% stenosis of the proximal left circumflex artery. He undergoes a percutaneous coronary intervention with placement of a bare-metal stent.

How long should he be on clopidogrel? And what if a drug-eluting stent had been placed instead of a bare-metal stent?

Dual therapy after bare-metal stent placement

Dual antiplatelet therapy with clopidogrel and aspirin is recommended in all patients receiving a stent (Table 2). The better safety and efficacy of clopidogrel compared with ticlopidine has been established in patients receiving a coronary artery stent,^12,13 and clopidogrel’s favorable safety profile soon made it the thienopyridine of choice.

The CREDO trial (Clopidogrel for the Reduction of Events During Observation)¹⁴ randomized 2,116 patients undergoing an elective percutaneous coronary intervention (bare-metal stent placement only) to receive a 300-mg loading dose of clopidogrel 3 to 24 hours before the procedure, or placebo. All patients received 325 mg of aspirin. After the intervention, all patients received clopidogrel 75 mg daily and aspirin 325 mg daily through day 28. For day 29 through 12 months, those who had received the 300-mg preprocedural loading dose of clopidogrel continued with 75 mg daily, and those who had not received clopidogrel before the procedure received placebo.

No significant difference was seen in the primary outcome for those who received pretreatment with clopidogrel; however, in a subgroup analysis, those who received clopidogrel at least 6 hours before the percutaneous coronary intervention had a 38.6% relative risk reduction (Table 1). Long-term use of clopidogrel (ie, for 12 months) was associated with an overall relative reduction of 26.9% in the combined risk of death, MI, or stroke.

PCI-CURE, an analysis of 2,658 patients in the CURE trial with non-ST-elevation acute coronary syndrome who underwent PCI,¹⁵ yielded results similar to those of CREDO, with a 31% reduction in the rate of cardiovascular death or MI at 30 days and at 9 months. Of note, however, clopidogrel was given for a median of 6 days prior to the procedure.

Comment. The minimum suggested duration of clopidogrel treatment after placement of a bare-metal stent is 1 month. However, these trial results indicate that patients who are not at high risk of bleeding should take clopidogrel for at least 12 months.

Dual antiplatelet therapy with drug-eluting stents

Although rates of in-stent restenosis are clearly lower with drug-eluting stents than with bare-metal stents, the antiproliferative effect of drug-eluting stents may delay complete endothelialization of every strut. This may contribute to late (> 1 month after placement) or very late (> 1 year) thrombosis of the stent after clopidogrel is discontinued.^16–18

In 2006, the FDA indicated that dual antiplatelet therapy was needed for 6 months with paclitaxel-eluting (Taxus) stents and 3 months with sirolimus-eluting (Cipher) stents. As reports of very late stent thrombosis began to appear in 2007, concern arose over the need to extend the duration of clopidogrel treatment.

Bavry et al¹⁹ quantified the incidence of late and very late stent thrombosis in a meta-analysis of 14 clinical trials that randomized patients to receive either a drug-eluting stent (paclitaxel or sirolimus) or a bare-metal stent.¹⁹ The incidence of stent thrombosis within 30 days in this analysis was similar for both groups—4.4 per 1,000 patients vs 5 per 1,000 (relative risk 0.89; 95% CI 0.46–1.75; P = .74). However, the rate of very late stent thrombosis was significantly higher in those receiving a drug-eluting stent vs a bare-metal stent—5 per 1,000 patients treated (relative risk 5.02, 95% CI 1.29–19.52; P = .02).

The results of this and other studies led the ACC and AHA to revise their joint guidelines to recommend thienopyridine treatment for at least 1 year for patients who receive a drug-eluting stent.^6,20–22 In fact, many cardiologists consider indefinite dual antiplatelet therapy in patients with a drug-eluting stent to avoid very late in-stent thrombosis, especially in patients undergoing high-risk interventions such as placement of multiple stents, bifurcation lesions, and unprotected left main trunk interventions.

Thus, when faced with a patient with a recent coronary stent implantation, the primary care physician should be aware of the type of stent and the duration of therapy recommended by the interventional cardiologist. Also, in the absence of a pressing indication, elective surgery should be deferred for 1 year after placement of a drug-eluting stent, as this would necessitate stopping clopidogrel and would increase the risk of perioperative stent thrombosis, which is associated with high rates of morbidity and death.

CASE 4: HIGH-RISK CORONARY ARTERY DISEASE

A 67-year-old woman presents to your office to establish care. She has a history of diabetes and established coronary artery disease with two bare-metal stents placed 2 years ago. She is taking aspirin 81 mg.

What would be the value of adding clopidogrel to her regimen?

No indication for clopidogrel in chronic coronary artery disease

The CHARISMA trial (Clopidogrel for High Atherothrombotic and Ischemic Stabilization, Management, and Avoidance)²³ randomized 15,603 patients with stable cardiovascular disease or multiple risk factors to receive either clopidogrel plus low-dose aspirin or placebo plus low-dose aspirin and followed them for a median of 28 months (Table 1).

The primary end point (a composite of MI, stroke, or death) was 6.8% with clopidogrel plus aspirin and 7.3% with aspirin alone, indicating no significant benefit with clopidogrel plus aspirin compared with aspirin alone in reducing the rate of MI, stroke, or cardiovascular death in patients with high-risk but stable atherothrombotic disease. A marginal statistical benefit with dual antiplatelet therapy was noted in the subgroup of patients with previously documented coronary, cerebrovascular, or peripheral vascular disease—6.9% with aspirin plus clopidogrel vs 7.9% with aspirin alone (relative risk 0.88; 95% CI 0.77–0.998; P = .046).

Consequently, there is no compelling reason to start clopidogrel in this patient.

PRASUGREL, THE NEWEST THIENOPYRIDINE

Prasugrel was recently approved by the FDA as antiplatelet treatment for patients with acute coronary syndromes planning to undergo a percutaneous coronary intervention.²⁴ It has been shown to inhibit adenosine-diphosphate-induced platelet activation in a more consistent and effective manner than clopidogrel.^25,26

Although both clopidogrel and prasugrel are prodrugs, 80% of absorbed clopidogrel is metabolized by esterases into inactive metabolites, and the availability of active metabolite can vary, as it is significantly influenced by polymorphisms in the cytochrome P450 system. ²⁷ In contrast, prasugrel is not degraded by esterases, and its conversion to active metabolite by the cytochrome P450 system is not influenced by common genetic polymorphisms, particularly CYP2C19*2.

TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction) provided most of the evidence for the approval of prasugrel for clinical use.^28,29 In this trial, a 60-mg loading dose of prasugrel followed by a daily maintenance dose of 10 mg was significantly superior to the current clopidogrel regimen in preventing death from cardiovascular causes, nonfatal MI, or nonfatal stroke during a study period of 15 months.²⁸ Also observed was a 24% lower rate of MI, a 34% lower rate of urgent target-vessel revascularization, and a 52% lower rate of stent thrombosis.

These benefits, however, came at the cost of a significantly higher risk of major bleeding, including the potential for three excess fatal bleeding events for every 1,000 patients treated. Patients at highest risk at the dosages evaluated included the elderly (age 75 and older), patients who weigh less than 60 kg, and patients with a history of stroke or transient ischemic attack. Based on these results, we recommend caution with the use of prasugrel in these patient subsets.

Clinical use of prasugrel is likely to be highest in patients presenting with ST-elevation MI who are undergoing a primary percutaneous coronary intervention. There is currently no evidence from any randomized clinical trial to support the safety of prasugrel given in the emergency room or “upstream” in the setting of non-ST-elevation acute coronary syndromes.

Of note, patients with non-ST-elevation acute coronary syndromes in the TRITON trial were randomized only after angiographic definition. As a result, only 179 patients exposed to prasugrel were referred for coronary artery bypass surgery, but the rate of surgery-related major bleeding in this group was 13.4% (vs 3.2% in the clopidogrel group). Based on these data, prasugrel should be withheld for at least 1 week prior to any surgery.

Catheter ablation for atrial fibrillation has evolved since it was introduced a decade ago. It will continue to improve as we gain experience with the procedure, better understand the pathophysiology of atrial fibrillation, and develop new technologies for imaging, catheter navigation, and more effective ablation of atrial tissue. The topic is reviewed by Chowdhury et al¹ in this issue of the Cleveland Clinic Journal of Medicine.

See related article

An important question is whether catheter ablation should replace antiarrhythmic drugs as the first line of therapy. The answer will be determined by the procedure’s success rate, complication rate, cost, and long-term outcomes compared with drug therapy.

RELATIVELY FEW RANDOMIZED TRIALS, BUT ENCOURAGING RESULTS

Relatively few randomized trials have compared catheter ablation and medical therapy.

In patients with paroxysmal atrial fibrillation, three important randomized trials^2–4 have shown catheter ablation to be superior to antiarrhythmic drug therapy. In these trials, freedom from atrial fibrillation or atrial flutter was achieved in 63% to 93% of patients who underwent ablation compared with 17% to 35% of those assigned to drug therapy. However, more than one ablation procedure may be required to achieve success rates in the higher range. Further, these studies were done at “high-volume” centers, and they excluded patients with major comorbidities.

Persistent or long-standing atrial fibrillation is more complex than paroxysmal atrial fibrillation. It is more often accompanied by significant comorbidities, and comparative trials have generally excluded patients with these attributes. Fewer of such patients obtain complete success (ie, cure), and more of them need a second ablation procedure.

Oral et al⁵ randomly assigned patients with long-standing atrial fibrillation to be treated with amiodarone (Cordarone) or catheter ablation. The analysis of this study was complicated by a high rate of crossover from the drug therapy group to the ablation group. Twenty-five (32%) of the 77 patients assigned to undergo ablation needed a second procedure, but at 12 months 74% were in sinus rhythm without amiodarone, compared with only 4% treated with amiodarone without ablation.

These results indicate that ablation is more effective than medical therapy for paroxysmal atrial fibrillation, and it appears to be more effective than drugs alone for long-standing persistent atrial fibrillation. In addition, quality of life was better after ablation, and complications were relatively few.^2–4

The limitations are that the trials were done at hospitals in which the ablation teams had a lot of experience, did many ablation procedures per year, and tracked their outcomes carefully: other hospitals may not be able to achieve the same results. Moreover, many patients referred for ablation have heart failure, significant valvular disease, or left atrial enlargement, which would have excluded them from the published trials.

MORE STUDIES UNDER WAY

Two other initiatives may help define the role of ablation for atrial fibrillation.

The Cardiac Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (the CABANA) trial is a multicenter randomized longitudinal study designed to determine whether ablation is more effective than drug therapy. Target enrollment is 3,000 patients.

The National Cardiovascular Data Registry is exploring the possibility of establishing a registry for ablation of atrial fibrillation. This database could be used by physicians, hospitals, the Centers for Medicare & Medicaid Services, and the US Food and Drug Administration to track overall outcomes of these complex procedures.

FOR NOW, DRUGS ARE STILL THE FIRST-LINE TREATMENT

For now, I believe that antiarrhythmic drugs should remain the first line of treatment for atrial fibrillation until cumulative evidence from additional randomized multicenter trials proves otherwise. However, the threshold for deciding to do an ablation procedure is getting lower, and it is reasonable for patients to make an informed decision to move directly to ablation as an alternative to drug therapy if that is their preference.

To make these decisions, patients need accurate information about success rates and the risk of complications at the center where the procedure is to be performed. At Cleveland Clinic, where more than 4,300 ablation procedures have been performed for atrial fibrillation, substantial resources are devoted to tracking outcomes. As the government and insurance companies focus on pay for performance and as ablation procedures for atrial fibrillation become more widespread and new technologies are introduced, it will be especially important for hospitals to track their own costs and outcomes.

The cumulative experience from well-designed clinical trials will provide guidance, but unless hospitals verify that they achieve results equivalent to those in the trials, physicians should be cautious about recommending ablation as the first-line therapy.

Catheter ablation for atrial fibrillation has evolved since it was introduced a decade ago. It will continue to improve as we gain experience with the procedure, better understand the pathophysiology of atrial fibrillation, and develop new technologies for imaging, catheter navigation, and more effective ablation of atrial tissue. The topic is reviewed by Chowdhury et al¹ in this issue of the Cleveland Clinic Journal of Medicine.

See related article

An important question is whether catheter ablation should replace antiarrhythmic drugs as the first line of therapy. The answer will be determined by the procedure’s success rate, complication rate, cost, and long-term outcomes compared with drug therapy.

RELATIVELY FEW RANDOMIZED TRIALS, BUT ENCOURAGING RESULTS

Relatively few randomized trials have compared catheter ablation and medical therapy.

In patients with paroxysmal atrial fibrillation, three important randomized trials^2–4 have shown catheter ablation to be superior to antiarrhythmic drug therapy. In these trials, freedom from atrial fibrillation or atrial flutter was achieved in 63% to 93% of patients who underwent ablation compared with 17% to 35% of those assigned to drug therapy. However, more than one ablation procedure may be required to achieve success rates in the higher range. Further, these studies were done at “high-volume” centers, and they excluded patients with major comorbidities.

Persistent or long-standing atrial fibrillation is more complex than paroxysmal atrial fibrillation. It is more often accompanied by significant comorbidities, and comparative trials have generally excluded patients with these attributes. Fewer of such patients obtain complete success (ie, cure), and more of them need a second ablation procedure.

Oral et al⁵ randomly assigned patients with long-standing atrial fibrillation to be treated with amiodarone (Cordarone) or catheter ablation. The analysis of this study was complicated by a high rate of crossover from the drug therapy group to the ablation group. Twenty-five (32%) of the 77 patients assigned to undergo ablation needed a second procedure, but at 12 months 74% were in sinus rhythm without amiodarone, compared with only 4% treated with amiodarone without ablation.

These results indicate that ablation is more effective than medical therapy for paroxysmal atrial fibrillation, and it appears to be more effective than drugs alone for long-standing persistent atrial fibrillation. In addition, quality of life was better after ablation, and complications were relatively few.^2–4

The limitations are that the trials were done at hospitals in which the ablation teams had a lot of experience, did many ablation procedures per year, and tracked their outcomes carefully: other hospitals may not be able to achieve the same results. Moreover, many patients referred for ablation have heart failure, significant valvular disease, or left atrial enlargement, which would have excluded them from the published trials.

MORE STUDIES UNDER WAY

Two other initiatives may help define the role of ablation for atrial fibrillation.

The Cardiac Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (the CABANA) trial is a multicenter randomized longitudinal study designed to determine whether ablation is more effective than drug therapy. Target enrollment is 3,000 patients.

The National Cardiovascular Data Registry is exploring the possibility of establishing a registry for ablation of atrial fibrillation. This database could be used by physicians, hospitals, the Centers for Medicare & Medicaid Services, and the US Food and Drug Administration to track overall outcomes of these complex procedures.

FOR NOW, DRUGS ARE STILL THE FIRST-LINE TREATMENT

For now, I believe that antiarrhythmic drugs should remain the first line of treatment for atrial fibrillation until cumulative evidence from additional randomized multicenter trials proves otherwise. However, the threshold for deciding to do an ablation procedure is getting lower, and it is reasonable for patients to make an informed decision to move directly to ablation as an alternative to drug therapy if that is their preference.

To make these decisions, patients need accurate information about success rates and the risk of complications at the center where the procedure is to be performed. At Cleveland Clinic, where more than 4,300 ablation procedures have been performed for atrial fibrillation, substantial resources are devoted to tracking outcomes. As the government and insurance companies focus on pay for performance and as ablation procedures for atrial fibrillation become more widespread and new technologies are introduced, it will be especially important for hospitals to track their own costs and outcomes.

The cumulative experience from well-designed clinical trials will provide guidance, but unless hospitals verify that they achieve results equivalent to those in the trials, physicians should be cautious about recommending ablation as the first-line therapy.

Catheter ablation for atrial fibrillation has evolved since it was introduced a decade ago. It will continue to improve as we gain experience with the procedure, better understand the pathophysiology of atrial fibrillation, and develop new technologies for imaging, catheter navigation, and more effective ablation of atrial tissue. The topic is reviewed by Chowdhury et al¹ in this issue of the Cleveland Clinic Journal of Medicine.

See related article

An important question is whether catheter ablation should replace antiarrhythmic drugs as the first line of therapy. The answer will be determined by the procedure’s success rate, complication rate, cost, and long-term outcomes compared with drug therapy.

RELATIVELY FEW RANDOMIZED TRIALS, BUT ENCOURAGING RESULTS

Relatively few randomized trials have compared catheter ablation and medical therapy.

In patients with paroxysmal atrial fibrillation, three important randomized trials^2–4 have shown catheter ablation to be superior to antiarrhythmic drug therapy. In these trials, freedom from atrial fibrillation or atrial flutter was achieved in 63% to 93% of patients who underwent ablation compared with 17% to 35% of those assigned to drug therapy. However, more than one ablation procedure may be required to achieve success rates in the higher range. Further, these studies were done at “high-volume” centers, and they excluded patients with major comorbidities.

Persistent or long-standing atrial fibrillation is more complex than paroxysmal atrial fibrillation. It is more often accompanied by significant comorbidities, and comparative trials have generally excluded patients with these attributes. Fewer of such patients obtain complete success (ie, cure), and more of them need a second ablation procedure.

Oral et al⁵ randomly assigned patients with long-standing atrial fibrillation to be treated with amiodarone (Cordarone) or catheter ablation. The analysis of this study was complicated by a high rate of crossover from the drug therapy group to the ablation group. Twenty-five (32%) of the 77 patients assigned to undergo ablation needed a second procedure, but at 12 months 74% were in sinus rhythm without amiodarone, compared with only 4% treated with amiodarone without ablation.

These results indicate that ablation is more effective than medical therapy for paroxysmal atrial fibrillation, and it appears to be more effective than drugs alone for long-standing persistent atrial fibrillation. In addition, quality of life was better after ablation, and complications were relatively few.^2–4

The limitations are that the trials were done at hospitals in which the ablation teams had a lot of experience, did many ablation procedures per year, and tracked their outcomes carefully: other hospitals may not be able to achieve the same results. Moreover, many patients referred for ablation have heart failure, significant valvular disease, or left atrial enlargement, which would have excluded them from the published trials.

MORE STUDIES UNDER WAY

Two other initiatives may help define the role of ablation for atrial fibrillation.

The Cardiac Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (the CABANA) trial is a multicenter randomized longitudinal study designed to determine whether ablation is more effective than drug therapy. Target enrollment is 3,000 patients.

The National Cardiovascular Data Registry is exploring the possibility of establishing a registry for ablation of atrial fibrillation. This database could be used by physicians, hospitals, the Centers for Medicare & Medicaid Services, and the US Food and Drug Administration to track overall outcomes of these complex procedures.

FOR NOW, DRUGS ARE STILL THE FIRST-LINE TREATMENT

For now, I believe that antiarrhythmic drugs should remain the first line of treatment for atrial fibrillation until cumulative evidence from additional randomized multicenter trials proves otherwise. However, the threshold for deciding to do an ablation procedure is getting lower, and it is reasonable for patients to make an informed decision to move directly to ablation as an alternative to drug therapy if that is their preference.

To make these decisions, patients need accurate information about success rates and the risk of complications at the center where the procedure is to be performed. At Cleveland Clinic, where more than 4,300 ablation procedures have been performed for atrial fibrillation, substantial resources are devoted to tracking outcomes. As the government and insurance companies focus on pay for performance and as ablation procedures for atrial fibrillation become more widespread and new technologies are introduced, it will be especially important for hospitals to track their own costs and outcomes.

The cumulative experience from well-designed clinical trials will provide guidance, but unless hospitals verify that they achieve results equivalent to those in the trials, physicians should be cautious about recommending ablation as the first-line therapy.

To the Editor: The article by Kim et al regarding the use of pregabalin (Lyrica) in fibromyalgia is interesting and timely.¹ We would like make some additional comments.

They claim that “many hail pregabalin as an important advance in our understanding of the pathogenesis of fibromyalgia and how to treat it,” but they fail to cite who those “many” are. We contend that aside from the pharmaceutical company’s representatives, physicians on its speaker’s bureau, and those participating in paid drug studies, it would be difficult to substantiate this statement.

The authors’ historical overview discusses Gowers’ description of fibrositis but misinterprets his discussion. Gowers did not believe that “inflammation of muscles” was a problem, but that fibrous tissue itself was inflamed (thus the term “fibrositis,” not “myositis”) and could thus produce pain such as pharyngitis and sciatica, as well as “muscular rheumatism.”²

The authors review functional abnormalities in central nervous system processing as an etiology of pain. Russell et al are cited as elucidating the role of substance P in the process.³ Although they showed that substance P was three times higher in the cerebrospinal fluid of fibromyalgia patients compared with normal controls, the cited paper also notes that there was an inverse relationship between substance P levels and tenderness. Substance P also did not correlate with the Visual Analogue Scale self-assessment of pain severity or “with any other clinical variable.”³

A question of whether appropriate controls were chosen for the study has to be raised as well, since 25 of 32 fibromyalgia patients and only 3 of 30 controls had “possible depression.”³ The discussion of other therapies has limitations. The authors rely on two meta-analyses and a review to suggest that the efficacy of tricyclics is supported by a variety of studies. We don’t disagree, but as we previously noted, long-term studies don’t support prolonged efficacy of these drugs, which raises questions of treatment of a chronic illness.⁴ Duloxetine (Cymbalta) and milnacipran (Savella) are briefly mentioned. The authors should have used at least a sentence for each drug to indicate that the drugs have their own substantial shortcomings.

Finally, the authors conclude their article by asking, “What role for pregabalin?” A careful reading of that section does not appear to provide an answer. We recently presented a study suggesting that pregabalin and standard therapy were equally effective (or equally not effective), suggesting that pregabalin neither represents a major pharmaceutical advance in therapy nor is likely to “advance our understanding of the pathogenesis of fibromyalgia.”⁵ We do agree with the authors that medications are only part of a comprehensive program of therapy, and further point out that fibromyalgia undoubtedly represents the end point of a variety of etiologic insults and is unlikely to be one specific syndrome.

To the Editor: The article by Kim et al regarding the use of pregabalin (Lyrica) in fibromyalgia is interesting and timely.¹ We would like make some additional comments.

They claim that “many hail pregabalin as an important advance in our understanding of the pathogenesis of fibromyalgia and how to treat it,” but they fail to cite who those “many” are. We contend that aside from the pharmaceutical company’s representatives, physicians on its speaker’s bureau, and those participating in paid drug studies, it would be difficult to substantiate this statement.

The authors’ historical overview discusses Gowers’ description of fibrositis but misinterprets his discussion. Gowers did not believe that “inflammation of muscles” was a problem, but that fibrous tissue itself was inflamed (thus the term “fibrositis,” not “myositis”) and could thus produce pain such as pharyngitis and sciatica, as well as “muscular rheumatism.”²

The authors review functional abnormalities in central nervous system processing as an etiology of pain. Russell et al are cited as elucidating the role of substance P in the process.³ Although they showed that substance P was three times higher in the cerebrospinal fluid of fibromyalgia patients compared with normal controls, the cited paper also notes that there was an inverse relationship between substance P levels and tenderness. Substance P also did not correlate with the Visual Analogue Scale self-assessment of pain severity or “with any other clinical variable.”³

A question of whether appropriate controls were chosen for the study has to be raised as well, since 25 of 32 fibromyalgia patients and only 3 of 30 controls had “possible depression.”³ The discussion of other therapies has limitations. The authors rely on two meta-analyses and a review to suggest that the efficacy of tricyclics is supported by a variety of studies. We don’t disagree, but as we previously noted, long-term studies don’t support prolonged efficacy of these drugs, which raises questions of treatment of a chronic illness.⁴ Duloxetine (Cymbalta) and milnacipran (Savella) are briefly mentioned. The authors should have used at least a sentence for each drug to indicate that the drugs have their own substantial shortcomings.

Finally, the authors conclude their article by asking, “What role for pregabalin?” A careful reading of that section does not appear to provide an answer. We recently presented a study suggesting that pregabalin and standard therapy were equally effective (or equally not effective), suggesting that pregabalin neither represents a major pharmaceutical advance in therapy nor is likely to “advance our understanding of the pathogenesis of fibromyalgia.”⁵ We do agree with the authors that medications are only part of a comprehensive program of therapy, and further point out that fibromyalgia undoubtedly represents the end point of a variety of etiologic insults and is unlikely to be one specific syndrome.

To the Editor: The article by Kim et al regarding the use of pregabalin (Lyrica) in fibromyalgia is interesting and timely.¹ We would like make some additional comments.

They claim that “many hail pregabalin as an important advance in our understanding of the pathogenesis of fibromyalgia and how to treat it,” but they fail to cite who those “many” are. We contend that aside from the pharmaceutical company’s representatives, physicians on its speaker’s bureau, and those participating in paid drug studies, it would be difficult to substantiate this statement.

The authors’ historical overview discusses Gowers’ description of fibrositis but misinterprets his discussion. Gowers did not believe that “inflammation of muscles” was a problem, but that fibrous tissue itself was inflamed (thus the term “fibrositis,” not “myositis”) and could thus produce pain such as pharyngitis and sciatica, as well as “muscular rheumatism.”²

The authors review functional abnormalities in central nervous system processing as an etiology of pain. Russell et al are cited as elucidating the role of substance P in the process.³ Although they showed that substance P was three times higher in the cerebrospinal fluid of fibromyalgia patients compared with normal controls, the cited paper also notes that there was an inverse relationship between substance P levels and tenderness. Substance P also did not correlate with the Visual Analogue Scale self-assessment of pain severity or “with any other clinical variable.”³

A question of whether appropriate controls were chosen for the study has to be raised as well, since 25 of 32 fibromyalgia patients and only 3 of 30 controls had “possible depression.”³ The discussion of other therapies has limitations. The authors rely on two meta-analyses and a review to suggest that the efficacy of tricyclics is supported by a variety of studies. We don’t disagree, but as we previously noted, long-term studies don’t support prolonged efficacy of these drugs, which raises questions of treatment of a chronic illness.⁴ Duloxetine (Cymbalta) and milnacipran (Savella) are briefly mentioned. The authors should have used at least a sentence for each drug to indicate that the drugs have their own substantial shortcomings.

Finally, the authors conclude their article by asking, “What role for pregabalin?” A careful reading of that section does not appear to provide an answer. We recently presented a study suggesting that pregabalin and standard therapy were equally effective (or equally not effective), suggesting that pregabalin neither represents a major pharmaceutical advance in therapy nor is likely to “advance our understanding of the pathogenesis of fibromyalgia.”⁵ We do agree with the authors that medications are only part of a comprehensive program of therapy, and further point out that fibromyalgia undoubtedly represents the end point of a variety of etiologic insults and is unlikely to be one specific syndrome.

In Reply: We would like to thank the Drs. Abeles for reading our paper¹ and providing valuable input. We are, however, surprised by their question as to who the “many” people are who believe that pregabalin is an important advance in the treatment of fibromyalgia. Anyone who is involved in taking care of fibromyalgia patients would know that several patients regularly report being helped by this medication to a varying degree. These patients rightly believe that this drug—the first drug approved by the US Food and Drug Administration for their oft-misunderstood condition—has started a much-needed dialogue in the medical community, and that in itself is a major advance.

We accept that Gowers, in his original paper on “fibrositis,” believed that fibrous tissue and not muscle was the source of inflammation in this condition.

We do believe that the paper by Russell et al² was one of the many investigations that helped establish the role of central sensitization or abnormalities in pain processing in the central nervous system as the root cause of fibromyalgia pain. However, we do not believe our paper on pregabalin was the right place to discuss the merits or shortcomings of that paper in any more detail.

As we mentioned in our paper, therapies for fibromyalgia have limitations, and duloxetine and milnacipran are no exceptions. However, both these drugs were approved after our review was completed. We believe that the role of pregabalin in the treatment of fibromyalgia is going to be limited simply because medications overall form a small part of the comprehensive program of therapy for this condition.

In Reply: We would like to thank the Drs. Abeles for reading our paper¹ and providing valuable input. We are, however, surprised by their question as to who the “many” people are who believe that pregabalin is an important advance in the treatment of fibromyalgia. Anyone who is involved in taking care of fibromyalgia patients would know that several patients regularly report being helped by this medication to a varying degree. These patients rightly believe that this drug—the first drug approved by the US Food and Drug Administration for their oft-misunderstood condition—has started a much-needed dialogue in the medical community, and that in itself is a major advance.

We accept that Gowers, in his original paper on “fibrositis,” believed that fibrous tissue and not muscle was the source of inflammation in this condition.

We do believe that the paper by Russell et al² was one of the many investigations that helped establish the role of central sensitization or abnormalities in pain processing in the central nervous system as the root cause of fibromyalgia pain. However, we do not believe our paper on pregabalin was the right place to discuss the merits or shortcomings of that paper in any more detail.

As we mentioned in our paper, therapies for fibromyalgia have limitations, and duloxetine and milnacipran are no exceptions. However, both these drugs were approved after our review was completed. We believe that the role of pregabalin in the treatment of fibromyalgia is going to be limited simply because medications overall form a small part of the comprehensive program of therapy for this condition.

In Reply: We would like to thank the Drs. Abeles for reading our paper¹ and providing valuable input. We are, however, surprised by their question as to who the “many” people are who believe that pregabalin is an important advance in the treatment of fibromyalgia. Anyone who is involved in taking care of fibromyalgia patients would know that several patients regularly report being helped by this medication to a varying degree. These patients rightly believe that this drug—the first drug approved by the US Food and Drug Administration for their oft-misunderstood condition—has started a much-needed dialogue in the medical community, and that in itself is a major advance.

We accept that Gowers, in his original paper on “fibrositis,” believed that fibrous tissue and not muscle was the source of inflammation in this condition.

We do believe that the paper by Russell et al² was one of the many investigations that helped establish the role of central sensitization or abnormalities in pain processing in the central nervous system as the root cause of fibromyalgia pain. However, we do not believe our paper on pregabalin was the right place to discuss the merits or shortcomings of that paper in any more detail.

As we mentioned in our paper, therapies for fibromyalgia have limitations, and duloxetine and milnacipran are no exceptions. However, both these drugs were approved after our review was completed. We believe that the role of pregabalin in the treatment of fibromyalgia is going to be limited simply because medications overall form a small part of the comprehensive program of therapy for this condition.

Menopause can bring oral health problems that physicians ought to keep in mind. The same processes that lead to loss of bone in the spine and hips can also lead to loss of the alveolar bone of the jaws, resulting in periodontal disease, loose teeth, and tooth loss. Although the mouth is traditionally the dentist’s responsibility, patients may need encouragement from their physicians to practice good oral hygiene and to see their dentists, and should be referred to a periodontist at the first sign of periodontal disease.

Moreover, bisphosphonates, the class of drugs most often prescribed for osteoporosis, have been linked by case reports (unfairly, we believe) to osteonecrosis of the jaw. This low-evidence-level information, its far-reaching interpretation, and misinformation in the lay media about hormonal changes associated with menopause have led to confusion among women; for clarification and reliable information, they are driven to ask their physicians challenging questions related to oral health.

This article reviews the published studies of the association between menopause and periodontal disease, specifically, the effects of hormonal changes, osteoporosis, and bisphosphonate use on the periodontal status of postmenopausal women. We will highlight the interrelationship of dental health and postmenopausal health and underscore the need for cross-communication and patient referral between physicians and dentists.

GINGIVITIS CAN PROGRESS TO PERIODONTITIS

AS ESTROGEN DECLINES, SO DO THE BONES AND, MAYBE, THE TEETH

The rate of bone loss in postmenopausal women predicts tooth loss—for every 1%-per-year decrease in whole-body bone mineral density, the risk of tooth loss increases more than four times.² In fact, Kribbs³ found that women with severe osteoporosis were three times more likely than healthy, age-matched controls to be edentulous (ie, to have fewer teeth).

Although a number of studies have found that the density of the alveolar bone in the mandible correlated with the density of the bone in the rest of the skeleton and that generalized bone loss may render the jaw susceptible to accelerated alveolar bone resorption,^3–11 these findings are not universal. In a longitudinal study, Famili et al¹² found no association between systemic bone loss, periodontal disease, and edentulism. This shows that the relationship between alveolar bone loss and systemic bone loss is multifactorial and not yet fully understood.¹³

Nevertheless, the American Academy of Periodontology considers osteoporosis to be a risk factor for periodontal disease.¹⁰ In fact, alveolar bone loss has been related not only to osteoporosis but also to osteopenia.¹⁴

Bone mineral density has also been studied in relation to the loss of periodontal ligament—the collagenous attachment of tooth to bone. Klemetti et al¹⁵ found that healthy postmenopausal women with high bone mineral density seemed to retain teeth more readily than those with low bone density or those with osteoporosis, even if they had deep periodontal pockets (a sign of periodontal disease). These findings were reiterated when osteoporotic women were found to have significantly greater loss of attachment compared with nonosteoporotic women.⁷

However, Hildebolt¹⁶ reported that loss of tooth attachment correlated with tooth loss but not with the density of the vertebrae or the proximal femur. This study called into question the findings of the previous studies and provoked debate.

Tezal et al¹⁷ found that low bone mineral density was related to the loss of interproximal alveolar bone (the alveolar bone between adjacent teeth) and, to a lesser extent, ligamentous attachment loss. These data implicated osteoporosis as a possible risk indicator for periodontal disease in white women. (This study was limited to white women because of different demographics in the incidence of osteoporosis.)

Another study showed only a weak correlation between changes in alveolar bone height (in periodontal disease, bone height decreases) and attachment levels. Although a correlation might be present, the relationship was complex and required further examination. The authors found no clear association between clinical attachment levels and bone mineral density in the lumbar spine, but they recognized that attachment loss often precedes the loss of alveolar bone by a significant time period.¹³

Several studies have found a possible relationship between the bone density in the jaw and the density in the rest of the skeleton. It appears that loss of bone mineral density in the hip, wrist, and lumbar areas is correlated with low density in the mandible. Taguchi et al¹⁸ reported that the density in the lumbar spine correlated with the density of the mandibular cortex in early menopause, and with the density of both the cortex and cancellous bone in later menopause.

But whatever the statistical measurement, the susceptibility to progressive periodontitis increases after menopause, and the primary cause is bacterial plaque. The best hedge against this increased susceptibility is regular dental care to remove bacterial plaque biofilm under the gum-line.

HORMONE THERAPY PRESERVES BONE IN THE JAW

Hormones have long been recognized as having some role in periodontal disease.

Payne et al¹⁹ reported that postmenopausal women who were estrogen-deficient had a higher frequency of sites with a net loss of alveolar bone density at follow-up. Furthermore, estrogen-deficient women undergoing supportive periodontal therapy following treatment of moderate to severe periodontitis had three times as many sites losing more than 0.4 mm of interproximal alveolar bone height. Patients who had sufficient estrogen levels did not lose bone during 1 year of follow-up.²⁰

Estrogen replacement improves bone density in postmenopausal women. In a 3-year randomized trial in postmenopausal women with moderate or advanced periodontal disease, estrogen therapy significantly increased alveolar bone mass compared with placebo (P = .04), and it increased bone density in the femur but not the lumbar spine.²¹ Furthermore, women receiving hormonal therapy had significantly less gingival inflammation, lower plaque scores, and less loss of attachment.

On the other hand, a report by Albandar and Kingman²² suggested that women who comply with hormonal therapy also comply with oral hygiene instructions. This compliance could explain the lower gingival inflammation scores, lower plaque scores, and lesser loss of attachment.

Norderyd et al,²³ in a cross-sectional study, found less periodontal disease in postmenopausal women who were on estrogen therapy than in those who were not, although the difference was not statistically significant.

In a 5-year longitudinal study of 69 postmenopausal women receiving estrogen, a moderate but significant relationship was found between bone mineral density of the lumbar spine and the mandible, and estrogen replacement therapy had a positive effect on the mandibular bone mass.²⁴

In a longitudinal study of 24 postmenopausal women, estrogen-deficient women had a mean net loss of alveolar bone density over time, while estrogen-sufficient women had a mean net gain, suggesting that estrogen deficiency may be a risk factor for alveolar bone loss.²⁰ More-recent studies had similar findings. A cross-sectional study by Meisel et al²⁵ found that hormone therapy significantly reduced the extent of clinical attachment loss and, hence, periodontal disease.

The findings of these studies are generally consistent, suggesting that estrogen builds up mandibular bone mass and attenuates the severity of periodontal disease in postmenopausal women.²⁶

DOES ESTROGEN THERAPY PROTECT THE TEETH?

Studies of the Leisure World,²⁷ Framingham,²⁸ and Nurses Health Study²⁹ cohorts suggest that hormone therapy protects against tooth loss in postmenopausal women.

On the other hand, Taguchi et al³⁰ evaluated more than 300 postmenopausal Japanese women and found no significant difference in the total number of teeth between estrogen users and nonusers. The population in this study was younger than in the other studies mentioned above,^27–29 which may explain the negative finding. However, the duration of estrogen use was significantly associated with the total number of teeth remaining, independent of age.³⁰ Meisel et al²⁵ reported that women receiving hormonal therapy had more teeth, though the difference was not significant.

CYTOKINES, PERIODONTITIS, AND SKELETAL BONE LOSS

Studies suggest that low estrogen production after menopause is associated with increased production of interleukin 1 (IL-1), IL-6, IL-8, IL-10, tumor necrosis factor alpha, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, which stimulate mature osteoclasts, modulate bone cell proliferation, and induce resorption of both skeletal and alveolar bone.^31–34

Based on Genco RJ, et al. Is estrogen deficiency a risk factor for periodontal disease? Compend Contin Educ Dent Suppl 1998; 22:S23–S29.

In this regard, osteoporosis and periodontitis appear to be mediated by common cytokines. Managing osteoporosis, removing bacterial plaque biofilm with good oral hygiene, and regular dental visits are important in avoiding periodontitis in susceptible women.

BISPHOSPHONATES PROTECT BONE

In the skeleton

Bisphosphonates, the most commonly prescribed therapy for osteoporosis, inhibit systemic bone resorption and reduce the incidence of vertebral and nonvertebral fractures. Among the bisphosphonates, alendronate (Fosamax), risedronate (Actonel), and intravenous zoledronic acid (Reclast) have been shown to reduce the risk of both hip and vertebral fractures, whereas ibandronate (Boniva) has only been shown to decrease the risk of vertebral fracture.³⁶ Specific findings:

• In the Fracture Intervention Trial,³⁷ alendronate reduced the risk of vertebral fracture by 47% and hip fracture by 51% in women with low bone mineral density and previous vertebral fractures.
• In the Hip Intervention Program,³⁸ risedronate decreased the risk of hip fracture by 40% in postmenopausal women 70 to 79 years old with osteoporosis, but not in those 80 years and older, who are at high risk of falls. Risedronate also reduced vertebral fracture risk by 49% after 3 years of treatment.³⁹
• In the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial,⁴⁰ annual infusion of zoledronic acid after a hip fracture reduced the rates of new clinical vertebral and nonvertebral fractures and death from all causes.

In the jaw

Not surprisingly, recent studies suggest that bisphosphonates slow the resorption of alveolar bone of the maxilla and mandible as well. Alendronate and risedronate, in particular, have been noted to improve periodontal status.^41–43 Findings:

• In a cross-sectional study by Palomo et al,⁴¹ postmenopausal women with low bone density using risedronate for at least 3 months showed significantly less plaque accumulation, less gingival inflammation, lower probing-depth measurments, less periodontal attachment loss, and greater alveolar bone levels.
• In a double-blind, controlled, prospective study by Rocha et al,⁴² 6 months of alendronate therapy significantly improved periodontal disease as assessed radiographically and clinically in 40 postmenopausal women with established periodontal disease.
• Jeffcoat et al⁴³ reported that 2 years of alendronate treatment significantly reduced alveolar bone loss relative to placebo in patients with low mandibular bone mineral density at baseline but not in those with normal baseline mandibular bone mineral density.

DO BISPHOSPHONATES CAUSE OSTEONECROSIS OF THE JAW?

The intravenous bisphosphonates most commonly used to treat hypercalcemia of malignancy, multiple myeloma, or metastatic bone disease are⁴⁷:

• Pamidronate (Aredia) 90 mg infused over 2 to 24 hours every 3 to 4 weeks
• Zoledronic acid (Zometa) 4 mg infused over 15 minutes monthly.

The doses of bisphosphonates indicated for the treatment of osteoporosis are much lower,¹ eg:

• Alendronate 70 mg by mouth once a week
• Risedronate 35 mg by mouth once a week or 150 mg once a month
• Ibandronate 150 mg by mouth once a month
• Ibandronate 3 mg intravenously every 3 months
• Zoledronic acid 5 mg intravenously once a year.

Moreover, less than 1% of an oral dose is absorbed by the gastrointestinal tract,⁴⁹ whereas more than 50% of the dose of bisphosphonates given intravenously is bioavailable,⁵⁰ which may account for the lower incidence of jaw ostenonecrosis with oral agents.

Osteonecrosis of the jaw can occur spontaneously but is more often associated with dental procedures that traumatize bone, such as tooth extraction.⁵¹ In a systematic review,⁴⁵ patients with multiple myeloma and metastatic cancer to the bone who were receiving intravenous bisphosphonates accounted for 94% of published cases. Sixty percent of cases were preceded by dental surgical procedures, and in 39% of cases that occurred spontaneously the lesions were located on bony exostoses, a possible source of trauma. Of 63 cases reported by Ruggiero et al,⁴⁷ 56 patients were receiving intravenous bisphosphonates and 7 were receiving oral bisphosphonates. Older age (> 65 years), chronic systemic steroid use, periodontitis, and prolonged use of bisphosphonates have also been associated with a higher risk of osteonecrosis of the jaw.⁵¹

The risk of developing osteonecrosis of the jaw in people taking bisphosphonates in doses recommended by the US Food and Drug Administration for treating osteoporosis is very low (the incidence is calculated at 0.7 per 100,000 person-years of exposure to alendronate).^51,52 In a 3-year prospective study in more than 7,000 women with post-menopausal osteoporosis, the incidence of osteonecrosis of the jaw was no different in those treated with zoledronic acid 5 mg intravenously than in those receiving placebo.⁵³ In a randomized, placebo-controlled study of the effect of 2 years of alendronate treatment on alveolar bone loss involving 335 patients with periodontal disease, no cases of osteonecrosis of the jaw were reported.⁴³

The American Dental Association (ADA) released a statement noting that osteonecrosis of the jaw can occur with or without bisphosphonate use.⁵¹ To date, a true cause-and-effect relationship between osteonecrosis of the jaw and bisphosphonate use has not been established. Further studies are needed to fully explore this relationship. Our group is currently exploring novel periodontal assessments comparing the oral health of postmenopausal women with osteoporosis who are on no bone therapy vs postmenopausal women with osteoporosis treated with bisphosphonates for 2 or more years.

Discussion of treatment for bisphosphonate-associated osteonecrosis of the jaw is beyond the scope of this article.

REGULAR DENTAL CARE IS ESSENTIAL

Regardless of whether the patient is receiving a bisphosphonate drug, physicians caring for postmenopausal women should be vigilant and encourage their patients to seek regular dental evaluation for prevention and early management of oral disorders. Conversely, dentists should be aware of the potential effects of menopause and its treatments on bone and dental health.

Questions from postmenopausal women can be managed, in part, by returning to the basics suggested by the ADA:

• Regular dental examinations; regular professional cleaning to remove bacterial plaque biofilm under the gum-line where a toothbrush will not reach
• Daily oral hygiene practices to remove biofilm at and above the gum-line including brushing twice daily with an ADA-accepted toothpaste
• Replacing the toothbrush every 3 to 4 months (or sooner if the bristles begin to look frayed)
• Cleaning interproximally (between teeth) with floss or interdental cleaner
• Maintaining a balanced diet
• No smoking.

Menopause can bring oral health problems that physicians ought to keep in mind. The same processes that lead to loss of bone in the spine and hips can also lead to loss of the alveolar bone of the jaws, resulting in periodontal disease, loose teeth, and tooth loss. Although the mouth is traditionally the dentist’s responsibility, patients may need encouragement from their physicians to practice good oral hygiene and to see their dentists, and should be referred to a periodontist at the first sign of periodontal disease.

Moreover, bisphosphonates, the class of drugs most often prescribed for osteoporosis, have been linked by case reports (unfairly, we believe) to osteonecrosis of the jaw. This low-evidence-level information, its far-reaching interpretation, and misinformation in the lay media about hormonal changes associated with menopause have led to confusion among women; for clarification and reliable information, they are driven to ask their physicians challenging questions related to oral health.

This article reviews the published studies of the association between menopause and periodontal disease, specifically, the effects of hormonal changes, osteoporosis, and bisphosphonate use on the periodontal status of postmenopausal women. We will highlight the interrelationship of dental health and postmenopausal health and underscore the need for cross-communication and patient referral between physicians and dentists.

GINGIVITIS CAN PROGRESS TO PERIODONTITIS

AS ESTROGEN DECLINES, SO DO THE BONES AND, MAYBE, THE TEETH

The rate of bone loss in postmenopausal women predicts tooth loss—for every 1%-per-year decrease in whole-body bone mineral density, the risk of tooth loss increases more than four times.² In fact, Kribbs³ found that women with severe osteoporosis were three times more likely than healthy, age-matched controls to be edentulous (ie, to have fewer teeth).

Although a number of studies have found that the density of the alveolar bone in the mandible correlated with the density of the bone in the rest of the skeleton and that generalized bone loss may render the jaw susceptible to accelerated alveolar bone resorption,^3–11 these findings are not universal. In a longitudinal study, Famili et al¹² found no association between systemic bone loss, periodontal disease, and edentulism. This shows that the relationship between alveolar bone loss and systemic bone loss is multifactorial and not yet fully understood.¹³

Nevertheless, the American Academy of Periodontology considers osteoporosis to be a risk factor for periodontal disease.¹⁰ In fact, alveolar bone loss has been related not only to osteoporosis but also to osteopenia.¹⁴

Bone mineral density has also been studied in relation to the loss of periodontal ligament—the collagenous attachment of tooth to bone. Klemetti et al¹⁵ found that healthy postmenopausal women with high bone mineral density seemed to retain teeth more readily than those with low bone density or those with osteoporosis, even if they had deep periodontal pockets (a sign of periodontal disease). These findings were reiterated when osteoporotic women were found to have significantly greater loss of attachment compared with nonosteoporotic women.⁷

However, Hildebolt¹⁶ reported that loss of tooth attachment correlated with tooth loss but not with the density of the vertebrae or the proximal femur. This study called into question the findings of the previous studies and provoked debate.

Tezal et al¹⁷ found that low bone mineral density was related to the loss of interproximal alveolar bone (the alveolar bone between adjacent teeth) and, to a lesser extent, ligamentous attachment loss. These data implicated osteoporosis as a possible risk indicator for periodontal disease in white women. (This study was limited to white women because of different demographics in the incidence of osteoporosis.)

Another study showed only a weak correlation between changes in alveolar bone height (in periodontal disease, bone height decreases) and attachment levels. Although a correlation might be present, the relationship was complex and required further examination. The authors found no clear association between clinical attachment levels and bone mineral density in the lumbar spine, but they recognized that attachment loss often precedes the loss of alveolar bone by a significant time period.¹³

Several studies have found a possible relationship between the bone density in the jaw and the density in the rest of the skeleton. It appears that loss of bone mineral density in the hip, wrist, and lumbar areas is correlated with low density in the mandible. Taguchi et al¹⁸ reported that the density in the lumbar spine correlated with the density of the mandibular cortex in early menopause, and with the density of both the cortex and cancellous bone in later menopause.

But whatever the statistical measurement, the susceptibility to progressive periodontitis increases after menopause, and the primary cause is bacterial plaque. The best hedge against this increased susceptibility is regular dental care to remove bacterial plaque biofilm under the gum-line.

HORMONE THERAPY PRESERVES BONE IN THE JAW

Hormones have long been recognized as having some role in periodontal disease.

Payne et al¹⁹ reported that postmenopausal women who were estrogen-deficient had a higher frequency of sites with a net loss of alveolar bone density at follow-up. Furthermore, estrogen-deficient women undergoing supportive periodontal therapy following treatment of moderate to severe periodontitis had three times as many sites losing more than 0.4 mm of interproximal alveolar bone height. Patients who had sufficient estrogen levels did not lose bone during 1 year of follow-up.²⁰

Estrogen replacement improves bone density in postmenopausal women. In a 3-year randomized trial in postmenopausal women with moderate or advanced periodontal disease, estrogen therapy significantly increased alveolar bone mass compared with placebo (P = .04), and it increased bone density in the femur but not the lumbar spine.²¹ Furthermore, women receiving hormonal therapy had significantly less gingival inflammation, lower plaque scores, and less loss of attachment.

On the other hand, a report by Albandar and Kingman²² suggested that women who comply with hormonal therapy also comply with oral hygiene instructions. This compliance could explain the lower gingival inflammation scores, lower plaque scores, and lesser loss of attachment.

Norderyd et al,²³ in a cross-sectional study, found less periodontal disease in postmenopausal women who were on estrogen therapy than in those who were not, although the difference was not statistically significant.

In a 5-year longitudinal study of 69 postmenopausal women receiving estrogen, a moderate but significant relationship was found between bone mineral density of the lumbar spine and the mandible, and estrogen replacement therapy had a positive effect on the mandibular bone mass.²⁴

In a longitudinal study of 24 postmenopausal women, estrogen-deficient women had a mean net loss of alveolar bone density over time, while estrogen-sufficient women had a mean net gain, suggesting that estrogen deficiency may be a risk factor for alveolar bone loss.²⁰ More-recent studies had similar findings. A cross-sectional study by Meisel et al²⁵ found that hormone therapy significantly reduced the extent of clinical attachment loss and, hence, periodontal disease.

The findings of these studies are generally consistent, suggesting that estrogen builds up mandibular bone mass and attenuates the severity of periodontal disease in postmenopausal women.²⁶

DOES ESTROGEN THERAPY PROTECT THE TEETH?

Studies of the Leisure World,²⁷ Framingham,²⁸ and Nurses Health Study²⁹ cohorts suggest that hormone therapy protects against tooth loss in postmenopausal women.

On the other hand, Taguchi et al³⁰ evaluated more than 300 postmenopausal Japanese women and found no significant difference in the total number of teeth between estrogen users and nonusers. The population in this study was younger than in the other studies mentioned above,^27–29 which may explain the negative finding. However, the duration of estrogen use was significantly associated with the total number of teeth remaining, independent of age.³⁰ Meisel et al²⁵ reported that women receiving hormonal therapy had more teeth, though the difference was not significant.

CYTOKINES, PERIODONTITIS, AND SKELETAL BONE LOSS

Studies suggest that low estrogen production after menopause is associated with increased production of interleukin 1 (IL-1), IL-6, IL-8, IL-10, tumor necrosis factor alpha, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, which stimulate mature osteoclasts, modulate bone cell proliferation, and induce resorption of both skeletal and alveolar bone.^31–34

Based on Genco RJ, et al. Is estrogen deficiency a risk factor for periodontal disease? Compend Contin Educ Dent Suppl 1998; 22:S23–S29.

In this regard, osteoporosis and periodontitis appear to be mediated by common cytokines. Managing osteoporosis, removing bacterial plaque biofilm with good oral hygiene, and regular dental visits are important in avoiding periodontitis in susceptible women.

BISPHOSPHONATES PROTECT BONE

In the skeleton

Bisphosphonates, the most commonly prescribed therapy for osteoporosis, inhibit systemic bone resorption and reduce the incidence of vertebral and nonvertebral fractures. Among the bisphosphonates, alendronate (Fosamax), risedronate (Actonel), and intravenous zoledronic acid (Reclast) have been shown to reduce the risk of both hip and vertebral fractures, whereas ibandronate (Boniva) has only been shown to decrease the risk of vertebral fracture.³⁶ Specific findings:

• In the Fracture Intervention Trial,³⁷ alendronate reduced the risk of vertebral fracture by 47% and hip fracture by 51% in women with low bone mineral density and previous vertebral fractures.
• In the Hip Intervention Program,³⁸ risedronate decreased the risk of hip fracture by 40% in postmenopausal women 70 to 79 years old with osteoporosis, but not in those 80 years and older, who are at high risk of falls. Risedronate also reduced vertebral fracture risk by 49% after 3 years of treatment.³⁹
• In the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial,⁴⁰ annual infusion of zoledronic acid after a hip fracture reduced the rates of new clinical vertebral and nonvertebral fractures and death from all causes.

In the jaw

Not surprisingly, recent studies suggest that bisphosphonates slow the resorption of alveolar bone of the maxilla and mandible as well. Alendronate and risedronate, in particular, have been noted to improve periodontal status.^41–43 Findings:

• In a cross-sectional study by Palomo et al,⁴¹ postmenopausal women with low bone density using risedronate for at least 3 months showed significantly less plaque accumulation, less gingival inflammation, lower probing-depth measurments, less periodontal attachment loss, and greater alveolar bone levels.
• In a double-blind, controlled, prospective study by Rocha et al,⁴² 6 months of alendronate therapy significantly improved periodontal disease as assessed radiographically and clinically in 40 postmenopausal women with established periodontal disease.
• Jeffcoat et al⁴³ reported that 2 years of alendronate treatment significantly reduced alveolar bone loss relative to placebo in patients with low mandibular bone mineral density at baseline but not in those with normal baseline mandibular bone mineral density.

DO BISPHOSPHONATES CAUSE OSTEONECROSIS OF THE JAW?

The intravenous bisphosphonates most commonly used to treat hypercalcemia of malignancy, multiple myeloma, or metastatic bone disease are⁴⁷:

• Pamidronate (Aredia) 90 mg infused over 2 to 24 hours every 3 to 4 weeks
• Zoledronic acid (Zometa) 4 mg infused over 15 minutes monthly.

The doses of bisphosphonates indicated for the treatment of osteoporosis are much lower,¹ eg:

• Alendronate 70 mg by mouth once a week
• Risedronate 35 mg by mouth once a week or 150 mg once a month
• Ibandronate 150 mg by mouth once a month
• Ibandronate 3 mg intravenously every 3 months
• Zoledronic acid 5 mg intravenously once a year.

Moreover, less than 1% of an oral dose is absorbed by the gastrointestinal tract,⁴⁹ whereas more than 50% of the dose of bisphosphonates given intravenously is bioavailable,⁵⁰ which may account for the lower incidence of jaw ostenonecrosis with oral agents.

Osteonecrosis of the jaw can occur spontaneously but is more often associated with dental procedures that traumatize bone, such as tooth extraction.⁵¹ In a systematic review,⁴⁵ patients with multiple myeloma and metastatic cancer to the bone who were receiving intravenous bisphosphonates accounted for 94% of published cases. Sixty percent of cases were preceded by dental surgical procedures, and in 39% of cases that occurred spontaneously the lesions were located on bony exostoses, a possible source of trauma. Of 63 cases reported by Ruggiero et al,⁴⁷ 56 patients were receiving intravenous bisphosphonates and 7 were receiving oral bisphosphonates. Older age (> 65 years), chronic systemic steroid use, periodontitis, and prolonged use of bisphosphonates have also been associated with a higher risk of osteonecrosis of the jaw.⁵¹

The risk of developing osteonecrosis of the jaw in people taking bisphosphonates in doses recommended by the US Food and Drug Administration for treating osteoporosis is very low (the incidence is calculated at 0.7 per 100,000 person-years of exposure to alendronate).^51,52 In a 3-year prospective study in more than 7,000 women with post-menopausal osteoporosis, the incidence of osteonecrosis of the jaw was no different in those treated with zoledronic acid 5 mg intravenously than in those receiving placebo.⁵³ In a randomized, placebo-controlled study of the effect of 2 years of alendronate treatment on alveolar bone loss involving 335 patients with periodontal disease, no cases of osteonecrosis of the jaw were reported.⁴³

The American Dental Association (ADA) released a statement noting that osteonecrosis of the jaw can occur with or without bisphosphonate use.⁵¹ To date, a true cause-and-effect relationship between osteonecrosis of the jaw and bisphosphonate use has not been established. Further studies are needed to fully explore this relationship. Our group is currently exploring novel periodontal assessments comparing the oral health of postmenopausal women with osteoporosis who are on no bone therapy vs postmenopausal women with osteoporosis treated with bisphosphonates for 2 or more years.

Discussion of treatment for bisphosphonate-associated osteonecrosis of the jaw is beyond the scope of this article.

REGULAR DENTAL CARE IS ESSENTIAL

Regardless of whether the patient is receiving a bisphosphonate drug, physicians caring for postmenopausal women should be vigilant and encourage their patients to seek regular dental evaluation for prevention and early management of oral disorders. Conversely, dentists should be aware of the potential effects of menopause and its treatments on bone and dental health.

Questions from postmenopausal women can be managed, in part, by returning to the basics suggested by the ADA:

• Regular dental examinations; regular professional cleaning to remove bacterial plaque biofilm under the gum-line where a toothbrush will not reach
• Daily oral hygiene practices to remove biofilm at and above the gum-line including brushing twice daily with an ADA-accepted toothpaste
• Replacing the toothbrush every 3 to 4 months (or sooner if the bristles begin to look frayed)
• Cleaning interproximally (between teeth) with floss or interdental cleaner
• Maintaining a balanced diet
• No smoking.

Menopause can bring oral health problems that physicians ought to keep in mind. The same processes that lead to loss of bone in the spine and hips can also lead to loss of the alveolar bone of the jaws, resulting in periodontal disease, loose teeth, and tooth loss. Although the mouth is traditionally the dentist’s responsibility, patients may need encouragement from their physicians to practice good oral hygiene and to see their dentists, and should be referred to a periodontist at the first sign of periodontal disease.

Moreover, bisphosphonates, the class of drugs most often prescribed for osteoporosis, have been linked by case reports (unfairly, we believe) to osteonecrosis of the jaw. This low-evidence-level information, its far-reaching interpretation, and misinformation in the lay media about hormonal changes associated with menopause have led to confusion among women; for clarification and reliable information, they are driven to ask their physicians challenging questions related to oral health.

This article reviews the published studies of the association between menopause and periodontal disease, specifically, the effects of hormonal changes, osteoporosis, and bisphosphonate use on the periodontal status of postmenopausal women. We will highlight the interrelationship of dental health and postmenopausal health and underscore the need for cross-communication and patient referral between physicians and dentists.

GINGIVITIS CAN PROGRESS TO PERIODONTITIS

AS ESTROGEN DECLINES, SO DO THE BONES AND, MAYBE, THE TEETH

The rate of bone loss in postmenopausal women predicts tooth loss—for every 1%-per-year decrease in whole-body bone mineral density, the risk of tooth loss increases more than four times.² In fact, Kribbs³ found that women with severe osteoporosis were three times more likely than healthy, age-matched controls to be edentulous (ie, to have fewer teeth).

Although a number of studies have found that the density of the alveolar bone in the mandible correlated with the density of the bone in the rest of the skeleton and that generalized bone loss may render the jaw susceptible to accelerated alveolar bone resorption,^3–11 these findings are not universal. In a longitudinal study, Famili et al¹² found no association between systemic bone loss, periodontal disease, and edentulism. This shows that the relationship between alveolar bone loss and systemic bone loss is multifactorial and not yet fully understood.¹³

Nevertheless, the American Academy of Periodontology considers osteoporosis to be a risk factor for periodontal disease.¹⁰ In fact, alveolar bone loss has been related not only to osteoporosis but also to osteopenia.¹⁴

Bone mineral density has also been studied in relation to the loss of periodontal ligament—the collagenous attachment of tooth to bone. Klemetti et al¹⁵ found that healthy postmenopausal women with high bone mineral density seemed to retain teeth more readily than those with low bone density or those with osteoporosis, even if they had deep periodontal pockets (a sign of periodontal disease). These findings were reiterated when osteoporotic women were found to have significantly greater loss of attachment compared with nonosteoporotic women.⁷

However, Hildebolt¹⁶ reported that loss of tooth attachment correlated with tooth loss but not with the density of the vertebrae or the proximal femur. This study called into question the findings of the previous studies and provoked debate.

Tezal et al¹⁷ found that low bone mineral density was related to the loss of interproximal alveolar bone (the alveolar bone between adjacent teeth) and, to a lesser extent, ligamentous attachment loss. These data implicated osteoporosis as a possible risk indicator for periodontal disease in white women. (This study was limited to white women because of different demographics in the incidence of osteoporosis.)

Another study showed only a weak correlation between changes in alveolar bone height (in periodontal disease, bone height decreases) and attachment levels. Although a correlation might be present, the relationship was complex and required further examination. The authors found no clear association between clinical attachment levels and bone mineral density in the lumbar spine, but they recognized that attachment loss often precedes the loss of alveolar bone by a significant time period.¹³

Several studies have found a possible relationship between the bone density in the jaw and the density in the rest of the skeleton. It appears that loss of bone mineral density in the hip, wrist, and lumbar areas is correlated with low density in the mandible. Taguchi et al¹⁸ reported that the density in the lumbar spine correlated with the density of the mandibular cortex in early menopause, and with the density of both the cortex and cancellous bone in later menopause.

But whatever the statistical measurement, the susceptibility to progressive periodontitis increases after menopause, and the primary cause is bacterial plaque. The best hedge against this increased susceptibility is regular dental care to remove bacterial plaque biofilm under the gum-line.

HORMONE THERAPY PRESERVES BONE IN THE JAW

Hormones have long been recognized as having some role in periodontal disease.

Payne et al¹⁹ reported that postmenopausal women who were estrogen-deficient had a higher frequency of sites with a net loss of alveolar bone density at follow-up. Furthermore, estrogen-deficient women undergoing supportive periodontal therapy following treatment of moderate to severe periodontitis had three times as many sites losing more than 0.4 mm of interproximal alveolar bone height. Patients who had sufficient estrogen levels did not lose bone during 1 year of follow-up.²⁰

Estrogen replacement improves bone density in postmenopausal women. In a 3-year randomized trial in postmenopausal women with moderate or advanced periodontal disease, estrogen therapy significantly increased alveolar bone mass compared with placebo (P = .04), and it increased bone density in the femur but not the lumbar spine.²¹ Furthermore, women receiving hormonal therapy had significantly less gingival inflammation, lower plaque scores, and less loss of attachment.

On the other hand, a report by Albandar and Kingman²² suggested that women who comply with hormonal therapy also comply with oral hygiene instructions. This compliance could explain the lower gingival inflammation scores, lower plaque scores, and lesser loss of attachment.

Norderyd et al,²³ in a cross-sectional study, found less periodontal disease in postmenopausal women who were on estrogen therapy than in those who were not, although the difference was not statistically significant.

In a 5-year longitudinal study of 69 postmenopausal women receiving estrogen, a moderate but significant relationship was found between bone mineral density of the lumbar spine and the mandible, and estrogen replacement therapy had a positive effect on the mandibular bone mass.²⁴

In a longitudinal study of 24 postmenopausal women, estrogen-deficient women had a mean net loss of alveolar bone density over time, while estrogen-sufficient women had a mean net gain, suggesting that estrogen deficiency may be a risk factor for alveolar bone loss.²⁰ More-recent studies had similar findings. A cross-sectional study by Meisel et al²⁵ found that hormone therapy significantly reduced the extent of clinical attachment loss and, hence, periodontal disease.

The findings of these studies are generally consistent, suggesting that estrogen builds up mandibular bone mass and attenuates the severity of periodontal disease in postmenopausal women.²⁶

DOES ESTROGEN THERAPY PROTECT THE TEETH?

Studies of the Leisure World,²⁷ Framingham,²⁸ and Nurses Health Study²⁹ cohorts suggest that hormone therapy protects against tooth loss in postmenopausal women.

On the other hand, Taguchi et al³⁰ evaluated more than 300 postmenopausal Japanese women and found no significant difference in the total number of teeth between estrogen users and nonusers. The population in this study was younger than in the other studies mentioned above,^27–29 which may explain the negative finding. However, the duration of estrogen use was significantly associated with the total number of teeth remaining, independent of age.³⁰ Meisel et al²⁵ reported that women receiving hormonal therapy had more teeth, though the difference was not significant.

CYTOKINES, PERIODONTITIS, AND SKELETAL BONE LOSS

Studies suggest that low estrogen production after menopause is associated with increased production of interleukin 1 (IL-1), IL-6, IL-8, IL-10, tumor necrosis factor alpha, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, which stimulate mature osteoclasts, modulate bone cell proliferation, and induce resorption of both skeletal and alveolar bone.^31–34

Based on Genco RJ, et al. Is estrogen deficiency a risk factor for periodontal disease? Compend Contin Educ Dent Suppl 1998; 22:S23–S29.

In this regard, osteoporosis and periodontitis appear to be mediated by common cytokines. Managing osteoporosis, removing bacterial plaque biofilm with good oral hygiene, and regular dental visits are important in avoiding periodontitis in susceptible women.

BISPHOSPHONATES PROTECT BONE

In the skeleton

Bisphosphonates, the most commonly prescribed therapy for osteoporosis, inhibit systemic bone resorption and reduce the incidence of vertebral and nonvertebral fractures. Among the bisphosphonates, alendronate (Fosamax), risedronate (Actonel), and intravenous zoledronic acid (Reclast) have been shown to reduce the risk of both hip and vertebral fractures, whereas ibandronate (Boniva) has only been shown to decrease the risk of vertebral fracture.³⁶ Specific findings:

• In the Fracture Intervention Trial,³⁷ alendronate reduced the risk of vertebral fracture by 47% and hip fracture by 51% in women with low bone mineral density and previous vertebral fractures.
• In the Hip Intervention Program,³⁸ risedronate decreased the risk of hip fracture by 40% in postmenopausal women 70 to 79 years old with osteoporosis, but not in those 80 years and older, who are at high risk of falls. Risedronate also reduced vertebral fracture risk by 49% after 3 years of treatment.³⁹
• In the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial,⁴⁰ annual infusion of zoledronic acid after a hip fracture reduced the rates of new clinical vertebral and nonvertebral fractures and death from all causes.

In the jaw

Not surprisingly, recent studies suggest that bisphosphonates slow the resorption of alveolar bone of the maxilla and mandible as well. Alendronate and risedronate, in particular, have been noted to improve periodontal status.^41–43 Findings:

• In a cross-sectional study by Palomo et al,⁴¹ postmenopausal women with low bone density using risedronate for at least 3 months showed significantly less plaque accumulation, less gingival inflammation, lower probing-depth measurments, less periodontal attachment loss, and greater alveolar bone levels.
• In a double-blind, controlled, prospective study by Rocha et al,⁴² 6 months of alendronate therapy significantly improved periodontal disease as assessed radiographically and clinically in 40 postmenopausal women with established periodontal disease.
• Jeffcoat et al⁴³ reported that 2 years of alendronate treatment significantly reduced alveolar bone loss relative to placebo in patients with low mandibular bone mineral density at baseline but not in those with normal baseline mandibular bone mineral density.

DO BISPHOSPHONATES CAUSE OSTEONECROSIS OF THE JAW?

The intravenous bisphosphonates most commonly used to treat hypercalcemia of malignancy, multiple myeloma, or metastatic bone disease are⁴⁷:

• Pamidronate (Aredia) 90 mg infused over 2 to 24 hours every 3 to 4 weeks
• Zoledronic acid (Zometa) 4 mg infused over 15 minutes monthly.

The doses of bisphosphonates indicated for the treatment of osteoporosis are much lower,¹ eg:

• Alendronate 70 mg by mouth once a week
• Risedronate 35 mg by mouth once a week or 150 mg once a month
• Ibandronate 150 mg by mouth once a month
• Ibandronate 3 mg intravenously every 3 months
• Zoledronic acid 5 mg intravenously once a year.

Moreover, less than 1% of an oral dose is absorbed by the gastrointestinal tract,⁴⁹ whereas more than 50% of the dose of bisphosphonates given intravenously is bioavailable,⁵⁰ which may account for the lower incidence of jaw ostenonecrosis with oral agents.

Osteonecrosis of the jaw can occur spontaneously but is more often associated with dental procedures that traumatize bone, such as tooth extraction.⁵¹ In a systematic review,⁴⁵ patients with multiple myeloma and metastatic cancer to the bone who were receiving intravenous bisphosphonates accounted for 94% of published cases. Sixty percent of cases were preceded by dental surgical procedures, and in 39% of cases that occurred spontaneously the lesions were located on bony exostoses, a possible source of trauma. Of 63 cases reported by Ruggiero et al,⁴⁷ 56 patients were receiving intravenous bisphosphonates and 7 were receiving oral bisphosphonates. Older age (> 65 years), chronic systemic steroid use, periodontitis, and prolonged use of bisphosphonates have also been associated with a higher risk of osteonecrosis of the jaw.⁵¹

The risk of developing osteonecrosis of the jaw in people taking bisphosphonates in doses recommended by the US Food and Drug Administration for treating osteoporosis is very low (the incidence is calculated at 0.7 per 100,000 person-years of exposure to alendronate).^51,52 In a 3-year prospective study in more than 7,000 women with post-menopausal osteoporosis, the incidence of osteonecrosis of the jaw was no different in those treated with zoledronic acid 5 mg intravenously than in those receiving placebo.⁵³ In a randomized, placebo-controlled study of the effect of 2 years of alendronate treatment on alveolar bone loss involving 335 patients with periodontal disease, no cases of osteonecrosis of the jaw were reported.⁴³

The American Dental Association (ADA) released a statement noting that osteonecrosis of the jaw can occur with or without bisphosphonate use.⁵¹ To date, a true cause-and-effect relationship between osteonecrosis of the jaw and bisphosphonate use has not been established. Further studies are needed to fully explore this relationship. Our group is currently exploring novel periodontal assessments comparing the oral health of postmenopausal women with osteoporosis who are on no bone therapy vs postmenopausal women with osteoporosis treated with bisphosphonates for 2 or more years.

Discussion of treatment for bisphosphonate-associated osteonecrosis of the jaw is beyond the scope of this article.

REGULAR DENTAL CARE IS ESSENTIAL

Regardless of whether the patient is receiving a bisphosphonate drug, physicians caring for postmenopausal women should be vigilant and encourage their patients to seek regular dental evaluation for prevention and early management of oral disorders. Conversely, dentists should be aware of the potential effects of menopause and its treatments on bone and dental health.

Questions from postmenopausal women can be managed, in part, by returning to the basics suggested by the ADA:

• Regular dental examinations; regular professional cleaning to remove bacterial plaque biofilm under the gum-line where a toothbrush will not reach
• Daily oral hygiene practices to remove biofilm at and above the gum-line including brushing twice daily with an ADA-accepted toothpaste
• Replacing the toothbrush every 3 to 4 months (or sooner if the bristles begin to look frayed)
• Cleaning interproximally (between teeth) with floss or interdental cleaner
• Maintaining a balanced diet
• No smoking.