Supplements

Statins have become an important therapeutic option for managing cardiovascular (CV) risk, yet many questions remain regarding their use. This article addresses some of these questions in the primary care management of patients and highlights the impact of long-term statin therapy on CV end points. Because pitavastatin has recently become available in the United States, more detailed information about this agent is also presented.

Recent Clinical Evidence

Findings from clinical trials continue to add to our understanding of the safety and efficacy of statin therapy; for example, extended follow-up studies from 2 landmark trials show lasting benefit and no evidence of emerging hazards. An analysis of the Heart Protection Study demonstrated that participants randomized to simvastatin 40 mg during the initial 5-year trial had maintained the vascular event reduction of 23% (95% confidence interval [CI], 19-28; P < .0001) at the 6-year follow-up.¹ Similarly, 8 years after the close of the 3-year lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), primary prevention patients originally randomized to atorvastatin had maintained a 14% reduction in all-cause mortality (95% CI, 0.76-0.98; P = .02) and a 15% lower rate of non-CV death (95% CI, 0.73-0.99; P = .03) compared with placebo.² Cancer incidence among those receiving a statin versus those receiving a placebo was similar in both trials. Collectively, these data provide reassurance for the long-term continuation of statin therapy.

Results from a meta-analysis involving 34,272 participants without coronary heart disease from 14 randomized controlled trials (16 trial arms) comparing statins to placebo demonstrated significant reductions in all major events with statins, including a reduction of 16% in all-cause mortality (95% CI, 0.73-0.96), 30% in combined fatal and nonfatal CV disease end points (95% CI, 0.61-0.79), and 34% in revascularization rates (95% CI, 0.53-0.83).³ The meta-analysis found no evidence of significant harm caused by a statin or negative effects on patient quality of life.

Pitavastatin

Pitavastatin was approved in the United States in 2009, although it has been available in Japan since 2003. Pitava-statin is a synthetic lipophilic statin with an 11-hour half-life. Following oral ingestion, it enters the enterohepatic circulation without the formation of active metabolites. Pitavastatin is principally metabolized by the cytochrome-P450 (CYP) 2C9 isoenzyme and avoids the major CYP3A4 pathway; thus CYP-mediated drug interactions are greatly reduced.⁴

Several 12-week dose comparative studies with pitavastatin have been conducted. The first study randomized subjects (N = 857) to 1 of 4 groups: pitavastatin 2 or 4 mg/d or simvastatin 20 or 40 mg/d.⁵ Pitavastatin 2 mg demonstrated significantly greater reductions in low- density lipoprotein cholesterol (LDL-C; 39% vs 35%; P = .014) and greater reductions in non–high-density lipoprotein cholesterol (non–HDL-C) than did simvastatin 20 mg/d. Pitavastatin 4 mg/d and simvastatin 40 mg/d each reduced LDL-C by about 44%. Pitavastatin 4 mg/d has also been compared to atorvastatin 20 mg/d in 418 subjects.⁶ After 12 weeks, pitavastatin 4 mg/d and atorvastatin 20 mg/d produced similar reductions in LDL-C (~42%). No differences between groups were noted for other parameters, including HDL-C and non–HDL-C.

Long-term extension studies have evaluated the safety and efficacy of pitavastatin. Patients randomized to pitava-statin, atorvastatin, or simvastatin for 12 weeks received open-label pitavastatin 4 mg/d for up to 52 weeks (N = 1353).⁷ Notable findings included maintenance of LDL-C reductions from the end of the 12-week trial to 52 weeks with all 3 treatments. HDL-C levels continued to increase during follow up, rising 14.3% from baseline. Another long-term study compared pitavastatin 4 mg/d and atorvastatin 20 or 40 mg/d (N = 212).⁶ Both statins produced similar reductions in LDL-C and improvements in other major lipoproteins; however, atorvastatin significantly increased fasting blood glucose from baseline (7.2%; P < .05), whereas pitavastatin showed a nonsignificant increase of 2.1%.

The Japanese LIVALO Effectiveness and Safety (LIVES) Study (N = 20,000) evaluated the effects of pitavastatin 1 to 4 mg daily in clinical practice.⁸ Among patients with abnormal baseline values, treatment with pitavastatin was associated with a 29% reduction in LDL-C and a 23% reduction in triglycerides after 2 years. There was a 5.9% overall increase in HDL-C and a 24.6% increase among those with baseline HDL-C values <40 mg/dL. Pitavastatin was also associated with an improvement in glycosylated hemoglobin (A1C) values among those with diabetes mellitus (DM). Concomitant antidiabetic therapy was continued during the study. These findings suggest that pitavastatin does not worsen glycemic parameters. A 5-year extension of the LIVES study (N = 6582) demonstrated that long-term treatment with pitavastatin maintained the LDL-C reductions observed in the 2-year trial.⁸ Furthermore, HDL-C levels continued to climb, with an overall 29% increase among those with baseline values < 40 mg/dL. Patients who achieved both LDL-C and HDL-C targets experienced the greatest reductions in CV and cerebrovascular risk.

Finally, the Japan Assessment of Pitavastatin and Ator-vastatin in Acute Coronary Syndrome (JAPAN-ACS) study was a prospective, open-label trial that investigated the effects of pitavastatin 4 mg/d and atorvastatin 20 mg/d on coronary plaque volume (PV) among patients with acute coronary syndrome (N = 252) undergoing intravascular ultrasound.⁹ After 8 to 12 months of treatment, the mean change in PV was – 16.9 ± 13.9% and – 18.1 ± 14.2% in the pitavastatin and atorvastatin groups, respectively. Each statin produced significant but equivalent regression of PV.

Other key findings from additional pitavastatin clinical trials are found in TABLE 1 .^10-17

table 1

Key findings from pitavastatin clinical trials

Key Questions

The following are common questions asked by family physicians when considering statin therapy to treat patients with dyslipidemia.

What are the key lipoprotein differences among available statins?

Nearly all statins are able to provide the minimal 30% to 40% LDL-C reduction as suggested by the National Cholesterol Education Program Adult Treatment Panel III for high-risk patients ( TABLE 2 ).^18-22 If greater reductions are required, higher doses of more potent agents, such as atorvastatin and rosuvastatin, may be needed.

Statins also provide moderate increases in HDL-C, with subtle differences observed among the agents. Atorvastatin and fluvastatin usually provide the smallest increases in HDL-C (up to ~6%), whereas simvastatin, pitavastatin, and rosuvastatin produce more robust increases (~5% to 10%).^20,21,23 The effect of statins on non–HDL-C is similar to their effect on LDL-C.²² Non–HDL-C is a secondary target of therapy in patients with triglyceride levels ≥200 mg/dL. Non–HDL-C includes all atherogenic particles (ie, LDL-C and triglyceride-rich lipoproteins) and is calculated as the difference between total cholesterol and HDL-C. The non–HDL-C goal is 30 mg/dL higher than the LDL-C goal. Clinical investigation continues to demonstrate that non–HDL-C is a valuable predictor of CV risk. An analysis of statin-treated patients indicated that compared with LDL-C and apolipoprotein B, non–HDL-C has a greater strength of association for risk of future CV events.²⁴

table 2

Range of Low-Density Lipoprotein Cholesterol (LDL-C)–lowering among statins^18-21

Is diabetes really a consequence of statin therapy? If so, do differences exist among the statins?

The US Food and Drug Administration (FDA) recently added warnings to all statin labeling indicating that statins can raise blood glucose and A1C levels.²⁵ These effects appear to be modest and dose dependent. This concern initially emerged in the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuva-statin (JUPITER) study when statin users experienced a 25% higher incidence of new onset DM compared to those receiving placebo.²⁶ The short-term effects of various atorvastatin doses on glycemic indices further support these findings.²⁷ Compared to placebo, all atorvastatin doses significantly increased A1C and fasting plasma insulin levels after 8 weeks (all, P < .01). Additionally, a meta-analysis of 5 major statin trials involving 32,752 patients demonstrated that patients receiving intensive-dose statin therapy had a 12% higher risk of developing DM than patients receiving moderate-dose statin therapy.²⁸

The association between statin therapy and DM is considered a class effect; differences among the statins are controversial. In an analysis of 13 major randomized controlled trials, pravastatin produced a nonsignificant 3% increase in new onset DM, whereas rosuvastatin was associated with an 18% increase.²⁸ A 16-week, head-to-head comparison showed that pitavastatin had no effect on A1C, while modest increases were seen with low-dose atorvastatin and rosuvastatin.¹⁰ In another study, atorvastatin but not pitavastatin produced significant (P < .03) increases in glycoalbumin and A1C (P < .01), whereas fasting glucose and insulin levels tended to decrease with pitavastatin.²⁹ However, findings from the meta-analysis showed that the individual studies lacked sufficient specific data to detect heterogeneity between statins.³⁰

Overall, statins are associated with modest increases in glycemic indices and new onset DM. This association appears to be greater with high-dose therapy; however, additional trials are needed to fully understand possible differences among statins.

Which drug interactions are clinically important?

As statin pharmacokinetic data have accumulated, critical drug interactions have become more apparent. The major concern is increased statin exposure secondary to limited metabolism, resulting in more dose-dependent AEs, such as muscle injury. CYP3A4 isoenzyme involvement is common in clinically significant interactions. Lovastatin, simvastatin, and to a lesser extent, atorvastatin are all substrates for CYP3A4.³¹ The FDA recently updated labeling for simvastatin and lovastatin to provide information on contraindications and dose limitations with concomitant agents [www.fda.gov/Drugs/DrugSafety/ucm293877.htm].^18,25

Statins have differing effects on warfarin metabolism, with most agents increasing the international normalized ratio (INR). Conversely, atorvastatin and pitavastatin have shown no significant effect on prothrombin time when added to chronic warfarin therapy.^23,32 Despite this, appropriate INR monitoring is suggested when any statin is added to warfarin treatment.

Another recent FDA advisory focusing on human immunodeficiency virus and hepatitis C virus protease inhibitors further emphasizes the importance of statin interactions.³³ The advisory provides specific dose limitations and contraindications for 7 statins. Similar to other potent CYP3A4 inhibitors, protease inhibitors can increase lovastatin and simvastatin levels by 13- to 20-fold. No information is available for fluvastatin, while no dose limitations are needed for pitavastatin or pravastatin.³³

Mechanisms implicating statins in other drug interactions include inhibition of CYP2C9, glucuronidation, and organic anion transporting polypeptide (OATP).³¹ Concomitant treatment with gemfibrozil and a statin produces a significant interaction, as this combination inhibits CYP2C9 and glucuronidation, resulting in marked increases in statin exposure. Similarly, the coadministration of a statin with cyclosporine is clinically relevant. Cyclosporine blocks another key step in statin metabolism, OATP, resulting in elevated concentrations of nearly all statins. The concomitant use of cyclosporine with lovastatin, simvastatin, or pitavastatin is contraindicated, whereas most other agents require dose limitations.^18,23,25,31

Do statins possess a dose-dependent threshold for adverse events?

A general dose-dependent threshold for AEs has been observed with statin therapy. This upper limit is more apparent with certain statins and primarily manifests as myotoxicity or increased hepatic transaminase levels. High-dose simvastatin has shown the most evidence regarding increased myopathy. In the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, 53 patients (0.9%) in the simvastatin 80-mg group experienced myopathy, including 7 cases (0.1%) of rhabdomyolysis, over a mean of 6.7 years of follow-up.³⁴ By comparison, there were 2 reports of myopathy (0.03%) in the 20-mg group. Similarly, in Phase Z of the A to Z trial, 9 reports (0.4%) of myopathy, including 3 cases of rhabdomyolysis (0.13%), were reported with simvastatin 80 mg over a median of 2 years of follow-up, compared to none with lower doses.³⁵ Lower rates of myopathy and rhabdomyolysis (0.0%-0.3% and 0.0%-0.1%, respectively) were found with atorvastatin 80 mg, fluvastatin 80 mg, and rosuvastatin 40 mg in major trials.³⁶ These data prompted the FDA to publish an advisory on simvastatin dose limitations, including restricting the 80-mg dose.¹⁸ A threshold also has been observed with other statins, as an approximate 3-fold higher incidence of creatine kinase (CK) and hepatic transaminase elevations occur when titrating from moderate to maximal doses.³⁷

Should ethnicity be a factor in selecting a statin?

While no specific recommendations presently exist regarding the selection of statin therapy based on ethnicity, rosuvastatin doses, including the 5-mg starting dose, should be reduced in patients of Asian ancestry because of a 2-fold increase in pharmacokinetic parameters compared to whites.³⁸ Otherwise, the few studies evaluating individual agents among various ethnic groups generally suggest similar effects on pharmacokinetic parameters, lipid changes, and CV outcomes.

One study compared pharmacokinetic parameters of pitavastatin between healthy Caucasian and Japanese men.³⁹ Pitavastatin demonstrated pharmacokinetic bioequivalence between the 2 groups with no clinically relevant differences. A substudy of ASCOT assessed the lipid effects of atorvastatin among whites, blacks, and South Asians.⁴⁰ No significant differences were observed in the reductions in total cholesterol, LDL-C, or triglycerides. Lastly, outcomes were evaluated among different ethnicities in the JUPITER study.⁴¹ Similar reductions in major CV events were noted for whites versus non-whites with Hispanics and blacks experiencing comparable risk reductions.

How should statin-associated myalgia be managed?

Approximately 11% of patients receiving moderate- to high-dose statin therapy experience muscle symptoms.⁴² This common AE can greatly affect therapy by reducing quality of life and adherence and limiting treatment outcomes. A step-wise approach can be implemented to minimize the risk of myotoxicity.

The first step is to avoid critical drug interactions that increase statin exposure. The statins most susceptible to interactions are those metabolized by CYP3A4—simvastatin, lovastatin, and atorvastatin. Medications commonly used that inhibit CYP3A4 include macrolide antibiotics and azole antifungals.⁴²

Second, establishing a firm diagnosis of statin- associated myalgia is critical. This is often challenging given that many comorbid conditions (eg, arthritis) are associated with muscle symptoms. Ruling out other possible contributors, such as thyroid dysfunction, electrolyte abnormalities, and recent muscle injury, also should be considered. Temporary discontinuation of the statin to determine if symptoms improve is suggested. Monitoring the CK level is prudent in symptomatic patients to gauge potential myotoxicity and determine if therapy should be discontinued. The National Lipid Association recommends stopping statin therapy when signs and symptoms of rhabdomyolysis are present, including CK >10,000 IU/L or >10 times the upper limit of normal with elevated serum creatinine or requiring intravenous hydration.⁴²

Other steps include switching to a different statin, reducing the statin dose, or using intermittent dosing (eg, every other day or twice weekly) with an extended half-life statin (eg, atorvastatin or rosuvastatin).⁴² Lastly, a bile acid resin or the cholesterol absorption inhibitor ezetimibe can be used. These classes produce only moderate reductions in LDL-C (~20%) but are unlikely to cause muscle symptoms.

Continue to complete the online evaluation and receive your certification of completion.

Statins have become an important therapeutic option for managing cardiovascular (CV) risk, yet many questions remain regarding their use. This article addresses some of these questions in the primary care management of patients and highlights the impact of long-term statin therapy on CV end points. Because pitavastatin has recently become available in the United States, more detailed information about this agent is also presented.

Recent Clinical Evidence

Findings from clinical trials continue to add to our understanding of the safety and efficacy of statin therapy; for example, extended follow-up studies from 2 landmark trials show lasting benefit and no evidence of emerging hazards. An analysis of the Heart Protection Study demonstrated that participants randomized to simvastatin 40 mg during the initial 5-year trial had maintained the vascular event reduction of 23% (95% confidence interval [CI], 19-28; P < .0001) at the 6-year follow-up.¹ Similarly, 8 years after the close of the 3-year lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), primary prevention patients originally randomized to atorvastatin had maintained a 14% reduction in all-cause mortality (95% CI, 0.76-0.98; P = .02) and a 15% lower rate of non-CV death (95% CI, 0.73-0.99; P = .03) compared with placebo.² Cancer incidence among those receiving a statin versus those receiving a placebo was similar in both trials. Collectively, these data provide reassurance for the long-term continuation of statin therapy.

Results from a meta-analysis involving 34,272 participants without coronary heart disease from 14 randomized controlled trials (16 trial arms) comparing statins to placebo demonstrated significant reductions in all major events with statins, including a reduction of 16% in all-cause mortality (95% CI, 0.73-0.96), 30% in combined fatal and nonfatal CV disease end points (95% CI, 0.61-0.79), and 34% in revascularization rates (95% CI, 0.53-0.83).³ The meta-analysis found no evidence of significant harm caused by a statin or negative effects on patient quality of life.

Pitavastatin

Pitavastatin was approved in the United States in 2009, although it has been available in Japan since 2003. Pitava-statin is a synthetic lipophilic statin with an 11-hour half-life. Following oral ingestion, it enters the enterohepatic circulation without the formation of active metabolites. Pitavastatin is principally metabolized by the cytochrome-P450 (CYP) 2C9 isoenzyme and avoids the major CYP3A4 pathway; thus CYP-mediated drug interactions are greatly reduced.⁴

Several 12-week dose comparative studies with pitavastatin have been conducted. The first study randomized subjects (N = 857) to 1 of 4 groups: pitavastatin 2 or 4 mg/d or simvastatin 20 or 40 mg/d.⁵ Pitavastatin 2 mg demonstrated significantly greater reductions in low- density lipoprotein cholesterol (LDL-C; 39% vs 35%; P = .014) and greater reductions in non–high-density lipoprotein cholesterol (non–HDL-C) than did simvastatin 20 mg/d. Pitavastatin 4 mg/d and simvastatin 40 mg/d each reduced LDL-C by about 44%. Pitavastatin 4 mg/d has also been compared to atorvastatin 20 mg/d in 418 subjects.⁶ After 12 weeks, pitavastatin 4 mg/d and atorvastatin 20 mg/d produced similar reductions in LDL-C (~42%). No differences between groups were noted for other parameters, including HDL-C and non–HDL-C.

Long-term extension studies have evaluated the safety and efficacy of pitavastatin. Patients randomized to pitava-statin, atorvastatin, or simvastatin for 12 weeks received open-label pitavastatin 4 mg/d for up to 52 weeks (N = 1353).⁷ Notable findings included maintenance of LDL-C reductions from the end of the 12-week trial to 52 weeks with all 3 treatments. HDL-C levels continued to increase during follow up, rising 14.3% from baseline. Another long-term study compared pitavastatin 4 mg/d and atorvastatin 20 or 40 mg/d (N = 212).⁶ Both statins produced similar reductions in LDL-C and improvements in other major lipoproteins; however, atorvastatin significantly increased fasting blood glucose from baseline (7.2%; P < .05), whereas pitavastatin showed a nonsignificant increase of 2.1%.

The Japanese LIVALO Effectiveness and Safety (LIVES) Study (N = 20,000) evaluated the effects of pitavastatin 1 to 4 mg daily in clinical practice.⁸ Among patients with abnormal baseline values, treatment with pitavastatin was associated with a 29% reduction in LDL-C and a 23% reduction in triglycerides after 2 years. There was a 5.9% overall increase in HDL-C and a 24.6% increase among those with baseline HDL-C values <40 mg/dL. Pitavastatin was also associated with an improvement in glycosylated hemoglobin (A1C) values among those with diabetes mellitus (DM). Concomitant antidiabetic therapy was continued during the study. These findings suggest that pitavastatin does not worsen glycemic parameters. A 5-year extension of the LIVES study (N = 6582) demonstrated that long-term treatment with pitavastatin maintained the LDL-C reductions observed in the 2-year trial.⁸ Furthermore, HDL-C levels continued to climb, with an overall 29% increase among those with baseline values < 40 mg/dL. Patients who achieved both LDL-C and HDL-C targets experienced the greatest reductions in CV and cerebrovascular risk.

Finally, the Japan Assessment of Pitavastatin and Ator-vastatin in Acute Coronary Syndrome (JAPAN-ACS) study was a prospective, open-label trial that investigated the effects of pitavastatin 4 mg/d and atorvastatin 20 mg/d on coronary plaque volume (PV) among patients with acute coronary syndrome (N = 252) undergoing intravascular ultrasound.⁹ After 8 to 12 months of treatment, the mean change in PV was – 16.9 ± 13.9% and – 18.1 ± 14.2% in the pitavastatin and atorvastatin groups, respectively. Each statin produced significant but equivalent regression of PV.

Other key findings from additional pitavastatin clinical trials are found in TABLE 1 .^10-17

table 1

Key findings from pitavastatin clinical trials

Key Questions

The following are common questions asked by family physicians when considering statin therapy to treat patients with dyslipidemia.

What are the key lipoprotein differences among available statins?

Nearly all statins are able to provide the minimal 30% to 40% LDL-C reduction as suggested by the National Cholesterol Education Program Adult Treatment Panel III for high-risk patients ( TABLE 2 ).^18-22 If greater reductions are required, higher doses of more potent agents, such as atorvastatin and rosuvastatin, may be needed.

Statins also provide moderate increases in HDL-C, with subtle differences observed among the agents. Atorvastatin and fluvastatin usually provide the smallest increases in HDL-C (up to ~6%), whereas simvastatin, pitavastatin, and rosuvastatin produce more robust increases (~5% to 10%).^20,21,23 The effect of statins on non–HDL-C is similar to their effect on LDL-C.²² Non–HDL-C is a secondary target of therapy in patients with triglyceride levels ≥200 mg/dL. Non–HDL-C includes all atherogenic particles (ie, LDL-C and triglyceride-rich lipoproteins) and is calculated as the difference between total cholesterol and HDL-C. The non–HDL-C goal is 30 mg/dL higher than the LDL-C goal. Clinical investigation continues to demonstrate that non–HDL-C is a valuable predictor of CV risk. An analysis of statin-treated patients indicated that compared with LDL-C and apolipoprotein B, non–HDL-C has a greater strength of association for risk of future CV events.²⁴

table 2

Range of Low-Density Lipoprotein Cholesterol (LDL-C)–lowering among statins^18-21

Is diabetes really a consequence of statin therapy? If so, do differences exist among the statins?

The US Food and Drug Administration (FDA) recently added warnings to all statin labeling indicating that statins can raise blood glucose and A1C levels.²⁵ These effects appear to be modest and dose dependent. This concern initially emerged in the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuva-statin (JUPITER) study when statin users experienced a 25% higher incidence of new onset DM compared to those receiving placebo.²⁶ The short-term effects of various atorvastatin doses on glycemic indices further support these findings.²⁷ Compared to placebo, all atorvastatin doses significantly increased A1C and fasting plasma insulin levels after 8 weeks (all, P < .01). Additionally, a meta-analysis of 5 major statin trials involving 32,752 patients demonstrated that patients receiving intensive-dose statin therapy had a 12% higher risk of developing DM than patients receiving moderate-dose statin therapy.²⁸

The association between statin therapy and DM is considered a class effect; differences among the statins are controversial. In an analysis of 13 major randomized controlled trials, pravastatin produced a nonsignificant 3% increase in new onset DM, whereas rosuvastatin was associated with an 18% increase.²⁸ A 16-week, head-to-head comparison showed that pitavastatin had no effect on A1C, while modest increases were seen with low-dose atorvastatin and rosuvastatin.¹⁰ In another study, atorvastatin but not pitavastatin produced significant (P < .03) increases in glycoalbumin and A1C (P < .01), whereas fasting glucose and insulin levels tended to decrease with pitavastatin.²⁹ However, findings from the meta-analysis showed that the individual studies lacked sufficient specific data to detect heterogeneity between statins.³⁰

Overall, statins are associated with modest increases in glycemic indices and new onset DM. This association appears to be greater with high-dose therapy; however, additional trials are needed to fully understand possible differences among statins.

Which drug interactions are clinically important?

As statin pharmacokinetic data have accumulated, critical drug interactions have become more apparent. The major concern is increased statin exposure secondary to limited metabolism, resulting in more dose-dependent AEs, such as muscle injury. CYP3A4 isoenzyme involvement is common in clinically significant interactions. Lovastatin, simvastatin, and to a lesser extent, atorvastatin are all substrates for CYP3A4.³¹ The FDA recently updated labeling for simvastatin and lovastatin to provide information on contraindications and dose limitations with concomitant agents [www.fda.gov/Drugs/DrugSafety/ucm293877.htm].^18,25

Statins have differing effects on warfarin metabolism, with most agents increasing the international normalized ratio (INR). Conversely, atorvastatin and pitavastatin have shown no significant effect on prothrombin time when added to chronic warfarin therapy.^23,32 Despite this, appropriate INR monitoring is suggested when any statin is added to warfarin treatment.

Another recent FDA advisory focusing on human immunodeficiency virus and hepatitis C virus protease inhibitors further emphasizes the importance of statin interactions.³³ The advisory provides specific dose limitations and contraindications for 7 statins. Similar to other potent CYP3A4 inhibitors, protease inhibitors can increase lovastatin and simvastatin levels by 13- to 20-fold. No information is available for fluvastatin, while no dose limitations are needed for pitavastatin or pravastatin.³³

Mechanisms implicating statins in other drug interactions include inhibition of CYP2C9, glucuronidation, and organic anion transporting polypeptide (OATP).³¹ Concomitant treatment with gemfibrozil and a statin produces a significant interaction, as this combination inhibits CYP2C9 and glucuronidation, resulting in marked increases in statin exposure. Similarly, the coadministration of a statin with cyclosporine is clinically relevant. Cyclosporine blocks another key step in statin metabolism, OATP, resulting in elevated concentrations of nearly all statins. The concomitant use of cyclosporine with lovastatin, simvastatin, or pitavastatin is contraindicated, whereas most other agents require dose limitations.^18,23,25,31

Do statins possess a dose-dependent threshold for adverse events?

A general dose-dependent threshold for AEs has been observed with statin therapy. This upper limit is more apparent with certain statins and primarily manifests as myotoxicity or increased hepatic transaminase levels. High-dose simvastatin has shown the most evidence regarding increased myopathy. In the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, 53 patients (0.9%) in the simvastatin 80-mg group experienced myopathy, including 7 cases (0.1%) of rhabdomyolysis, over a mean of 6.7 years of follow-up.³⁴ By comparison, there were 2 reports of myopathy (0.03%) in the 20-mg group. Similarly, in Phase Z of the A to Z trial, 9 reports (0.4%) of myopathy, including 3 cases of rhabdomyolysis (0.13%), were reported with simvastatin 80 mg over a median of 2 years of follow-up, compared to none with lower doses.³⁵ Lower rates of myopathy and rhabdomyolysis (0.0%-0.3% and 0.0%-0.1%, respectively) were found with atorvastatin 80 mg, fluvastatin 80 mg, and rosuvastatin 40 mg in major trials.³⁶ These data prompted the FDA to publish an advisory on simvastatin dose limitations, including restricting the 80-mg dose.¹⁸ A threshold also has been observed with other statins, as an approximate 3-fold higher incidence of creatine kinase (CK) and hepatic transaminase elevations occur when titrating from moderate to maximal doses.³⁷

Should ethnicity be a factor in selecting a statin?

While no specific recommendations presently exist regarding the selection of statin therapy based on ethnicity, rosuvastatin doses, including the 5-mg starting dose, should be reduced in patients of Asian ancestry because of a 2-fold increase in pharmacokinetic parameters compared to whites.³⁸ Otherwise, the few studies evaluating individual agents among various ethnic groups generally suggest similar effects on pharmacokinetic parameters, lipid changes, and CV outcomes.

One study compared pharmacokinetic parameters of pitavastatin between healthy Caucasian and Japanese men.³⁹ Pitavastatin demonstrated pharmacokinetic bioequivalence between the 2 groups with no clinically relevant differences. A substudy of ASCOT assessed the lipid effects of atorvastatin among whites, blacks, and South Asians.⁴⁰ No significant differences were observed in the reductions in total cholesterol, LDL-C, or triglycerides. Lastly, outcomes were evaluated among different ethnicities in the JUPITER study.⁴¹ Similar reductions in major CV events were noted for whites versus non-whites with Hispanics and blacks experiencing comparable risk reductions.

How should statin-associated myalgia be managed?

Approximately 11% of patients receiving moderate- to high-dose statin therapy experience muscle symptoms.⁴² This common AE can greatly affect therapy by reducing quality of life and adherence and limiting treatment outcomes. A step-wise approach can be implemented to minimize the risk of myotoxicity.

The first step is to avoid critical drug interactions that increase statin exposure. The statins most susceptible to interactions are those metabolized by CYP3A4—simvastatin, lovastatin, and atorvastatin. Medications commonly used that inhibit CYP3A4 include macrolide antibiotics and azole antifungals.⁴²

Second, establishing a firm diagnosis of statin- associated myalgia is critical. This is often challenging given that many comorbid conditions (eg, arthritis) are associated with muscle symptoms. Ruling out other possible contributors, such as thyroid dysfunction, electrolyte abnormalities, and recent muscle injury, also should be considered. Temporary discontinuation of the statin to determine if symptoms improve is suggested. Monitoring the CK level is prudent in symptomatic patients to gauge potential myotoxicity and determine if therapy should be discontinued. The National Lipid Association recommends stopping statin therapy when signs and symptoms of rhabdomyolysis are present, including CK >10,000 IU/L or >10 times the upper limit of normal with elevated serum creatinine or requiring intravenous hydration.⁴²

Other steps include switching to a different statin, reducing the statin dose, or using intermittent dosing (eg, every other day or twice weekly) with an extended half-life statin (eg, atorvastatin or rosuvastatin).⁴² Lastly, a bile acid resin or the cholesterol absorption inhibitor ezetimibe can be used. These classes produce only moderate reductions in LDL-C (~20%) but are unlikely to cause muscle symptoms.

Continue to complete the online evaluation and receive your certification of completion.

Statins have become an important therapeutic option for managing cardiovascular (CV) risk, yet many questions remain regarding their use. This article addresses some of these questions in the primary care management of patients and highlights the impact of long-term statin therapy on CV end points. Because pitavastatin has recently become available in the United States, more detailed information about this agent is also presented.

Recent Clinical Evidence

Findings from clinical trials continue to add to our understanding of the safety and efficacy of statin therapy; for example, extended follow-up studies from 2 landmark trials show lasting benefit and no evidence of emerging hazards. An analysis of the Heart Protection Study demonstrated that participants randomized to simvastatin 40 mg during the initial 5-year trial had maintained the vascular event reduction of 23% (95% confidence interval [CI], 19-28; P < .0001) at the 6-year follow-up.¹ Similarly, 8 years after the close of the 3-year lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), primary prevention patients originally randomized to atorvastatin had maintained a 14% reduction in all-cause mortality (95% CI, 0.76-0.98; P = .02) and a 15% lower rate of non-CV death (95% CI, 0.73-0.99; P = .03) compared with placebo.² Cancer incidence among those receiving a statin versus those receiving a placebo was similar in both trials. Collectively, these data provide reassurance for the long-term continuation of statin therapy.

Results from a meta-analysis involving 34,272 participants without coronary heart disease from 14 randomized controlled trials (16 trial arms) comparing statins to placebo demonstrated significant reductions in all major events with statins, including a reduction of 16% in all-cause mortality (95% CI, 0.73-0.96), 30% in combined fatal and nonfatal CV disease end points (95% CI, 0.61-0.79), and 34% in revascularization rates (95% CI, 0.53-0.83).³ The meta-analysis found no evidence of significant harm caused by a statin or negative effects on patient quality of life.

Pitavastatin

Pitavastatin was approved in the United States in 2009, although it has been available in Japan since 2003. Pitava-statin is a synthetic lipophilic statin with an 11-hour half-life. Following oral ingestion, it enters the enterohepatic circulation without the formation of active metabolites. Pitavastatin is principally metabolized by the cytochrome-P450 (CYP) 2C9 isoenzyme and avoids the major CYP3A4 pathway; thus CYP-mediated drug interactions are greatly reduced.⁴

Several 12-week dose comparative studies with pitavastatin have been conducted. The first study randomized subjects (N = 857) to 1 of 4 groups: pitavastatin 2 or 4 mg/d or simvastatin 20 or 40 mg/d.⁵ Pitavastatin 2 mg demonstrated significantly greater reductions in low- density lipoprotein cholesterol (LDL-C; 39% vs 35%; P = .014) and greater reductions in non–high-density lipoprotein cholesterol (non–HDL-C) than did simvastatin 20 mg/d. Pitavastatin 4 mg/d and simvastatin 40 mg/d each reduced LDL-C by about 44%. Pitavastatin 4 mg/d has also been compared to atorvastatin 20 mg/d in 418 subjects.⁶ After 12 weeks, pitavastatin 4 mg/d and atorvastatin 20 mg/d produced similar reductions in LDL-C (~42%). No differences between groups were noted for other parameters, including HDL-C and non–HDL-C.

Long-term extension studies have evaluated the safety and efficacy of pitavastatin. Patients randomized to pitava-statin, atorvastatin, or simvastatin for 12 weeks received open-label pitavastatin 4 mg/d for up to 52 weeks (N = 1353).⁷ Notable findings included maintenance of LDL-C reductions from the end of the 12-week trial to 52 weeks with all 3 treatments. HDL-C levels continued to increase during follow up, rising 14.3% from baseline. Another long-term study compared pitavastatin 4 mg/d and atorvastatin 20 or 40 mg/d (N = 212).⁶ Both statins produced similar reductions in LDL-C and improvements in other major lipoproteins; however, atorvastatin significantly increased fasting blood glucose from baseline (7.2%; P < .05), whereas pitavastatin showed a nonsignificant increase of 2.1%.

The Japanese LIVALO Effectiveness and Safety (LIVES) Study (N = 20,000) evaluated the effects of pitavastatin 1 to 4 mg daily in clinical practice.⁸ Among patients with abnormal baseline values, treatment with pitavastatin was associated with a 29% reduction in LDL-C and a 23% reduction in triglycerides after 2 years. There was a 5.9% overall increase in HDL-C and a 24.6% increase among those with baseline HDL-C values <40 mg/dL. Pitavastatin was also associated with an improvement in glycosylated hemoglobin (A1C) values among those with diabetes mellitus (DM). Concomitant antidiabetic therapy was continued during the study. These findings suggest that pitavastatin does not worsen glycemic parameters. A 5-year extension of the LIVES study (N = 6582) demonstrated that long-term treatment with pitavastatin maintained the LDL-C reductions observed in the 2-year trial.⁸ Furthermore, HDL-C levels continued to climb, with an overall 29% increase among those with baseline values < 40 mg/dL. Patients who achieved both LDL-C and HDL-C targets experienced the greatest reductions in CV and cerebrovascular risk.

Finally, the Japan Assessment of Pitavastatin and Ator-vastatin in Acute Coronary Syndrome (JAPAN-ACS) study was a prospective, open-label trial that investigated the effects of pitavastatin 4 mg/d and atorvastatin 20 mg/d on coronary plaque volume (PV) among patients with acute coronary syndrome (N = 252) undergoing intravascular ultrasound.⁹ After 8 to 12 months of treatment, the mean change in PV was – 16.9 ± 13.9% and – 18.1 ± 14.2% in the pitavastatin and atorvastatin groups, respectively. Each statin produced significant but equivalent regression of PV.

Other key findings from additional pitavastatin clinical trials are found in TABLE 1 .^10-17

table 1

Key findings from pitavastatin clinical trials

Key Questions

The following are common questions asked by family physicians when considering statin therapy to treat patients with dyslipidemia.

What are the key lipoprotein differences among available statins?

Nearly all statins are able to provide the minimal 30% to 40% LDL-C reduction as suggested by the National Cholesterol Education Program Adult Treatment Panel III for high-risk patients ( TABLE 2 ).^18-22 If greater reductions are required, higher doses of more potent agents, such as atorvastatin and rosuvastatin, may be needed.

Statins also provide moderate increases in HDL-C, with subtle differences observed among the agents. Atorvastatin and fluvastatin usually provide the smallest increases in HDL-C (up to ~6%), whereas simvastatin, pitavastatin, and rosuvastatin produce more robust increases (~5% to 10%).^20,21,23 The effect of statins on non–HDL-C is similar to their effect on LDL-C.²² Non–HDL-C is a secondary target of therapy in patients with triglyceride levels ≥200 mg/dL. Non–HDL-C includes all atherogenic particles (ie, LDL-C and triglyceride-rich lipoproteins) and is calculated as the difference between total cholesterol and HDL-C. The non–HDL-C goal is 30 mg/dL higher than the LDL-C goal. Clinical investigation continues to demonstrate that non–HDL-C is a valuable predictor of CV risk. An analysis of statin-treated patients indicated that compared with LDL-C and apolipoprotein B, non–HDL-C has a greater strength of association for risk of future CV events.²⁴

table 2

Range of Low-Density Lipoprotein Cholesterol (LDL-C)–lowering among statins^18-21

Is diabetes really a consequence of statin therapy? If so, do differences exist among the statins?

The US Food and Drug Administration (FDA) recently added warnings to all statin labeling indicating that statins can raise blood glucose and A1C levels.²⁵ These effects appear to be modest and dose dependent. This concern initially emerged in the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuva-statin (JUPITER) study when statin users experienced a 25% higher incidence of new onset DM compared to those receiving placebo.²⁶ The short-term effects of various atorvastatin doses on glycemic indices further support these findings.²⁷ Compared to placebo, all atorvastatin doses significantly increased A1C and fasting plasma insulin levels after 8 weeks (all, P < .01). Additionally, a meta-analysis of 5 major statin trials involving 32,752 patients demonstrated that patients receiving intensive-dose statin therapy had a 12% higher risk of developing DM than patients receiving moderate-dose statin therapy.²⁸

The association between statin therapy and DM is considered a class effect; differences among the statins are controversial. In an analysis of 13 major randomized controlled trials, pravastatin produced a nonsignificant 3% increase in new onset DM, whereas rosuvastatin was associated with an 18% increase.²⁸ A 16-week, head-to-head comparison showed that pitavastatin had no effect on A1C, while modest increases were seen with low-dose atorvastatin and rosuvastatin.¹⁰ In another study, atorvastatin but not pitavastatin produced significant (P < .03) increases in glycoalbumin and A1C (P < .01), whereas fasting glucose and insulin levels tended to decrease with pitavastatin.²⁹ However, findings from the meta-analysis showed that the individual studies lacked sufficient specific data to detect heterogeneity between statins.³⁰

Overall, statins are associated with modest increases in glycemic indices and new onset DM. This association appears to be greater with high-dose therapy; however, additional trials are needed to fully understand possible differences among statins.

Which drug interactions are clinically important?

As statin pharmacokinetic data have accumulated, critical drug interactions have become more apparent. The major concern is increased statin exposure secondary to limited metabolism, resulting in more dose-dependent AEs, such as muscle injury. CYP3A4 isoenzyme involvement is common in clinically significant interactions. Lovastatin, simvastatin, and to a lesser extent, atorvastatin are all substrates for CYP3A4.³¹ The FDA recently updated labeling for simvastatin and lovastatin to provide information on contraindications and dose limitations with concomitant agents [www.fda.gov/Drugs/DrugSafety/ucm293877.htm].^18,25

Statins have differing effects on warfarin metabolism, with most agents increasing the international normalized ratio (INR). Conversely, atorvastatin and pitavastatin have shown no significant effect on prothrombin time when added to chronic warfarin therapy.^23,32 Despite this, appropriate INR monitoring is suggested when any statin is added to warfarin treatment.

Another recent FDA advisory focusing on human immunodeficiency virus and hepatitis C virus protease inhibitors further emphasizes the importance of statin interactions.³³ The advisory provides specific dose limitations and contraindications for 7 statins. Similar to other potent CYP3A4 inhibitors, protease inhibitors can increase lovastatin and simvastatin levels by 13- to 20-fold. No information is available for fluvastatin, while no dose limitations are needed for pitavastatin or pravastatin.³³

Mechanisms implicating statins in other drug interactions include inhibition of CYP2C9, glucuronidation, and organic anion transporting polypeptide (OATP).³¹ Concomitant treatment with gemfibrozil and a statin produces a significant interaction, as this combination inhibits CYP2C9 and glucuronidation, resulting in marked increases in statin exposure. Similarly, the coadministration of a statin with cyclosporine is clinically relevant. Cyclosporine blocks another key step in statin metabolism, OATP, resulting in elevated concentrations of nearly all statins. The concomitant use of cyclosporine with lovastatin, simvastatin, or pitavastatin is contraindicated, whereas most other agents require dose limitations.^18,23,25,31

Do statins possess a dose-dependent threshold for adverse events?

A general dose-dependent threshold for AEs has been observed with statin therapy. This upper limit is more apparent with certain statins and primarily manifests as myotoxicity or increased hepatic transaminase levels. High-dose simvastatin has shown the most evidence regarding increased myopathy. In the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, 53 patients (0.9%) in the simvastatin 80-mg group experienced myopathy, including 7 cases (0.1%) of rhabdomyolysis, over a mean of 6.7 years of follow-up.³⁴ By comparison, there were 2 reports of myopathy (0.03%) in the 20-mg group. Similarly, in Phase Z of the A to Z trial, 9 reports (0.4%) of myopathy, including 3 cases of rhabdomyolysis (0.13%), were reported with simvastatin 80 mg over a median of 2 years of follow-up, compared to none with lower doses.³⁵ Lower rates of myopathy and rhabdomyolysis (0.0%-0.3% and 0.0%-0.1%, respectively) were found with atorvastatin 80 mg, fluvastatin 80 mg, and rosuvastatin 40 mg in major trials.³⁶ These data prompted the FDA to publish an advisory on simvastatin dose limitations, including restricting the 80-mg dose.¹⁸ A threshold also has been observed with other statins, as an approximate 3-fold higher incidence of creatine kinase (CK) and hepatic transaminase elevations occur when titrating from moderate to maximal doses.³⁷

Should ethnicity be a factor in selecting a statin?

While no specific recommendations presently exist regarding the selection of statin therapy based on ethnicity, rosuvastatin doses, including the 5-mg starting dose, should be reduced in patients of Asian ancestry because of a 2-fold increase in pharmacokinetic parameters compared to whites.³⁸ Otherwise, the few studies evaluating individual agents among various ethnic groups generally suggest similar effects on pharmacokinetic parameters, lipid changes, and CV outcomes.

One study compared pharmacokinetic parameters of pitavastatin between healthy Caucasian and Japanese men.³⁹ Pitavastatin demonstrated pharmacokinetic bioequivalence between the 2 groups with no clinically relevant differences. A substudy of ASCOT assessed the lipid effects of atorvastatin among whites, blacks, and South Asians.⁴⁰ No significant differences were observed in the reductions in total cholesterol, LDL-C, or triglycerides. Lastly, outcomes were evaluated among different ethnicities in the JUPITER study.⁴¹ Similar reductions in major CV events were noted for whites versus non-whites with Hispanics and blacks experiencing comparable risk reductions.

How should statin-associated myalgia be managed?

Approximately 11% of patients receiving moderate- to high-dose statin therapy experience muscle symptoms.⁴² This common AE can greatly affect therapy by reducing quality of life and adherence and limiting treatment outcomes. A step-wise approach can be implemented to minimize the risk of myotoxicity.

The first step is to avoid critical drug interactions that increase statin exposure. The statins most susceptible to interactions are those metabolized by CYP3A4—simvastatin, lovastatin, and atorvastatin. Medications commonly used that inhibit CYP3A4 include macrolide antibiotics and azole antifungals.⁴²

Second, establishing a firm diagnosis of statin- associated myalgia is critical. This is often challenging given that many comorbid conditions (eg, arthritis) are associated with muscle symptoms. Ruling out other possible contributors, such as thyroid dysfunction, electrolyte abnormalities, and recent muscle injury, also should be considered. Temporary discontinuation of the statin to determine if symptoms improve is suggested. Monitoring the CK level is prudent in symptomatic patients to gauge potential myotoxicity and determine if therapy should be discontinued. The National Lipid Association recommends stopping statin therapy when signs and symptoms of rhabdomyolysis are present, including CK >10,000 IU/L or >10 times the upper limit of normal with elevated serum creatinine or requiring intravenous hydration.⁴²

Other steps include switching to a different statin, reducing the statin dose, or using intermittent dosing (eg, every other day or twice weekly) with an extended half-life statin (eg, atorvastatin or rosuvastatin).⁴² Lastly, a bile acid resin or the cholesterol absorption inhibitor ezetimibe can be used. These classes produce only moderate reductions in LDL-C (~20%) but are unlikely to cause muscle symptoms.

Continue to complete the online evaluation and receive your certification of completion.

The death rate from coronary heart disease (CHD) declined by 59% from 1950 to 1999 in the United States, yet CHD remains a major cause of morbidity and mortality, resulting in an estimated 1.5 million heart attacks in 2011.¹ Better recognition and treatment of the 9 modifiable risk factors for CHD identified by the INTERHEART study ( FIGURE 1 ), as well as changes in lifestyle practices, undoubtedly contributed to the decline in CHD mortality, but further improvement is possible.² Estimates derived from the Second National Health and Nutrition Examination Survey (NHANES II) baseline data and 17-year mortality follow-up data indicate that 45% of CHD deaths in men and 64% in women could be avoided by eliminating 3 major risk factors: elevated total cholesterol (≥240 mg/dL), hypertension, and smoking.³

The evidence indicates that these 3 risk factors are not well controlled. Data from the National Cholesterol Education Program (NCEP) Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey and the Lipid Treatment Assessment Project 2 (L-TAP 2), as well as more recent evidence, indicate that many patients do not achieve low-density lipoprotein cholesterol (LDL-C) and triglyceride targets.^4-10 Similarly, although there has been significant improvement in blood pressure (BP) control over the past 2 decades, BP is controlled in only half of all hypertensive patients.^11,12 Finally, the sharp declines in the prevalence of cigarette smoking seen in the past have slowed in recent years, such that approximately 20% of US adults still smoke cigarettes.¹³

These trends are a concern since a greater risk factor burden in middle age is associated with poorer quality of life and higher medical costs, as well as a higher incidence of cardiovascular events in older age.¹ A recent meta-analysis of 18 cohort studies involving 257,384 adults showed a higher incidence of cardiovascular events in later life with an increasing number of risk factors.¹⁴ For example, adults 55 years of age with an optimal risk factor profile (ie, total cholesterol <180 mg/dL, BP <120/80 mm Hg, nonsmoker, nondiabetic) had much lower risks of death from cardiovascular disease (CVD) through the age of 80 years than those with 2 or more risk factors (4.7% vs 29.6% among men, 6.4% vs 20.5% among women). This translates into a relative risk (RR) of cardiovascular death of 6 times for men and 3 times for women without optimal risk profiles. Similar trends were observed for risk of fatal CHD/nonfatal myocardial infarction (MI) (3.6% vs 37.5% among men, <1% vs 18.3% among women). These findings point to the critical importance of modifying multiple risk factors early in adulthood, well in advance of symptoms. However, the Study to Help Improve Early Evaluation and Management of Risk Factors Leading to Diabetes (SHIELD) showed that about half of patients with CHD are not diagnosed until symptoms become apparent, and fewer than one quarter are diagnosed as a result of screening.¹⁵

This review focuses on patient assessment and treatment strategies to modify abnormal lipid levels and high BP for primary prevention. Addressing other modifiable risk factors is also important, especially since risk factors such as abdominal obesity impact other risk factors ( FIGURE 1 ). An emphasis is placed on strategies in men, since the prevalence of CHD among patients aged 45 years and older is higher in men than in women ( FIGURE 2 ).¹⁶ Furthermore, men experience a first cardiovascular event a decade earlier than women, and a more serious CHD event, such as MI or sudden death, 2 decades earlier.¹

FIGURE 1

Modifiable risk factors for myocardial infarction (MI)²

FIGURE 2

Prevalence of heart disease by age and gender¹⁶

Assessment

The assessment of CHD risk in men need not be complicated and should be made practical so that it is applied consistently. A family and personal medical history and physical examination combined with laboratory determination of lipid levels and glycosylated hemoglobin can help assess modifiable risk factors. The assessment of CHD risk can be facilitated by using 1 of 2 risk calculators. The Framingham Risk Score [www.framinghamheartstudy.org/risk/gencardio.html] is widely used but may underestimate risk, especially in younger persons or those who appear to be healthy but may have other risk factors for CHD.^17-19 The Reynolds Risk Score [www.reynoldsriskscore.org/] includes other risk factors, such as parental history of MI before age 60 years, low levels of apolipoprotein A (apoA), high levels of apolipoprotein B (apoB), and increased levels of high-sensitivity C-reactive protein (hs-CRP).¹⁹ The Reynolds Risk Score has been validated in healthy, nondiabetic men.²⁰

The relevance of apolipoprotein levels, particularly apoB, to cardiovascular risk is increasingly appreciated.²¹ ApoB concentration represents the sum of atherogenic particles found on all atherogenic lipoproteins, including very-low-density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein, and lipoprotein(a) cholesterol, whereas apoA represents the sum of antiatherogenic particles found on high-density lipoprotein cholesterol (HDL-C), the antiatherogenic lipoprotein.²² The ratio of apoB/apoA-I has, in fact, been shown to be a good predictor of cardiovascular events in young men without hypertension and diabetes but with chest pain.²³ High-sensitivity C-reactive protein is a sensitive marker of acute inflammation and is associated with coronary risk.²⁴ Measuring hs-CRP is a recommended option to determine enhanced absolute risk in people with an intermediate 10-year CHD risk of 10% to 20%.²⁵

There remains some uncertainty regarding which lipid levels should be measured when screening for cardiovascular risk. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) advises that total cholesterol, LDL-C, HDL-C, and triglycerides be measured.²⁶ More recent results from The Emerging Risk Factors Collaboration suggest that a more simplified approach may be reasonable.²⁷ Review of data from 68 long-term prospective studies involving 302,430 people without initial vascular disease and 2.79 million person-years of follow-up showed that lipid assessment of vascular risk could be accomplished by measuring either total cholesterol and HDL-C levels or apolipoprotein levels; measuring the triglyceride level was of no added benefit in assessing vascular risk. In addition, fasting and nonfasting lipid levels were found to be of similar value in assessing risk. Other evidence shows that the combination of a triglyceride level ≥178 mg/dL and waist circumference ≥35.4 inches—the hypertriglyceridemic waist phenotype—is as discriminatory a screening tool as the NCEP ATP III guidelines to identify individuals at increased cardiometabolic risk.²⁸ The use of more comprehensive lipoprotein and apolipoprotein testing, as well as noninvasive imaging, may have value in future cardiovascular risk assessment.

Treatment

The main goal of treatment in persons with 1 or more modifiable risk factors is to prevent an incident or primary cardiovascular event. Treatment strategies to achieve this goal in men and women are the same. Prevention of recurrent or secondary events will not be addressed here.

Lipids

Numerous clinical trials, such as the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS),²⁹ Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA),³⁰ and West of Scotland Coronary Prevention Study (WOSCOPS),³¹ definitively established the benefit of cardiovascular risk reduction with lipid-lowering treatment, particularly LDL-C-lowering treatment. Low-density lipoprotein cholesterol is the principal lipid target in most patients, with the treatment goal based on the presence of additional risk factors.³² Discussion of treatments for low HDL-C and elevated triglyceride levels is beyond the scope of this review but is expected to be included in the NCEP ATP IV guidelines scheduled for release later in 2012.

The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) also established significant benefits of statin therapy in primary prevention, compared with placebo, in persons with normal or modestly elevated LDL-C (<130 mg/dL) and elevated hs-CRP (≥2 mg/L).³³ Rates of the primary end point (MI, stroke, arterial revascularization, hospitalization for unstable angina, or cardiovascular death) were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio [HR], 0.56; 95% CI, 0.46-0.69; P < .00001). Further analysis showed that patients who achieved LDL-C <70 mg/dL had a 55% lower rate of vascular events compared with placebo.³⁴

Results from large primary prevention clinical trials such as JUPITER have led to recommendations over the past decade or so for progressively lower LDL-C goals. A meta-analysis of 25 large clinical trials involving 155,613 subjects showed that for every 25 mg/dL reduction in LDL-C, the RR for several cardiovascular outcomes was reduced: vascular mortality, 0.89; major vascular events, 0.86; major coronary events, 0.84; and stroke, 0.90. Put differently, there was a 20% reduction in major coronary events for every 39 mg/dL LDL-C reduction.³⁵

Recent trials support the benefits of intensive high-dose statin therapy in greatly reducing lipid levels, with associated benefits in terms of cardiovascular events. A meta-analysis of 7 trials involving 50,972 high-risk patients with a mean follow-up of 3.1 years showed significant reductions in the risk for cardiovascular events with intensive statin therapy. Those who achieved LDL-C <82 mg/dL with intensive statin therapy had lower cardiovascular risks compared with those with LDL-C ≥82 mg/dL: stroke, odds ratio (OR): 0.80; major coronary events, OR: 0.74; and CVD or CHD death, OR: 0.84.³⁶ Significantly higher liver enzyme abnormalities were observed in patients treated with high-dose statin therapy. [See also Addressing Key Questions with Statin Therapy in this supplement.] The benefits of intensive statin therapy on the progression of coronary atherosclerosis have also been investigated. The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin (SATURN) by Nicholls et al³⁷ included patients (N = 1039) with documented coronary vessel stenosis of at least 20% and a target vessel for imaging with less than 50% obstruction. Patients received either atorvastatin 80 mg daily or rosu-vastatin 40 mg daily for 104 weeks. In the rosuvastatin group, end-of-study LDL-C levels were lower (62.6 vs 70.2 mg/dL; P < .001) and HDL-C levels higher (50.4 vs 48.6 mg/dL; P = .01) compared with the atorvastatin group, respectively. The percent atheroma volume decreased by 1.22% with rosuvastatin and 0.99% with atorvastatin (P = .17). The normalized total atheroma volume decreased 6.39 mm³ with rosuvastatin and 4.42 mm³ with atorvastatin (P = .01). Atheroma regression was induced in the majority of patients in both groups.

Further support for treating with statin doses higher than those recommended for initial therapy comes from a prospective trial involving 1337 consecutive patients followed over a median of 33 months.¹⁰ Although 83% of these patients were on statin therapy, only 51% had an LDL-C <100 mg/dL, and only 15% of the very high-risk patients (n = 941) had an LDL-C <70 mg/dL. The use of intensive statin therapy was associated with a 12-fold higher possibility of achieving an LDL-C <70 mg/dL. Very high-risk patients who achieved an LDL-C <70 mg/dL had a significantly lower risk of all cardiovascular events (HR, 0.34; P = .003).

Blood pressure

As with dyslipidemia, the cardiovascular benefits of lowering elevated BP are well established. While the usual BP goal is <140/90 mm Hg, in those with hypertension and concomitant diabetes or renal disease, the goal is <130/80 mm Hg.³⁸ It is not clear how best to achieve these goals, but therapy must be individualized based on patient comorbidities and drug side effects as recommended in current guidelines.^38-40 With these guidelines as a basis, a simplified ABCD approach can be considered in selecting initial antihypertensive therapy ( FIGURE 3 ).

FIGURE 3

ABCD approach to initial antihypertensive therapy^38-40

Several meta-analyses have been conducted recently to assess the magnitude of BP (systolic/diastolic) lowering in the different classes of antihypertensive drugs. While these meta-analyses have important limitations, such as differences in study design and the lack of a clear description of outcomes, some general impressions can be made. In 1 meta-analysis, thiazide diuretics were found to lower BP by 6/3 and 8/4 mm Hg at doses of 1 and 2 times the recommended starting dose, respectively. A BP-lowering effect of 6/3 mm Hg was observed with starting doses of loop diuretics.⁴² Another meta-analysis failed to find a statistically or clinically significant BP-lowering effect with potassium-sparing diuretics at low doses.⁴³ For spironolactone, a review of 5 crossover studies found a reduction in BP of 21/7 mm Hg. In this review, daily doses of 25 to 100 mg were found to provide the best balance between BP reduction and safety and tolerability.⁴⁴

Several meta-analyses of angiotensin receptor blockers (ARBs) have found BP reductions to be similar among the various ARB drugs. Generally, at maximum recommended doses, a BP reduction of 8/5 mm Hg is observed with these drugs, except for losartan, which produces a smaller BP reduction.^45-49 Heran et al⁴⁵ found a BP reduction of 12/7 mm Hg among the ARBs 1 to 12 hours after the dose was taken. When cost per quality-adjusted life-year gained was considered, 1 meta-analysis found that the slightly greater BP reduction with candesartan compared with losartan was not cost-effective.⁴⁶ However, other benefits of candesartan compared with losartan therapy (eg, lower risk for cardiovascular disease, heart failure, dysrhythmias, and peripheral artery disease) should be considered.⁵⁰ Adverse events were generally found to be similar among the ARBs.

No differences in BP lowering were observed among 92 trials of 14 different angiotensin-converting enzyme inhibitors. As a class, these drugs were found to produce a reduction in BP of 8/5 mm Hg.⁵¹

Because of the modest BP-lowering effects of each of the antihypertensive drugs currently available, consideration should be given to starting antihypertensive therapy with 2 agents for patients with stage 2 hypertension (ie, BP ≥160/100 mm Hg).

Summary

Elimination of key risk factors such as dyslipidemia and hypertension is important for reducing cardiovascular events later in life. A medical history, physical examination, and laboratory determination of lipid and glycosylated hemoglobin levels provide a good assessment of cardiovascular risk. A statin is first-line therapy for reducing LDL-C, which is the primary lipid target in most patients. High-dose statin therapy may be required to reach desired target levels. The choice of initial antihypertensive therapy is based on patient comorbidities and drug side effects; however, most patients require combination antihypertensive therapy to reach goal. The combination of this multifactorial risk approach along with smoking cessation and modification of other risk factors should complement current and future cardiovascular care for men.

The death rate from coronary heart disease (CHD) declined by 59% from 1950 to 1999 in the United States, yet CHD remains a major cause of morbidity and mortality, resulting in an estimated 1.5 million heart attacks in 2011.¹ Better recognition and treatment of the 9 modifiable risk factors for CHD identified by the INTERHEART study ( FIGURE 1 ), as well as changes in lifestyle practices, undoubtedly contributed to the decline in CHD mortality, but further improvement is possible.² Estimates derived from the Second National Health and Nutrition Examination Survey (NHANES II) baseline data and 17-year mortality follow-up data indicate that 45% of CHD deaths in men and 64% in women could be avoided by eliminating 3 major risk factors: elevated total cholesterol (≥240 mg/dL), hypertension, and smoking.³

The evidence indicates that these 3 risk factors are not well controlled. Data from the National Cholesterol Education Program (NCEP) Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey and the Lipid Treatment Assessment Project 2 (L-TAP 2), as well as more recent evidence, indicate that many patients do not achieve low-density lipoprotein cholesterol (LDL-C) and triglyceride targets.^4-10 Similarly, although there has been significant improvement in blood pressure (BP) control over the past 2 decades, BP is controlled in only half of all hypertensive patients.^11,12 Finally, the sharp declines in the prevalence of cigarette smoking seen in the past have slowed in recent years, such that approximately 20% of US adults still smoke cigarettes.¹³

These trends are a concern since a greater risk factor burden in middle age is associated with poorer quality of life and higher medical costs, as well as a higher incidence of cardiovascular events in older age.¹ A recent meta-analysis of 18 cohort studies involving 257,384 adults showed a higher incidence of cardiovascular events in later life with an increasing number of risk factors.¹⁴ For example, adults 55 years of age with an optimal risk factor profile (ie, total cholesterol <180 mg/dL, BP <120/80 mm Hg, nonsmoker, nondiabetic) had much lower risks of death from cardiovascular disease (CVD) through the age of 80 years than those with 2 or more risk factors (4.7% vs 29.6% among men, 6.4% vs 20.5% among women). This translates into a relative risk (RR) of cardiovascular death of 6 times for men and 3 times for women without optimal risk profiles. Similar trends were observed for risk of fatal CHD/nonfatal myocardial infarction (MI) (3.6% vs 37.5% among men, <1% vs 18.3% among women). These findings point to the critical importance of modifying multiple risk factors early in adulthood, well in advance of symptoms. However, the Study to Help Improve Early Evaluation and Management of Risk Factors Leading to Diabetes (SHIELD) showed that about half of patients with CHD are not diagnosed until symptoms become apparent, and fewer than one quarter are diagnosed as a result of screening.¹⁵

This review focuses on patient assessment and treatment strategies to modify abnormal lipid levels and high BP for primary prevention. Addressing other modifiable risk factors is also important, especially since risk factors such as abdominal obesity impact other risk factors ( FIGURE 1 ). An emphasis is placed on strategies in men, since the prevalence of CHD among patients aged 45 years and older is higher in men than in women ( FIGURE 2 ).¹⁶ Furthermore, men experience a first cardiovascular event a decade earlier than women, and a more serious CHD event, such as MI or sudden death, 2 decades earlier.¹

FIGURE 1

Modifiable risk factors for myocardial infarction (MI)²

FIGURE 2

Prevalence of heart disease by age and gender¹⁶

Assessment

The assessment of CHD risk in men need not be complicated and should be made practical so that it is applied consistently. A family and personal medical history and physical examination combined with laboratory determination of lipid levels and glycosylated hemoglobin can help assess modifiable risk factors. The assessment of CHD risk can be facilitated by using 1 of 2 risk calculators. The Framingham Risk Score [www.framinghamheartstudy.org/risk/gencardio.html] is widely used but may underestimate risk, especially in younger persons or those who appear to be healthy but may have other risk factors for CHD.^17-19 The Reynolds Risk Score [www.reynoldsriskscore.org/] includes other risk factors, such as parental history of MI before age 60 years, low levels of apolipoprotein A (apoA), high levels of apolipoprotein B (apoB), and increased levels of high-sensitivity C-reactive protein (hs-CRP).¹⁹ The Reynolds Risk Score has been validated in healthy, nondiabetic men.²⁰

The relevance of apolipoprotein levels, particularly apoB, to cardiovascular risk is increasingly appreciated.²¹ ApoB concentration represents the sum of atherogenic particles found on all atherogenic lipoproteins, including very-low-density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein, and lipoprotein(a) cholesterol, whereas apoA represents the sum of antiatherogenic particles found on high-density lipoprotein cholesterol (HDL-C), the antiatherogenic lipoprotein.²² The ratio of apoB/apoA-I has, in fact, been shown to be a good predictor of cardiovascular events in young men without hypertension and diabetes but with chest pain.²³ High-sensitivity C-reactive protein is a sensitive marker of acute inflammation and is associated with coronary risk.²⁴ Measuring hs-CRP is a recommended option to determine enhanced absolute risk in people with an intermediate 10-year CHD risk of 10% to 20%.²⁵

There remains some uncertainty regarding which lipid levels should be measured when screening for cardiovascular risk. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) advises that total cholesterol, LDL-C, HDL-C, and triglycerides be measured.²⁶ More recent results from The Emerging Risk Factors Collaboration suggest that a more simplified approach may be reasonable.²⁷ Review of data from 68 long-term prospective studies involving 302,430 people without initial vascular disease and 2.79 million person-years of follow-up showed that lipid assessment of vascular risk could be accomplished by measuring either total cholesterol and HDL-C levels or apolipoprotein levels; measuring the triglyceride level was of no added benefit in assessing vascular risk. In addition, fasting and nonfasting lipid levels were found to be of similar value in assessing risk. Other evidence shows that the combination of a triglyceride level ≥178 mg/dL and waist circumference ≥35.4 inches—the hypertriglyceridemic waist phenotype—is as discriminatory a screening tool as the NCEP ATP III guidelines to identify individuals at increased cardiometabolic risk.²⁸ The use of more comprehensive lipoprotein and apolipoprotein testing, as well as noninvasive imaging, may have value in future cardiovascular risk assessment.

Treatment

The main goal of treatment in persons with 1 or more modifiable risk factors is to prevent an incident or primary cardiovascular event. Treatment strategies to achieve this goal in men and women are the same. Prevention of recurrent or secondary events will not be addressed here.

Lipids

Numerous clinical trials, such as the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS),²⁹ Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA),³⁰ and West of Scotland Coronary Prevention Study (WOSCOPS),³¹ definitively established the benefit of cardiovascular risk reduction with lipid-lowering treatment, particularly LDL-C-lowering treatment. Low-density lipoprotein cholesterol is the principal lipid target in most patients, with the treatment goal based on the presence of additional risk factors.³² Discussion of treatments for low HDL-C and elevated triglyceride levels is beyond the scope of this review but is expected to be included in the NCEP ATP IV guidelines scheduled for release later in 2012.

The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) also established significant benefits of statin therapy in primary prevention, compared with placebo, in persons with normal or modestly elevated LDL-C (<130 mg/dL) and elevated hs-CRP (≥2 mg/L).³³ Rates of the primary end point (MI, stroke, arterial revascularization, hospitalization for unstable angina, or cardiovascular death) were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio [HR], 0.56; 95% CI, 0.46-0.69; P < .00001). Further analysis showed that patients who achieved LDL-C <70 mg/dL had a 55% lower rate of vascular events compared with placebo.³⁴

Results from large primary prevention clinical trials such as JUPITER have led to recommendations over the past decade or so for progressively lower LDL-C goals. A meta-analysis of 25 large clinical trials involving 155,613 subjects showed that for every 25 mg/dL reduction in LDL-C, the RR for several cardiovascular outcomes was reduced: vascular mortality, 0.89; major vascular events, 0.86; major coronary events, 0.84; and stroke, 0.90. Put differently, there was a 20% reduction in major coronary events for every 39 mg/dL LDL-C reduction.³⁵

Recent trials support the benefits of intensive high-dose statin therapy in greatly reducing lipid levels, with associated benefits in terms of cardiovascular events. A meta-analysis of 7 trials involving 50,972 high-risk patients with a mean follow-up of 3.1 years showed significant reductions in the risk for cardiovascular events with intensive statin therapy. Those who achieved LDL-C <82 mg/dL with intensive statin therapy had lower cardiovascular risks compared with those with LDL-C ≥82 mg/dL: stroke, odds ratio (OR): 0.80; major coronary events, OR: 0.74; and CVD or CHD death, OR: 0.84.³⁶ Significantly higher liver enzyme abnormalities were observed in patients treated with high-dose statin therapy. [See also Addressing Key Questions with Statin Therapy in this supplement.] The benefits of intensive statin therapy on the progression of coronary atherosclerosis have also been investigated. The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin (SATURN) by Nicholls et al³⁷ included patients (N = 1039) with documented coronary vessel stenosis of at least 20% and a target vessel for imaging with less than 50% obstruction. Patients received either atorvastatin 80 mg daily or rosu-vastatin 40 mg daily for 104 weeks. In the rosuvastatin group, end-of-study LDL-C levels were lower (62.6 vs 70.2 mg/dL; P < .001) and HDL-C levels higher (50.4 vs 48.6 mg/dL; P = .01) compared with the atorvastatin group, respectively. The percent atheroma volume decreased by 1.22% with rosuvastatin and 0.99% with atorvastatin (P = .17). The normalized total atheroma volume decreased 6.39 mm³ with rosuvastatin and 4.42 mm³ with atorvastatin (P = .01). Atheroma regression was induced in the majority of patients in both groups.

Further support for treating with statin doses higher than those recommended for initial therapy comes from a prospective trial involving 1337 consecutive patients followed over a median of 33 months.¹⁰ Although 83% of these patients were on statin therapy, only 51% had an LDL-C <100 mg/dL, and only 15% of the very high-risk patients (n = 941) had an LDL-C <70 mg/dL. The use of intensive statin therapy was associated with a 12-fold higher possibility of achieving an LDL-C <70 mg/dL. Very high-risk patients who achieved an LDL-C <70 mg/dL had a significantly lower risk of all cardiovascular events (HR, 0.34; P = .003).

Blood pressure

As with dyslipidemia, the cardiovascular benefits of lowering elevated BP are well established. While the usual BP goal is <140/90 mm Hg, in those with hypertension and concomitant diabetes or renal disease, the goal is <130/80 mm Hg.³⁸ It is not clear how best to achieve these goals, but therapy must be individualized based on patient comorbidities and drug side effects as recommended in current guidelines.^38-40 With these guidelines as a basis, a simplified ABCD approach can be considered in selecting initial antihypertensive therapy ( FIGURE 3 ).

FIGURE 3

ABCD approach to initial antihypertensive therapy^38-40

Several meta-analyses have been conducted recently to assess the magnitude of BP (systolic/diastolic) lowering in the different classes of antihypertensive drugs. While these meta-analyses have important limitations, such as differences in study design and the lack of a clear description of outcomes, some general impressions can be made. In 1 meta-analysis, thiazide diuretics were found to lower BP by 6/3 and 8/4 mm Hg at doses of 1 and 2 times the recommended starting dose, respectively. A BP-lowering effect of 6/3 mm Hg was observed with starting doses of loop diuretics.⁴² Another meta-analysis failed to find a statistically or clinically significant BP-lowering effect with potassium-sparing diuretics at low doses.⁴³ For spironolactone, a review of 5 crossover studies found a reduction in BP of 21/7 mm Hg. In this review, daily doses of 25 to 100 mg were found to provide the best balance between BP reduction and safety and tolerability.⁴⁴

Several meta-analyses of angiotensin receptor blockers (ARBs) have found BP reductions to be similar among the various ARB drugs. Generally, at maximum recommended doses, a BP reduction of 8/5 mm Hg is observed with these drugs, except for losartan, which produces a smaller BP reduction.^45-49 Heran et al⁴⁵ found a BP reduction of 12/7 mm Hg among the ARBs 1 to 12 hours after the dose was taken. When cost per quality-adjusted life-year gained was considered, 1 meta-analysis found that the slightly greater BP reduction with candesartan compared with losartan was not cost-effective.⁴⁶ However, other benefits of candesartan compared with losartan therapy (eg, lower risk for cardiovascular disease, heart failure, dysrhythmias, and peripheral artery disease) should be considered.⁵⁰ Adverse events were generally found to be similar among the ARBs.

No differences in BP lowering were observed among 92 trials of 14 different angiotensin-converting enzyme inhibitors. As a class, these drugs were found to produce a reduction in BP of 8/5 mm Hg.⁵¹

Because of the modest BP-lowering effects of each of the antihypertensive drugs currently available, consideration should be given to starting antihypertensive therapy with 2 agents for patients with stage 2 hypertension (ie, BP ≥160/100 mm Hg).

Summary

Elimination of key risk factors such as dyslipidemia and hypertension is important for reducing cardiovascular events later in life. A medical history, physical examination, and laboratory determination of lipid and glycosylated hemoglobin levels provide a good assessment of cardiovascular risk. A statin is first-line therapy for reducing LDL-C, which is the primary lipid target in most patients. High-dose statin therapy may be required to reach desired target levels. The choice of initial antihypertensive therapy is based on patient comorbidities and drug side effects; however, most patients require combination antihypertensive therapy to reach goal. The combination of this multifactorial risk approach along with smoking cessation and modification of other risk factors should complement current and future cardiovascular care for men.

The death rate from coronary heart disease (CHD) declined by 59% from 1950 to 1999 in the United States, yet CHD remains a major cause of morbidity and mortality, resulting in an estimated 1.5 million heart attacks in 2011.¹ Better recognition and treatment of the 9 modifiable risk factors for CHD identified by the INTERHEART study ( FIGURE 1 ), as well as changes in lifestyle practices, undoubtedly contributed to the decline in CHD mortality, but further improvement is possible.² Estimates derived from the Second National Health and Nutrition Examination Survey (NHANES II) baseline data and 17-year mortality follow-up data indicate that 45% of CHD deaths in men and 64% in women could be avoided by eliminating 3 major risk factors: elevated total cholesterol (≥240 mg/dL), hypertension, and smoking.³

The evidence indicates that these 3 risk factors are not well controlled. Data from the National Cholesterol Education Program (NCEP) Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey and the Lipid Treatment Assessment Project 2 (L-TAP 2), as well as more recent evidence, indicate that many patients do not achieve low-density lipoprotein cholesterol (LDL-C) and triglyceride targets.^4-10 Similarly, although there has been significant improvement in blood pressure (BP) control over the past 2 decades, BP is controlled in only half of all hypertensive patients.^11,12 Finally, the sharp declines in the prevalence of cigarette smoking seen in the past have slowed in recent years, such that approximately 20% of US adults still smoke cigarettes.¹³

These trends are a concern since a greater risk factor burden in middle age is associated with poorer quality of life and higher medical costs, as well as a higher incidence of cardiovascular events in older age.¹ A recent meta-analysis of 18 cohort studies involving 257,384 adults showed a higher incidence of cardiovascular events in later life with an increasing number of risk factors.¹⁴ For example, adults 55 years of age with an optimal risk factor profile (ie, total cholesterol <180 mg/dL, BP <120/80 mm Hg, nonsmoker, nondiabetic) had much lower risks of death from cardiovascular disease (CVD) through the age of 80 years than those with 2 or more risk factors (4.7% vs 29.6% among men, 6.4% vs 20.5% among women). This translates into a relative risk (RR) of cardiovascular death of 6 times for men and 3 times for women without optimal risk profiles. Similar trends were observed for risk of fatal CHD/nonfatal myocardial infarction (MI) (3.6% vs 37.5% among men, <1% vs 18.3% among women). These findings point to the critical importance of modifying multiple risk factors early in adulthood, well in advance of symptoms. However, the Study to Help Improve Early Evaluation and Management of Risk Factors Leading to Diabetes (SHIELD) showed that about half of patients with CHD are not diagnosed until symptoms become apparent, and fewer than one quarter are diagnosed as a result of screening.¹⁵

This review focuses on patient assessment and treatment strategies to modify abnormal lipid levels and high BP for primary prevention. Addressing other modifiable risk factors is also important, especially since risk factors such as abdominal obesity impact other risk factors ( FIGURE 1 ). An emphasis is placed on strategies in men, since the prevalence of CHD among patients aged 45 years and older is higher in men than in women ( FIGURE 2 ).¹⁶ Furthermore, men experience a first cardiovascular event a decade earlier than women, and a more serious CHD event, such as MI or sudden death, 2 decades earlier.¹

FIGURE 1

Modifiable risk factors for myocardial infarction (MI)²

FIGURE 2

Prevalence of heart disease by age and gender¹⁶

Assessment

The assessment of CHD risk in men need not be complicated and should be made practical so that it is applied consistently. A family and personal medical history and physical examination combined with laboratory determination of lipid levels and glycosylated hemoglobin can help assess modifiable risk factors. The assessment of CHD risk can be facilitated by using 1 of 2 risk calculators. The Framingham Risk Score [www.framinghamheartstudy.org/risk/gencardio.html] is widely used but may underestimate risk, especially in younger persons or those who appear to be healthy but may have other risk factors for CHD.^17-19 The Reynolds Risk Score [www.reynoldsriskscore.org/] includes other risk factors, such as parental history of MI before age 60 years, low levels of apolipoprotein A (apoA), high levels of apolipoprotein B (apoB), and increased levels of high-sensitivity C-reactive protein (hs-CRP).¹⁹ The Reynolds Risk Score has been validated in healthy, nondiabetic men.²⁰

The relevance of apolipoprotein levels, particularly apoB, to cardiovascular risk is increasingly appreciated.²¹ ApoB concentration represents the sum of atherogenic particles found on all atherogenic lipoproteins, including very-low-density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein, and lipoprotein(a) cholesterol, whereas apoA represents the sum of antiatherogenic particles found on high-density lipoprotein cholesterol (HDL-C), the antiatherogenic lipoprotein.²² The ratio of apoB/apoA-I has, in fact, been shown to be a good predictor of cardiovascular events in young men without hypertension and diabetes but with chest pain.²³ High-sensitivity C-reactive protein is a sensitive marker of acute inflammation and is associated with coronary risk.²⁴ Measuring hs-CRP is a recommended option to determine enhanced absolute risk in people with an intermediate 10-year CHD risk of 10% to 20%.²⁵

There remains some uncertainty regarding which lipid levels should be measured when screening for cardiovascular risk. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) advises that total cholesterol, LDL-C, HDL-C, and triglycerides be measured.²⁶ More recent results from The Emerging Risk Factors Collaboration suggest that a more simplified approach may be reasonable.²⁷ Review of data from 68 long-term prospective studies involving 302,430 people without initial vascular disease and 2.79 million person-years of follow-up showed that lipid assessment of vascular risk could be accomplished by measuring either total cholesterol and HDL-C levels or apolipoprotein levels; measuring the triglyceride level was of no added benefit in assessing vascular risk. In addition, fasting and nonfasting lipid levels were found to be of similar value in assessing risk. Other evidence shows that the combination of a triglyceride level ≥178 mg/dL and waist circumference ≥35.4 inches—the hypertriglyceridemic waist phenotype—is as discriminatory a screening tool as the NCEP ATP III guidelines to identify individuals at increased cardiometabolic risk.²⁸ The use of more comprehensive lipoprotein and apolipoprotein testing, as well as noninvasive imaging, may have value in future cardiovascular risk assessment.

Treatment

The main goal of treatment in persons with 1 or more modifiable risk factors is to prevent an incident or primary cardiovascular event. Treatment strategies to achieve this goal in men and women are the same. Prevention of recurrent or secondary events will not be addressed here.

Lipids

Numerous clinical trials, such as the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS),²⁹ Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA),³⁰ and West of Scotland Coronary Prevention Study (WOSCOPS),³¹ definitively established the benefit of cardiovascular risk reduction with lipid-lowering treatment, particularly LDL-C-lowering treatment. Low-density lipoprotein cholesterol is the principal lipid target in most patients, with the treatment goal based on the presence of additional risk factors.³² Discussion of treatments for low HDL-C and elevated triglyceride levels is beyond the scope of this review but is expected to be included in the NCEP ATP IV guidelines scheduled for release later in 2012.

The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) also established significant benefits of statin therapy in primary prevention, compared with placebo, in persons with normal or modestly elevated LDL-C (<130 mg/dL) and elevated hs-CRP (≥2 mg/L).³³ Rates of the primary end point (MI, stroke, arterial revascularization, hospitalization for unstable angina, or cardiovascular death) were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio [HR], 0.56; 95% CI, 0.46-0.69; P < .00001). Further analysis showed that patients who achieved LDL-C <70 mg/dL had a 55% lower rate of vascular events compared with placebo.³⁴

Results from large primary prevention clinical trials such as JUPITER have led to recommendations over the past decade or so for progressively lower LDL-C goals. A meta-analysis of 25 large clinical trials involving 155,613 subjects showed that for every 25 mg/dL reduction in LDL-C, the RR for several cardiovascular outcomes was reduced: vascular mortality, 0.89; major vascular events, 0.86; major coronary events, 0.84; and stroke, 0.90. Put differently, there was a 20% reduction in major coronary events for every 39 mg/dL LDL-C reduction.³⁵

Recent trials support the benefits of intensive high-dose statin therapy in greatly reducing lipid levels, with associated benefits in terms of cardiovascular events. A meta-analysis of 7 trials involving 50,972 high-risk patients with a mean follow-up of 3.1 years showed significant reductions in the risk for cardiovascular events with intensive statin therapy. Those who achieved LDL-C <82 mg/dL with intensive statin therapy had lower cardiovascular risks compared with those with LDL-C ≥82 mg/dL: stroke, odds ratio (OR): 0.80; major coronary events, OR: 0.74; and CVD or CHD death, OR: 0.84.³⁶ Significantly higher liver enzyme abnormalities were observed in patients treated with high-dose statin therapy. [See also Addressing Key Questions with Statin Therapy in this supplement.] The benefits of intensive statin therapy on the progression of coronary atherosclerosis have also been investigated. The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin (SATURN) by Nicholls et al³⁷ included patients (N = 1039) with documented coronary vessel stenosis of at least 20% and a target vessel for imaging with less than 50% obstruction. Patients received either atorvastatin 80 mg daily or rosu-vastatin 40 mg daily for 104 weeks. In the rosuvastatin group, end-of-study LDL-C levels were lower (62.6 vs 70.2 mg/dL; P < .001) and HDL-C levels higher (50.4 vs 48.6 mg/dL; P = .01) compared with the atorvastatin group, respectively. The percent atheroma volume decreased by 1.22% with rosuvastatin and 0.99% with atorvastatin (P = .17). The normalized total atheroma volume decreased 6.39 mm³ with rosuvastatin and 4.42 mm³ with atorvastatin (P = .01). Atheroma regression was induced in the majority of patients in both groups.

Further support for treating with statin doses higher than those recommended for initial therapy comes from a prospective trial involving 1337 consecutive patients followed over a median of 33 months.¹⁰ Although 83% of these patients were on statin therapy, only 51% had an LDL-C <100 mg/dL, and only 15% of the very high-risk patients (n = 941) had an LDL-C <70 mg/dL. The use of intensive statin therapy was associated with a 12-fold higher possibility of achieving an LDL-C <70 mg/dL. Very high-risk patients who achieved an LDL-C <70 mg/dL had a significantly lower risk of all cardiovascular events (HR, 0.34; P = .003).

Blood pressure

As with dyslipidemia, the cardiovascular benefits of lowering elevated BP are well established. While the usual BP goal is <140/90 mm Hg, in those with hypertension and concomitant diabetes or renal disease, the goal is <130/80 mm Hg.³⁸ It is not clear how best to achieve these goals, but therapy must be individualized based on patient comorbidities and drug side effects as recommended in current guidelines.^38-40 With these guidelines as a basis, a simplified ABCD approach can be considered in selecting initial antihypertensive therapy ( FIGURE 3 ).

FIGURE 3

ABCD approach to initial antihypertensive therapy^38-40

Several meta-analyses have been conducted recently to assess the magnitude of BP (systolic/diastolic) lowering in the different classes of antihypertensive drugs. While these meta-analyses have important limitations, such as differences in study design and the lack of a clear description of outcomes, some general impressions can be made. In 1 meta-analysis, thiazide diuretics were found to lower BP by 6/3 and 8/4 mm Hg at doses of 1 and 2 times the recommended starting dose, respectively. A BP-lowering effect of 6/3 mm Hg was observed with starting doses of loop diuretics.⁴² Another meta-analysis failed to find a statistically or clinically significant BP-lowering effect with potassium-sparing diuretics at low doses.⁴³ For spironolactone, a review of 5 crossover studies found a reduction in BP of 21/7 mm Hg. In this review, daily doses of 25 to 100 mg were found to provide the best balance between BP reduction and safety and tolerability.⁴⁴

Several meta-analyses of angiotensin receptor blockers (ARBs) have found BP reductions to be similar among the various ARB drugs. Generally, at maximum recommended doses, a BP reduction of 8/5 mm Hg is observed with these drugs, except for losartan, which produces a smaller BP reduction.^45-49 Heran et al⁴⁵ found a BP reduction of 12/7 mm Hg among the ARBs 1 to 12 hours after the dose was taken. When cost per quality-adjusted life-year gained was considered, 1 meta-analysis found that the slightly greater BP reduction with candesartan compared with losartan was not cost-effective.⁴⁶ However, other benefits of candesartan compared with losartan therapy (eg, lower risk for cardiovascular disease, heart failure, dysrhythmias, and peripheral artery disease) should be considered.⁵⁰ Adverse events were generally found to be similar among the ARBs.

No differences in BP lowering were observed among 92 trials of 14 different angiotensin-converting enzyme inhibitors. As a class, these drugs were found to produce a reduction in BP of 8/5 mm Hg.⁵¹

Because of the modest BP-lowering effects of each of the antihypertensive drugs currently available, consideration should be given to starting antihypertensive therapy with 2 agents for patients with stage 2 hypertension (ie, BP ≥160/100 mm Hg).

Summary

Elimination of key risk factors such as dyslipidemia and hypertension is important for reducing cardiovascular events later in life. A medical history, physical examination, and laboratory determination of lipid and glycosylated hemoglobin levels provide a good assessment of cardiovascular risk. A statin is first-line therapy for reducing LDL-C, which is the primary lipid target in most patients. High-dose statin therapy may be required to reach desired target levels. The choice of initial antihypertensive therapy is based on patient comorbidities and drug side effects; however, most patients require combination antihypertensive therapy to reach goal. The combination of this multifactorial risk approach along with smoking cessation and modification of other risk factors should complement current and future cardiovascular care for men.

Introduction

The importance of acute coronary syndrome (ACS) (ie, patients with ST-segment elevation myocardial infarction [MI] [STEMI], non-ST segment elevation MI [NSTEMI], or unstable angina) in primary care is highlighted by its prevalence. Acute coronary syndrome was the primary or secondary discharge diagnosis in 1.19 million hospitalizations in the United States in 2009, a slight majority of which were in men.¹ Platelet activation plays a central role in the pathophysiology of ACS. Despite well established benefits of antiplatelet therapy in both primary and secondary prevention of ACS, adverse events—particularly bleeding—require ongoing vigilance.² Among the several classes of antiplatelet agents currently available, the thromboxane A₂ inhibitor (ie, aspirin) and P2Y₁₂ inhibitors (ie, clopidogrel, prasugrel, and ticagrelor) are those most commonly used; ticlopidine is not commonly used due to nausea/vomiting and bone marrow toxicity.³

Antiplatelet Agents

It is well established that hemostasis is protected by multilayered, overlapping, and sometimes redundant pathways. Even though currently available antiplatelet agents are highly efficacious in inhibiting 1 or more phases of platelet activity pertinent to coagulation (eg, activation, adhesion, and aggregation), because of the multiple backup pathways involved, no single antiplatelet agent is anticipated to totally eliminate platelet activity. In addition, every combination of antiplatelet agents—though potentially more efficacious because of multipathway activity—is also laden with greater bleeding risk. The 3 primary pathways of platelet activation for which pharmacologic antagonists have been developed are the thromboxane, adenosine diphosphonate (ADP)-P2Y₁₂, and ADP-A₂ pathways. While dual antiplatelet therapy with aspirin and clopidogrel may be the current standard of care, the focus of this review is on the ADP-P2Y₁₂ inhibitors as the two newest agents, prasugrel and ticagrelor, are less familiar to family physicians. The second section addresses questions often encountered by family physicians when caring for patients who have recently experienced ACS.

P2Y₁₂ Inhibitors

Two groups of agents exert their antiplatelet effects by inhibiting the platelet P2Y₁₂ receptor: (1) thienopyridines (ie, ticlopidine, clopidogrel, and prasugrel) and (2) the cyclopentyltriazolopyrimidines (ie, ticagrelor). Both groups inhibit ADP-dependent platelet function but at different sites on the platelet P2Y₁₂ receptor. Thienopyridine activity is mediated via short-lived active metabolites formed in the liver. Platelet exposure to the active metabolite of prasugrel is about 10-fold higher than to the active metabolite of clopidogrel, resulting in a higher level and less individual variation of platelet inhibition with prasugrel. Hepatic metabolism of clopidogrel makes it subject to genetic, as well as drug-induced, variation in activity; prasugrel is not affected by these same limitations. Recovery of platelet function following withdrawal of thienopyridine therapy occurs over 7 to 8 days as a function of platelet turnover.^2,3 This slow recovery of platelet function has important implications when any surgical intervention is needed.

In contrast to the thienopyridines, ticagrelor does not require metabolic activation by the liver. Ticagrelor and its active metabolite display approximately equipotent antiplatelet activity and are direct P2Y₁₂ inhibitors. Ticargrelor non-competitively antagonizes ADP-induced receptor activation. Ticagrelor is rapidly absorbed reaching its peak plasma concentration in 1.5 to 3 hours, thereby providing a rapid antiplatelet effect. Twice-daily administration is required because of its rapid offset of platelet inhibition.^2,4,5

Prasugrel

Prasugrel is indicated by the US Food and Drug Administration (FDA) for reduction of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention (PCI) as follows: (1) unstable angina or NSTEMI or (2) STEMI when managed with primary or delayed PCI.⁶

The efficacy and safety of prasugrel have been investigated in several clinical trials. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 is the largest and has many planned sub-analyses ( TABLE 1 ).^7-9 TRITON TIMI 38 involved patients with moderate- to high-risk ACS scheduled for PCI
(N = 13,608).⁷ Patients were randomized to prasugrel 60 mg as a loading dose followed by 10 mg daily or clopidogrel 300 mg as a loading dose followed by 75 mg daily for 6 to 15 months. Aspirin 75 to 162 mg once daily was recommended, but was left up to the physician. The primary efficacy end point was a composite of CV death, nonfatal MI, or nonfatal stroke.

Findings from TRITON TIMI 38 show that, compared with clopidogrel, prasugrel was associated with significantly reduced rates of ischemic events, including nonfatal MI and stent thrombosis. The benefit with prasugrel was primarily due to a significant reduction in the rate of MI compared with clopidogrel. However, patients treated with prasugrel experienced a higher rate of major bleeding, including fatal and life-threatening bleeding. Prasugrel was found to be more effective than clopidogrel in preventing ischemic events without excess bleeding in patients with STEMI undergoing secondary PCI (treated between 12 hours and 14 days after symptom onset). In patients with ACS undergoing PCI without stent implantation, ischemic events occurred at similar rates in patients treated with prasugrel or clopidogrel; however, bleeding was more common with prasugrel.

Not all patients benefited from prasugrel therapy. Compared with clopidogrel, patients with previous stroke/transient ischemic attack (TIA) had net harm from prasugrel. In addition, no net benefit from prasugrel compared with clopidogrel was observed in patients age ≥75 years or body weight <60 kg. The results of TRITON TIMI 38 contributed to the boxed warnings regarding bleeding risk recommending that prasugrel not be used in patients age ≥75 years, in patients with active pathological bleeding or a history of TIA or stroke, or patients likely to undergo coronary artery bypass graft (CABG) surgery. In addition, patients with body weight < 60 kg are also at increased risk for bleeding.⁶

TABLE 1

Prasugrel: TRITON-TIMI 38 and subanalyses

Ticagrelor

Ticagrelor is the most recent antiplatelet agent to be approved by the US FDA. Ticagrelor is indicated to reduce the rate of thrombotic CV events in patients with ACS (eg, unstable angina, NSTEMI, or STEMI).¹⁰

The efficacy and safety of ticagrelor has been assessed in the Study of Platelet Inhibition and Patient Outcomes (PLATO) and several planned sub-analyses ( TABLE 2 ).^11-16 PLATO was a 12-month, multicenter, double-blind, randomized trial that involved patients with ACS with or without ST-segment elevation (N = 18,624).¹¹ Patients were randomized to ticagrelor 180 mg loading dose then 90 mg twice daily or clopidogrel 300 to 600 mg loading dose then 75 mg once daily for 12 months. The primary efficacy end point was a composite of death from vascular causes, MI, or stroke.

The results of PLATO and sub-analyses show that in patients with ACS and compared with clopidogrel, ticagrelor significantly reduced the primary efficacy end point with a similar rate of major bleeding
( TABLE 1 ). These safety results contributed to the boxed warnings regarding bleeding risk that ticagrelor not be used in patients with active pathological bleeding or a history of intracranial hemorrhage, or in patients planned to undergo urgent CABG surgery. In addition, maintenance aspirin therapy at a dose above 100 mg reduces the effectiveness of ticagrelor and should be avoided.¹⁰

Consistent with the general PLATO population, in patients intended for non-invasive management, ticagrelor significantly reduced the rate of death from vascular causes, MI, or stroke compared with clopidogrel with a similar rate of major bleeding. In patients with ACS and ST elevation or left bundle branch block planned for PCI, ticagrelor reduced CV and all-cause death, MI, stent thrombosis, and improved survival compared with clopidogrel, with a similar rate of major bleeding. Ticagrelor, compared with clopidogrel, reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. Finally, in ACS with chronic kidney disease (estimated creatinine clearance < 60 mL/minute), ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non–CABG-related bleeding.

TABLE 2

Ticagrelor: PLATO and subanalyses

Common Questions Regarding Antiplatelet Therapy in Primary Care

The preceding discussion confirms that many patients with ACS benefit from antiplatelet therapy. However, the use of antiplatelet agents in primary care can be challenging. The following are some of the evolving issues and questions regarding antiplatelet therapy faced by family physicians.

If a patient has experienced gastrointestinal bleeding while taking low-dose aspirin in the past and has an acute coronary syndrome, what course of action should be taken?

Dual antiplatelet therapy is still recommended in this setting, but therapy with a proton pump inhibitor (PPI) for gastrointestinal (GI) protection is recommended.^2,3,17 For patients at low risk of upper GI bleeding, routine PPI prophylaxis is not recommended. Currently available data do not demonstrate the prophylactic superiority of one PPI over another, but do show that PPI therapy is more effective in decreasing GI bleeding associated with aspirin and is, therefore, preferred over a histamine H₂ receptor antagonist.¹⁷ For instance, high-dose famotidine has been shown to be less effective than pantoprazole in patients with aspirin-related peptic ulcers/erosions.¹⁸

Can a proton pump inhibitor be used for gastrointestinal protection in conjunction with clopidogrel?

Yes, although the evidence is conflicting about whether specific PPIs should be avoided because of reduced clinical efficacy of clopidogrel. The results of a meta-analysis of 23 studies demonstrated a clinically significant interaction that reduces the antiplatelet effectiveness of clopidogrel when combined with some PPIs.¹⁹ The results of 4 prospective, crossover pharmacokinetic studies in healthy subjects (N = 282) also suggest an interaction between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.²⁰ A subanalysis of PLATO showed that the use of a PPI was independently associated with a higher rate of CV events in patients with ACS treated with clopidogrel or ticagrelor.²¹ The observed effect with both agents, as well as a higher rate of major bleeding among PPI vs non-PPI users suggests that PPI use may be more of a marker for rather than a cause of higher rates of CV events. In fact, data from the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) found that in patients treated with clopidogrel and aspirin, the addition of omeprazole reduced the rate of a GI event, compared with placebo at 180 days (1.1% vs. 2.9%, respectively;
P < .001).²² Overt upper GI bleeding occurred less frequently in the omeprazole group (hazard ratio, 0.13; 95% confidence interval, 0.03 to 0.56; P = .001). A CV event was observed in 4.9% of patients treated with omeprazole and 5.7% of placebo patients (P = .96). While limited, these prospective data do not suggest a detriment to clopidogrel efficacy when used in combination with a PPI. The dose of PPI to use for GI protection is not well-established; the following drugs and doses have been used: omeprazole 20 to 40 mg once daily; esomeprazole 20 mg once or twice daily; pantoprazole 20 mg once daily; or lansoprazole 30 mg once daily.^18,23-28

Should I avoid starting clopidogrel in patients with acute coronary syndrome because of concerns about “poor metabolizers”?

Clopidogrel is a prodrug, requiring CYP450 metabolism to its active metabolite. Because of genetic CYP450 variations, as many as one-third of patients lack fully active CYP450 pathways, resulting in reduced (or even absent) conversion from the parent drug to the active metabolite, with a corresponding diminution of antiplatelet effects.^3,29 Recent recommendations about dealing with these genetic polymorphisms include direct measurement of CYP450 pathway status and selection of alternative pharmacologic agents which are not dependent upon similar CYP pathway activation. There are, unfortunately, no prospective clinical trials based upon CYP2C19 genotyping confirming that patient selection based upon genotyping is associated with improved outcomes.

In terms of alternative antiplatelet therapy in clopidogrel nonresponders, the Response to Ticagrelor in Clopidogrel Nonresponders and Responders (RESPOND) study shows ticagrelor to be beneficial, at least as measured in vitro.³⁰ Following laboratory assessment of patients’ responsiveness to clopidogrel, both responders and nonresponders were randomized to clopidogrel or ticagrelor. After 14 days, all clopidogrel nonresponders and half of the responders switched treatment. The antiplatelet effects of ticagrelor were similar whether the patient was a clopidogrel responder or not. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) showed higher inhibition of platelet aggregation (IPA) with prasugrel 60 mg compared with clopidogrel 600 mg 6 hours after initiation.³¹ Following crossover, IPA was higher in subjects receiving prasugrel 10 mg/d compared with clopidogrel 150 mg/d (61% vs 46%, respectively; P < .0001). While not measuring clopidogrel responsiveness, this suggests that prasugrel might be effective in clopidogrel nonresponders. Not all patients treated with prasugrel achieve optimal inhibition of platelet reactivity. In patients who underwent successful PCI for ACS (N = 301) 25.2% were observed to have high on-treatment platelet reactivity following a 60 mg loading dose of prasugrel.³² Such patients had a significantly higher risk for a major adverse cardiovascular event after PCI. The clinical trials which demonstrate improved clinical outcomes when clopidogrel is compared with other antiplatelet agents suggest that the above-mentioned in vitro metrics are clinically relevant.

I’ve heard a lot about testing platelet aggregability. Should I be considering that for my patients?

Not at the present time. One prospective study evaluated the capability of platelet function tests to predict clinical outcome in patients taking clopidogrel undergoing elective stent implantation.³³ On-treatment platelet reactivity was measured using: light transmittance aggregometry, VerifyNow P2Y12, Plateletworks, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/ADP cartridge and Innovance PFA P2Y). After 1 year of follow-up, only the light transmittance aggregometry, VerifyNow, Plateletworks, and Innovance PFA P2Y tests were significantly associated with patient outcome, but had only modest predictive accuracy. Also, none of the tests studied provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation.

How concerning are the findings on ticagrelor and dyspnea?

The occurrence of dyspnea associated with ticagrelor was observed during its clinical development. While the mechanism is not known, dyspnea is a transient phenomenon, and there is no suggestion that ticagrelor is associated with an increased incidence of heart failure.

The incidence and characterization of dyspnea has been investigated in subanalyses of 2 large clinical trials of ticagrelor. Prospective analysis of the ONSET/OFFSET study (N = 123) showed that dyspnea was experienced by more patients treated with ticagrelor than clopidogrel or placebo over 6 weeks (38.6% vs 9.3% vs 8.3%, respectively; P < .001).³⁴ Episodes of dyspnea were generally mild, lasted <24 hours, and easily tolerated. Moderate dyspnea that led to study discontinuation occurred in 3 patients (5.3%) treated with ticagrelor. Dyspnea occurred within the first 24 hours in 8 of 22 patients (36.4%) and within the first week in 17 of 22 patients (77.3%) of the ticagrelor-treated patients who experienced dyspnea. Dyspnea persisted through the study follow-up (10 days after the 6 week study) in 3 of 22 patients (13.6%) treated with ticagrelor. Dyspnea was not associated with any significant adverse change in cardiac or pulmonary function tests.³⁴

In a subanalysis of the PLATO study to investigate the occurrence of dyspnea (N = 18,421), dyspnea occurred in 14.5% of patients treated with ticagrelor and 8.7% of patients treated with clopidogrel.³⁵ Severe dyspnea occurred in 0.4% and 0.3% of patients, respectively. Dyspnea had no impact on the composite end point after excluding dyspnea that occurred after the secondary end point of MI. The mechanism whereby ticagrelor induces dyspnea is not certain, but may be mediated via an adenosine-related mechanism.³⁶

Conclusion

Aspirin and clopidogrel have been the predominant antiplatelet agents used in the management of patients with ACS, yet their use can be challenging. Differences in the clinical pharmacology of prasugrel and ticagrelor provide the opportunity to address some of these challenges and better enable antiplatelet therapy to be individualized.

Introduction

The importance of acute coronary syndrome (ACS) (ie, patients with ST-segment elevation myocardial infarction [MI] [STEMI], non-ST segment elevation MI [NSTEMI], or unstable angina) in primary care is highlighted by its prevalence. Acute coronary syndrome was the primary or secondary discharge diagnosis in 1.19 million hospitalizations in the United States in 2009, a slight majority of which were in men.¹ Platelet activation plays a central role in the pathophysiology of ACS. Despite well established benefits of antiplatelet therapy in both primary and secondary prevention of ACS, adverse events—particularly bleeding—require ongoing vigilance.² Among the several classes of antiplatelet agents currently available, the thromboxane A₂ inhibitor (ie, aspirin) and P2Y₁₂ inhibitors (ie, clopidogrel, prasugrel, and ticagrelor) are those most commonly used; ticlopidine is not commonly used due to nausea/vomiting and bone marrow toxicity.³

Antiplatelet Agents

It is well established that hemostasis is protected by multilayered, overlapping, and sometimes redundant pathways. Even though currently available antiplatelet agents are highly efficacious in inhibiting 1 or more phases of platelet activity pertinent to coagulation (eg, activation, adhesion, and aggregation), because of the multiple backup pathways involved, no single antiplatelet agent is anticipated to totally eliminate platelet activity. In addition, every combination of antiplatelet agents—though potentially more efficacious because of multipathway activity—is also laden with greater bleeding risk. The 3 primary pathways of platelet activation for which pharmacologic antagonists have been developed are the thromboxane, adenosine diphosphonate (ADP)-P2Y₁₂, and ADP-A₂ pathways. While dual antiplatelet therapy with aspirin and clopidogrel may be the current standard of care, the focus of this review is on the ADP-P2Y₁₂ inhibitors as the two newest agents, prasugrel and ticagrelor, are less familiar to family physicians. The second section addresses questions often encountered by family physicians when caring for patients who have recently experienced ACS.

P2Y₁₂ Inhibitors

Two groups of agents exert their antiplatelet effects by inhibiting the platelet P2Y₁₂ receptor: (1) thienopyridines (ie, ticlopidine, clopidogrel, and prasugrel) and (2) the cyclopentyltriazolopyrimidines (ie, ticagrelor). Both groups inhibit ADP-dependent platelet function but at different sites on the platelet P2Y₁₂ receptor. Thienopyridine activity is mediated via short-lived active metabolites formed in the liver. Platelet exposure to the active metabolite of prasugrel is about 10-fold higher than to the active metabolite of clopidogrel, resulting in a higher level and less individual variation of platelet inhibition with prasugrel. Hepatic metabolism of clopidogrel makes it subject to genetic, as well as drug-induced, variation in activity; prasugrel is not affected by these same limitations. Recovery of platelet function following withdrawal of thienopyridine therapy occurs over 7 to 8 days as a function of platelet turnover.^2,3 This slow recovery of platelet function has important implications when any surgical intervention is needed.

In contrast to the thienopyridines, ticagrelor does not require metabolic activation by the liver. Ticagrelor and its active metabolite display approximately equipotent antiplatelet activity and are direct P2Y₁₂ inhibitors. Ticargrelor non-competitively antagonizes ADP-induced receptor activation. Ticagrelor is rapidly absorbed reaching its peak plasma concentration in 1.5 to 3 hours, thereby providing a rapid antiplatelet effect. Twice-daily administration is required because of its rapid offset of platelet inhibition.^2,4,5

Prasugrel

Prasugrel is indicated by the US Food and Drug Administration (FDA) for reduction of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention (PCI) as follows: (1) unstable angina or NSTEMI or (2) STEMI when managed with primary or delayed PCI.⁶

The efficacy and safety of prasugrel have been investigated in several clinical trials. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 is the largest and has many planned sub-analyses ( TABLE 1 ).^7-9 TRITON TIMI 38 involved patients with moderate- to high-risk ACS scheduled for PCI
(N = 13,608).⁷ Patients were randomized to prasugrel 60 mg as a loading dose followed by 10 mg daily or clopidogrel 300 mg as a loading dose followed by 75 mg daily for 6 to 15 months. Aspirin 75 to 162 mg once daily was recommended, but was left up to the physician. The primary efficacy end point was a composite of CV death, nonfatal MI, or nonfatal stroke.

Findings from TRITON TIMI 38 show that, compared with clopidogrel, prasugrel was associated with significantly reduced rates of ischemic events, including nonfatal MI and stent thrombosis. The benefit with prasugrel was primarily due to a significant reduction in the rate of MI compared with clopidogrel. However, patients treated with prasugrel experienced a higher rate of major bleeding, including fatal and life-threatening bleeding. Prasugrel was found to be more effective than clopidogrel in preventing ischemic events without excess bleeding in patients with STEMI undergoing secondary PCI (treated between 12 hours and 14 days after symptom onset). In patients with ACS undergoing PCI without stent implantation, ischemic events occurred at similar rates in patients treated with prasugrel or clopidogrel; however, bleeding was more common with prasugrel.

Not all patients benefited from prasugrel therapy. Compared with clopidogrel, patients with previous stroke/transient ischemic attack (TIA) had net harm from prasugrel. In addition, no net benefit from prasugrel compared with clopidogrel was observed in patients age ≥75 years or body weight <60 kg. The results of TRITON TIMI 38 contributed to the boxed warnings regarding bleeding risk recommending that prasugrel not be used in patients age ≥75 years, in patients with active pathological bleeding or a history of TIA or stroke, or patients likely to undergo coronary artery bypass graft (CABG) surgery. In addition, patients with body weight < 60 kg are also at increased risk for bleeding.⁶

TABLE 1

Prasugrel: TRITON-TIMI 38 and subanalyses

Ticagrelor

Ticagrelor is the most recent antiplatelet agent to be approved by the US FDA. Ticagrelor is indicated to reduce the rate of thrombotic CV events in patients with ACS (eg, unstable angina, NSTEMI, or STEMI).¹⁰

The efficacy and safety of ticagrelor has been assessed in the Study of Platelet Inhibition and Patient Outcomes (PLATO) and several planned sub-analyses ( TABLE 2 ).^11-16 PLATO was a 12-month, multicenter, double-blind, randomized trial that involved patients with ACS with or without ST-segment elevation (N = 18,624).¹¹ Patients were randomized to ticagrelor 180 mg loading dose then 90 mg twice daily or clopidogrel 300 to 600 mg loading dose then 75 mg once daily for 12 months. The primary efficacy end point was a composite of death from vascular causes, MI, or stroke.

The results of PLATO and sub-analyses show that in patients with ACS and compared with clopidogrel, ticagrelor significantly reduced the primary efficacy end point with a similar rate of major bleeding
( TABLE 1 ). These safety results contributed to the boxed warnings regarding bleeding risk that ticagrelor not be used in patients with active pathological bleeding or a history of intracranial hemorrhage, or in patients planned to undergo urgent CABG surgery. In addition, maintenance aspirin therapy at a dose above 100 mg reduces the effectiveness of ticagrelor and should be avoided.¹⁰

Consistent with the general PLATO population, in patients intended for non-invasive management, ticagrelor significantly reduced the rate of death from vascular causes, MI, or stroke compared with clopidogrel with a similar rate of major bleeding. In patients with ACS and ST elevation or left bundle branch block planned for PCI, ticagrelor reduced CV and all-cause death, MI, stent thrombosis, and improved survival compared with clopidogrel, with a similar rate of major bleeding. Ticagrelor, compared with clopidogrel, reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. Finally, in ACS with chronic kidney disease (estimated creatinine clearance < 60 mL/minute), ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non–CABG-related bleeding.

TABLE 2

Ticagrelor: PLATO and subanalyses

Common Questions Regarding Antiplatelet Therapy in Primary Care

The preceding discussion confirms that many patients with ACS benefit from antiplatelet therapy. However, the use of antiplatelet agents in primary care can be challenging. The following are some of the evolving issues and questions regarding antiplatelet therapy faced by family physicians.

If a patient has experienced gastrointestinal bleeding while taking low-dose aspirin in the past and has an acute coronary syndrome, what course of action should be taken?

Dual antiplatelet therapy is still recommended in this setting, but therapy with a proton pump inhibitor (PPI) for gastrointestinal (GI) protection is recommended.^2,3,17 For patients at low risk of upper GI bleeding, routine PPI prophylaxis is not recommended. Currently available data do not demonstrate the prophylactic superiority of one PPI over another, but do show that PPI therapy is more effective in decreasing GI bleeding associated with aspirin and is, therefore, preferred over a histamine H₂ receptor antagonist.¹⁷ For instance, high-dose famotidine has been shown to be less effective than pantoprazole in patients with aspirin-related peptic ulcers/erosions.¹⁸

Can a proton pump inhibitor be used for gastrointestinal protection in conjunction with clopidogrel?

Yes, although the evidence is conflicting about whether specific PPIs should be avoided because of reduced clinical efficacy of clopidogrel. The results of a meta-analysis of 23 studies demonstrated a clinically significant interaction that reduces the antiplatelet effectiveness of clopidogrel when combined with some PPIs.¹⁹ The results of 4 prospective, crossover pharmacokinetic studies in healthy subjects (N = 282) also suggest an interaction between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.²⁰ A subanalysis of PLATO showed that the use of a PPI was independently associated with a higher rate of CV events in patients with ACS treated with clopidogrel or ticagrelor.²¹ The observed effect with both agents, as well as a higher rate of major bleeding among PPI vs non-PPI users suggests that PPI use may be more of a marker for rather than a cause of higher rates of CV events. In fact, data from the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) found that in patients treated with clopidogrel and aspirin, the addition of omeprazole reduced the rate of a GI event, compared with placebo at 180 days (1.1% vs. 2.9%, respectively;
P < .001).²² Overt upper GI bleeding occurred less frequently in the omeprazole group (hazard ratio, 0.13; 95% confidence interval, 0.03 to 0.56; P = .001). A CV event was observed in 4.9% of patients treated with omeprazole and 5.7% of placebo patients (P = .96). While limited, these prospective data do not suggest a detriment to clopidogrel efficacy when used in combination with a PPI. The dose of PPI to use for GI protection is not well-established; the following drugs and doses have been used: omeprazole 20 to 40 mg once daily; esomeprazole 20 mg once or twice daily; pantoprazole 20 mg once daily; or lansoprazole 30 mg once daily.^18,23-28

Should I avoid starting clopidogrel in patients with acute coronary syndrome because of concerns about “poor metabolizers”?

Clopidogrel is a prodrug, requiring CYP450 metabolism to its active metabolite. Because of genetic CYP450 variations, as many as one-third of patients lack fully active CYP450 pathways, resulting in reduced (or even absent) conversion from the parent drug to the active metabolite, with a corresponding diminution of antiplatelet effects.^3,29 Recent recommendations about dealing with these genetic polymorphisms include direct measurement of CYP450 pathway status and selection of alternative pharmacologic agents which are not dependent upon similar CYP pathway activation. There are, unfortunately, no prospective clinical trials based upon CYP2C19 genotyping confirming that patient selection based upon genotyping is associated with improved outcomes.

In terms of alternative antiplatelet therapy in clopidogrel nonresponders, the Response to Ticagrelor in Clopidogrel Nonresponders and Responders (RESPOND) study shows ticagrelor to be beneficial, at least as measured in vitro.³⁰ Following laboratory assessment of patients’ responsiveness to clopidogrel, both responders and nonresponders were randomized to clopidogrel or ticagrelor. After 14 days, all clopidogrel nonresponders and half of the responders switched treatment. The antiplatelet effects of ticagrelor were similar whether the patient was a clopidogrel responder or not. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) showed higher inhibition of platelet aggregation (IPA) with prasugrel 60 mg compared with clopidogrel 600 mg 6 hours after initiation.³¹ Following crossover, IPA was higher in subjects receiving prasugrel 10 mg/d compared with clopidogrel 150 mg/d (61% vs 46%, respectively; P < .0001). While not measuring clopidogrel responsiveness, this suggests that prasugrel might be effective in clopidogrel nonresponders. Not all patients treated with prasugrel achieve optimal inhibition of platelet reactivity. In patients who underwent successful PCI for ACS (N = 301) 25.2% were observed to have high on-treatment platelet reactivity following a 60 mg loading dose of prasugrel.³² Such patients had a significantly higher risk for a major adverse cardiovascular event after PCI. The clinical trials which demonstrate improved clinical outcomes when clopidogrel is compared with other antiplatelet agents suggest that the above-mentioned in vitro metrics are clinically relevant.

I’ve heard a lot about testing platelet aggregability. Should I be considering that for my patients?

Not at the present time. One prospective study evaluated the capability of platelet function tests to predict clinical outcome in patients taking clopidogrel undergoing elective stent implantation.³³ On-treatment platelet reactivity was measured using: light transmittance aggregometry, VerifyNow P2Y12, Plateletworks, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/ADP cartridge and Innovance PFA P2Y). After 1 year of follow-up, only the light transmittance aggregometry, VerifyNow, Plateletworks, and Innovance PFA P2Y tests were significantly associated with patient outcome, but had only modest predictive accuracy. Also, none of the tests studied provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation.

How concerning are the findings on ticagrelor and dyspnea?

The occurrence of dyspnea associated with ticagrelor was observed during its clinical development. While the mechanism is not known, dyspnea is a transient phenomenon, and there is no suggestion that ticagrelor is associated with an increased incidence of heart failure.

The incidence and characterization of dyspnea has been investigated in subanalyses of 2 large clinical trials of ticagrelor. Prospective analysis of the ONSET/OFFSET study (N = 123) showed that dyspnea was experienced by more patients treated with ticagrelor than clopidogrel or placebo over 6 weeks (38.6% vs 9.3% vs 8.3%, respectively; P < .001).³⁴ Episodes of dyspnea were generally mild, lasted <24 hours, and easily tolerated. Moderate dyspnea that led to study discontinuation occurred in 3 patients (5.3%) treated with ticagrelor. Dyspnea occurred within the first 24 hours in 8 of 22 patients (36.4%) and within the first week in 17 of 22 patients (77.3%) of the ticagrelor-treated patients who experienced dyspnea. Dyspnea persisted through the study follow-up (10 days after the 6 week study) in 3 of 22 patients (13.6%) treated with ticagrelor. Dyspnea was not associated with any significant adverse change in cardiac or pulmonary function tests.³⁴

In a subanalysis of the PLATO study to investigate the occurrence of dyspnea (N = 18,421), dyspnea occurred in 14.5% of patients treated with ticagrelor and 8.7% of patients treated with clopidogrel.³⁵ Severe dyspnea occurred in 0.4% and 0.3% of patients, respectively. Dyspnea had no impact on the composite end point after excluding dyspnea that occurred after the secondary end point of MI. The mechanism whereby ticagrelor induces dyspnea is not certain, but may be mediated via an adenosine-related mechanism.³⁶

Conclusion

Aspirin and clopidogrel have been the predominant antiplatelet agents used in the management of patients with ACS, yet their use can be challenging. Differences in the clinical pharmacology of prasugrel and ticagrelor provide the opportunity to address some of these challenges and better enable antiplatelet therapy to be individualized.

Introduction

The importance of acute coronary syndrome (ACS) (ie, patients with ST-segment elevation myocardial infarction [MI] [STEMI], non-ST segment elevation MI [NSTEMI], or unstable angina) in primary care is highlighted by its prevalence. Acute coronary syndrome was the primary or secondary discharge diagnosis in 1.19 million hospitalizations in the United States in 2009, a slight majority of which were in men.¹ Platelet activation plays a central role in the pathophysiology of ACS. Despite well established benefits of antiplatelet therapy in both primary and secondary prevention of ACS, adverse events—particularly bleeding—require ongoing vigilance.² Among the several classes of antiplatelet agents currently available, the thromboxane A₂ inhibitor (ie, aspirin) and P2Y₁₂ inhibitors (ie, clopidogrel, prasugrel, and ticagrelor) are those most commonly used; ticlopidine is not commonly used due to nausea/vomiting and bone marrow toxicity.³

Antiplatelet Agents

It is well established that hemostasis is protected by multilayered, overlapping, and sometimes redundant pathways. Even though currently available antiplatelet agents are highly efficacious in inhibiting 1 or more phases of platelet activity pertinent to coagulation (eg, activation, adhesion, and aggregation), because of the multiple backup pathways involved, no single antiplatelet agent is anticipated to totally eliminate platelet activity. In addition, every combination of antiplatelet agents—though potentially more efficacious because of multipathway activity—is also laden with greater bleeding risk. The 3 primary pathways of platelet activation for which pharmacologic antagonists have been developed are the thromboxane, adenosine diphosphonate (ADP)-P2Y₁₂, and ADP-A₂ pathways. While dual antiplatelet therapy with aspirin and clopidogrel may be the current standard of care, the focus of this review is on the ADP-P2Y₁₂ inhibitors as the two newest agents, prasugrel and ticagrelor, are less familiar to family physicians. The second section addresses questions often encountered by family physicians when caring for patients who have recently experienced ACS.

P2Y₁₂ Inhibitors

Two groups of agents exert their antiplatelet effects by inhibiting the platelet P2Y₁₂ receptor: (1) thienopyridines (ie, ticlopidine, clopidogrel, and prasugrel) and (2) the cyclopentyltriazolopyrimidines (ie, ticagrelor). Both groups inhibit ADP-dependent platelet function but at different sites on the platelet P2Y₁₂ receptor. Thienopyridine activity is mediated via short-lived active metabolites formed in the liver. Platelet exposure to the active metabolite of prasugrel is about 10-fold higher than to the active metabolite of clopidogrel, resulting in a higher level and less individual variation of platelet inhibition with prasugrel. Hepatic metabolism of clopidogrel makes it subject to genetic, as well as drug-induced, variation in activity; prasugrel is not affected by these same limitations. Recovery of platelet function following withdrawal of thienopyridine therapy occurs over 7 to 8 days as a function of platelet turnover.^2,3 This slow recovery of platelet function has important implications when any surgical intervention is needed.

In contrast to the thienopyridines, ticagrelor does not require metabolic activation by the liver. Ticagrelor and its active metabolite display approximately equipotent antiplatelet activity and are direct P2Y₁₂ inhibitors. Ticargrelor non-competitively antagonizes ADP-induced receptor activation. Ticagrelor is rapidly absorbed reaching its peak plasma concentration in 1.5 to 3 hours, thereby providing a rapid antiplatelet effect. Twice-daily administration is required because of its rapid offset of platelet inhibition.^2,4,5

Prasugrel

Prasugrel is indicated by the US Food and Drug Administration (FDA) for reduction of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention (PCI) as follows: (1) unstable angina or NSTEMI or (2) STEMI when managed with primary or delayed PCI.⁶

The efficacy and safety of prasugrel have been investigated in several clinical trials. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 is the largest and has many planned sub-analyses ( TABLE 1 ).^7-9 TRITON TIMI 38 involved patients with moderate- to high-risk ACS scheduled for PCI
(N = 13,608).⁷ Patients were randomized to prasugrel 60 mg as a loading dose followed by 10 mg daily or clopidogrel 300 mg as a loading dose followed by 75 mg daily for 6 to 15 months. Aspirin 75 to 162 mg once daily was recommended, but was left up to the physician. The primary efficacy end point was a composite of CV death, nonfatal MI, or nonfatal stroke.

Findings from TRITON TIMI 38 show that, compared with clopidogrel, prasugrel was associated with significantly reduced rates of ischemic events, including nonfatal MI and stent thrombosis. The benefit with prasugrel was primarily due to a significant reduction in the rate of MI compared with clopidogrel. However, patients treated with prasugrel experienced a higher rate of major bleeding, including fatal and life-threatening bleeding. Prasugrel was found to be more effective than clopidogrel in preventing ischemic events without excess bleeding in patients with STEMI undergoing secondary PCI (treated between 12 hours and 14 days after symptom onset). In patients with ACS undergoing PCI without stent implantation, ischemic events occurred at similar rates in patients treated with prasugrel or clopidogrel; however, bleeding was more common with prasugrel.

Not all patients benefited from prasugrel therapy. Compared with clopidogrel, patients with previous stroke/transient ischemic attack (TIA) had net harm from prasugrel. In addition, no net benefit from prasugrel compared with clopidogrel was observed in patients age ≥75 years or body weight <60 kg. The results of TRITON TIMI 38 contributed to the boxed warnings regarding bleeding risk recommending that prasugrel not be used in patients age ≥75 years, in patients with active pathological bleeding or a history of TIA or stroke, or patients likely to undergo coronary artery bypass graft (CABG) surgery. In addition, patients with body weight < 60 kg are also at increased risk for bleeding.⁶

TABLE 1

Prasugrel: TRITON-TIMI 38 and subanalyses

Ticagrelor

Ticagrelor is the most recent antiplatelet agent to be approved by the US FDA. Ticagrelor is indicated to reduce the rate of thrombotic CV events in patients with ACS (eg, unstable angina, NSTEMI, or STEMI).¹⁰

The efficacy and safety of ticagrelor has been assessed in the Study of Platelet Inhibition and Patient Outcomes (PLATO) and several planned sub-analyses ( TABLE 2 ).^11-16 PLATO was a 12-month, multicenter, double-blind, randomized trial that involved patients with ACS with or without ST-segment elevation (N = 18,624).¹¹ Patients were randomized to ticagrelor 180 mg loading dose then 90 mg twice daily or clopidogrel 300 to 600 mg loading dose then 75 mg once daily for 12 months. The primary efficacy end point was a composite of death from vascular causes, MI, or stroke.

The results of PLATO and sub-analyses show that in patients with ACS and compared with clopidogrel, ticagrelor significantly reduced the primary efficacy end point with a similar rate of major bleeding
( TABLE 1 ). These safety results contributed to the boxed warnings regarding bleeding risk that ticagrelor not be used in patients with active pathological bleeding or a history of intracranial hemorrhage, or in patients planned to undergo urgent CABG surgery. In addition, maintenance aspirin therapy at a dose above 100 mg reduces the effectiveness of ticagrelor and should be avoided.¹⁰

Consistent with the general PLATO population, in patients intended for non-invasive management, ticagrelor significantly reduced the rate of death from vascular causes, MI, or stroke compared with clopidogrel with a similar rate of major bleeding. In patients with ACS and ST elevation or left bundle branch block planned for PCI, ticagrelor reduced CV and all-cause death, MI, stent thrombosis, and improved survival compared with clopidogrel, with a similar rate of major bleeding. Ticagrelor, compared with clopidogrel, reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. Finally, in ACS with chronic kidney disease (estimated creatinine clearance < 60 mL/minute), ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non–CABG-related bleeding.

TABLE 2

Ticagrelor: PLATO and subanalyses

Common Questions Regarding Antiplatelet Therapy in Primary Care

The preceding discussion confirms that many patients with ACS benefit from antiplatelet therapy. However, the use of antiplatelet agents in primary care can be challenging. The following are some of the evolving issues and questions regarding antiplatelet therapy faced by family physicians.

If a patient has experienced gastrointestinal bleeding while taking low-dose aspirin in the past and has an acute coronary syndrome, what course of action should be taken?

Dual antiplatelet therapy is still recommended in this setting, but therapy with a proton pump inhibitor (PPI) for gastrointestinal (GI) protection is recommended.^2,3,17 For patients at low risk of upper GI bleeding, routine PPI prophylaxis is not recommended. Currently available data do not demonstrate the prophylactic superiority of one PPI over another, but do show that PPI therapy is more effective in decreasing GI bleeding associated with aspirin and is, therefore, preferred over a histamine H₂ receptor antagonist.¹⁷ For instance, high-dose famotidine has been shown to be less effective than pantoprazole in patients with aspirin-related peptic ulcers/erosions.¹⁸

Can a proton pump inhibitor be used for gastrointestinal protection in conjunction with clopidogrel?

Yes, although the evidence is conflicting about whether specific PPIs should be avoided because of reduced clinical efficacy of clopidogrel. The results of a meta-analysis of 23 studies demonstrated a clinically significant interaction that reduces the antiplatelet effectiveness of clopidogrel when combined with some PPIs.¹⁹ The results of 4 prospective, crossover pharmacokinetic studies in healthy subjects (N = 282) also suggest an interaction between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.²⁰ A subanalysis of PLATO showed that the use of a PPI was independently associated with a higher rate of CV events in patients with ACS treated with clopidogrel or ticagrelor.²¹ The observed effect with both agents, as well as a higher rate of major bleeding among PPI vs non-PPI users suggests that PPI use may be more of a marker for rather than a cause of higher rates of CV events. In fact, data from the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) found that in patients treated with clopidogrel and aspirin, the addition of omeprazole reduced the rate of a GI event, compared with placebo at 180 days (1.1% vs. 2.9%, respectively;
P < .001).²² Overt upper GI bleeding occurred less frequently in the omeprazole group (hazard ratio, 0.13; 95% confidence interval, 0.03 to 0.56; P = .001). A CV event was observed in 4.9% of patients treated with omeprazole and 5.7% of placebo patients (P = .96). While limited, these prospective data do not suggest a detriment to clopidogrel efficacy when used in combination with a PPI. The dose of PPI to use for GI protection is not well-established; the following drugs and doses have been used: omeprazole 20 to 40 mg once daily; esomeprazole 20 mg once or twice daily; pantoprazole 20 mg once daily; or lansoprazole 30 mg once daily.^18,23-28

Should I avoid starting clopidogrel in patients with acute coronary syndrome because of concerns about “poor metabolizers”?

Clopidogrel is a prodrug, requiring CYP450 metabolism to its active metabolite. Because of genetic CYP450 variations, as many as one-third of patients lack fully active CYP450 pathways, resulting in reduced (or even absent) conversion from the parent drug to the active metabolite, with a corresponding diminution of antiplatelet effects.^3,29 Recent recommendations about dealing with these genetic polymorphisms include direct measurement of CYP450 pathway status and selection of alternative pharmacologic agents which are not dependent upon similar CYP pathway activation. There are, unfortunately, no prospective clinical trials based upon CYP2C19 genotyping confirming that patient selection based upon genotyping is associated with improved outcomes.

In terms of alternative antiplatelet therapy in clopidogrel nonresponders, the Response to Ticagrelor in Clopidogrel Nonresponders and Responders (RESPOND) study shows ticagrelor to be beneficial, at least as measured in vitro.³⁰ Following laboratory assessment of patients’ responsiveness to clopidogrel, both responders and nonresponders were randomized to clopidogrel or ticagrelor. After 14 days, all clopidogrel nonresponders and half of the responders switched treatment. The antiplatelet effects of ticagrelor were similar whether the patient was a clopidogrel responder or not. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) showed higher inhibition of platelet aggregation (IPA) with prasugrel 60 mg compared with clopidogrel 600 mg 6 hours after initiation.³¹ Following crossover, IPA was higher in subjects receiving prasugrel 10 mg/d compared with clopidogrel 150 mg/d (61% vs 46%, respectively; P < .0001). While not measuring clopidogrel responsiveness, this suggests that prasugrel might be effective in clopidogrel nonresponders. Not all patients treated with prasugrel achieve optimal inhibition of platelet reactivity. In patients who underwent successful PCI for ACS (N = 301) 25.2% were observed to have high on-treatment platelet reactivity following a 60 mg loading dose of prasugrel.³² Such patients had a significantly higher risk for a major adverse cardiovascular event after PCI. The clinical trials which demonstrate improved clinical outcomes when clopidogrel is compared with other antiplatelet agents suggest that the above-mentioned in vitro metrics are clinically relevant.

I’ve heard a lot about testing platelet aggregability. Should I be considering that for my patients?

Not at the present time. One prospective study evaluated the capability of platelet function tests to predict clinical outcome in patients taking clopidogrel undergoing elective stent implantation.³³ On-treatment platelet reactivity was measured using: light transmittance aggregometry, VerifyNow P2Y12, Plateletworks, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/ADP cartridge and Innovance PFA P2Y). After 1 year of follow-up, only the light transmittance aggregometry, VerifyNow, Plateletworks, and Innovance PFA P2Y tests were significantly associated with patient outcome, but had only modest predictive accuracy. Also, none of the tests studied provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation.

How concerning are the findings on ticagrelor and dyspnea?

The occurrence of dyspnea associated with ticagrelor was observed during its clinical development. While the mechanism is not known, dyspnea is a transient phenomenon, and there is no suggestion that ticagrelor is associated with an increased incidence of heart failure.

The incidence and characterization of dyspnea has been investigated in subanalyses of 2 large clinical trials of ticagrelor. Prospective analysis of the ONSET/OFFSET study (N = 123) showed that dyspnea was experienced by more patients treated with ticagrelor than clopidogrel or placebo over 6 weeks (38.6% vs 9.3% vs 8.3%, respectively; P < .001).³⁴ Episodes of dyspnea were generally mild, lasted <24 hours, and easily tolerated. Moderate dyspnea that led to study discontinuation occurred in 3 patients (5.3%) treated with ticagrelor. Dyspnea occurred within the first 24 hours in 8 of 22 patients (36.4%) and within the first week in 17 of 22 patients (77.3%) of the ticagrelor-treated patients who experienced dyspnea. Dyspnea persisted through the study follow-up (10 days after the 6 week study) in 3 of 22 patients (13.6%) treated with ticagrelor. Dyspnea was not associated with any significant adverse change in cardiac or pulmonary function tests.³⁴

In a subanalysis of the PLATO study to investigate the occurrence of dyspnea (N = 18,421), dyspnea occurred in 14.5% of patients treated with ticagrelor and 8.7% of patients treated with clopidogrel.³⁵ Severe dyspnea occurred in 0.4% and 0.3% of patients, respectively. Dyspnea had no impact on the composite end point after excluding dyspnea that occurred after the secondary end point of MI. The mechanism whereby ticagrelor induces dyspnea is not certain, but may be mediated via an adenosine-related mechanism.³⁶

Conclusion

Aspirin and clopidogrel have been the predominant antiplatelet agents used in the management of patients with ACS, yet their use can be challenging. Differences in the clinical pharmacology of prasugrel and ticagrelor provide the opportunity to address some of these challenges and better enable antiplatelet therapy to be individualized.

This article reviews screening tools for benign prostatic hyperplasia (BPH) and steps to be taken to confirm a diagnosis of BPH. Among the treatment options for BPH, emphasis is placed on pharmacologic treatment with alpha₁-adrenergic blockers (AABs), 5-alpha-reductase inhibitors (5-ARIs), and phosphodiesterase-5 inhibitors (PDE-5Is). The two newest agents silodosin and tadalafil are discussed in greater detail.

Introduction

BPH is commonly experienced in men as they age. Lower urinary tract symptoms (LUTS) associated with BPH often begin in the fourth decade of life and affect nearly 3 in 4 men by the seventh decade of life.^1,2 Lower urinary tract symptoms that prompt men to seek medical care typically include nocturia, frequency, incomplete emptying, and urgency.^3,4 Men typically wait almost 2 years before seeking medical care for their urinary symptoms. Among men who do not seek medical care for LUTS, the most common reason is the belief that urinary symptoms are an inevitable part of aging. Many men who do not seek treatment indicate that they would rather accept their urinary symptoms than discuss them with a physician.⁴

In addition to urinary symptoms, BPH has been associated with symptoms of sexual dysfunction independent of the effects of aging and other comorbidities (eg, diabetes) and lifestyle factors.^5-8 Erectile dysfunction and ejaculatory dysfunction are the most common symptoms of sexual dysfunction in men with BPH.^9-11 Symptoms of sexual dysfunction may also be caused by some pharmacologic agents used for the treatment of BPH.^6,9,10

Evaluation

Although BPH and the symptoms associated with it are not often life-threatening, ruling out other causes such as prostate cancer, diabetes mellitus, or Parkinson disease is an important diagnostic goal.

Screening

Because many men are slow to seek medical care and reluctant to speak with a physician about their symptoms, it is important that family physicians routinely inquire about urinary function in men over the age of 50 years. Beyond simply asking whether there have been changes in urinary function, posing the last question on the International Prostate Symptom Score (IPSS) questionnaire may be helpful: “If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?”¹² This question may be followed with, “Are you bothered enough by your symptoms that you would accept taking a medication?” Inquiries such as these, coupled with education to help the patient to understand that LUTS are not simply due to aging and that effective treatments are available, may motivate patients to share their concerns regarding urinary function. In addition, helping patients to understand that BPH is not a risk factor for prostate cancer, but that there are other causes of LUTS, which are best detected early, may be helpful.

Assessment

A history and focused urologic examination are crucial for the diagnosis of BPH. The medical history should identify a patient’s LUTS and their severity. To do this, a questionnaire such as the IPSS or the American Urological Association BPH Symptom Score Index Questionnaire can be administered [www.adultpediatricuro.com/apuauass.pdf]. As noted earlier, the eighth question on the IPSS questionnaire is useful for assessing the degree to which a patient is bothered by LUTS, with a higher score suggesting a greater willingness of the patient to be treated.¹³ Lower urinary tract symptoms are generally categorized into storage or bladder-emptying symptoms, with the latter subclassified as voiding or postmicturition symptoms.¹⁴ Storage problems are generally of greater concern to patients. Possible sexual dysfunction should also be assessed. A thorough medication history must be taken to identify AEs possibly related to the use of diuretics, anticholinergics, opioids, or decongestants.

The digital rectal examination (DRE) and prostate specific antigen (PSA) test are helpful to rule out a diagnosis of prostate cancer.^15,16 The DRE is used for assessing the size, shape, symmetry, nodularity, and consistency of the prostate. The suprapubic area and genitals should be examined as well.¹⁷ The PSA test is also useful in the diagnosis and treatment of BPH because the PSA level rises as the prostate increases in size.^13,14 A PSA level of 1.5 ng/mL roughly correlates with a prostate size of 30 mL.¹⁸ A urinalysis is needed to screen for urinary tract infections, bladder cancer, and kidney stones. Other laboratory analyses such as a fasting plasma glucose test may be needed based on the patient’s history and other findings.¹⁷

Treatment

Goals

Because BPH is not often life-threatening, the focus of treatment has typically been to alleviate bothersome LUTS and other symptoms. With advances in treatment, additional goals include the alteration of disease progression and the prevention of associated complications such as recurrent urinary tract infections, hematuria, or acute urinary retention, particularly in men with an enlarged prostate (ie, volume >30 mL or PSA >1.5 ng/mL), since disease progression is more likely in these patients.^17,19 A recent Medline-based systematic review reported that men prefer therapies that affect long-term progression over therapies that provide short-term symptom improvement.²⁰ These results were consistent with those from a 2006 survey of 400 men with an enlarged prostate, which also reported that men are generally willing to wait up to 3 months for symptom relief if treatment would resolve the underlying condition.²¹ It is, therefore, important to discuss with the patient the natural history of BPH and its complications, and the benefits and risks of currently available noninvasive and invasive treatment options.

Options

Treatment options for BPH are watchful waiting, lifestyle and behavioral management, pharmacologic therapy, and surgical intervention. Many men use phytobotannical therapy such as saw palmetto, African plum tree, pumpkin seed, rye pollen, stinging nettle, South African star grass, and quercetin to relieve LUTS, although investigations regarding their use are often of poor quality. Saw palmetto is the best studied, yet a Cochrane review found few high-quality studies. The authors of the review concluded that saw palmetto was not more effective than placebo for treatment of LUTS.²² Similar results were observed in a randomized, double-blind, placebo-controlled trial more recently published by the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) Study Group.²³

Watchful waiting is appropriate when only LUTS are present, with or without some degree of nonsuspicious prostate enlargement, and the symptoms are not particularly bothersome to the patient or if the patient does not want treatment.¹⁹ Lifestyle management and behavioral modification should generally be used in combination with other treatment options in an effort to alleviate symptoms, especially in men in whom storage symptoms predominate. Lifestyle management may include reducing fluid intake (particularly if polyuria is present), increasing physical activity, achieving a normal weight, timed voiding (bladder retraining), pelvic floor exercises, treatment for constipation, and avoidance of irritative foods and beverages.^17,19 Epidemiologic evidence over 7 years of surveillance suggests that a diet low in fat and red meat and high in protein and vegetables, as well as regular alcohol consumption (>1 drink/month), may reduce the risk of symptomatic BPH.²⁴ Evidence was weak concerning the benefits of lycopene, zinc, and supplemental vitamin D. No dietary supplement, combination phytotherapeutic agent, or other nonconventional therapy is recommended by the American Urological Association (AUA) for the management of LUTS secondary to BPH.¹⁹

Surgical intervention is considered appropriate in patients with moderate to severe LUTS in whom other medical therapies have not achieved treatment goals and in those in whom benign prostatic obstruction has led to complications such as renal insufficiency, urinary retention, recurrent urinary tract infections, bladder calculi, or hydronephrosis. Patients in whom surgical intervention is contemplated should be referred to a urologist.^17,19

Pharmacologic Options

Three classes of pharmacologic agents have been approved by the US Food and Drug Administration (FDA) for the treatment of symptomatic BPH: AABs, 5-ARIs, and PDE-5Is. The AABs include alfuzosin, doxazosin, silodosin, tamsulosin, and terazosin, and target the dynamic (smooth muscle tone) component of BPH-induced bladder outlet obstruction. The 5-ARIs finasteride and dutasteride target the static (prostate mass) component of BPH-induced bladder outlet obstruction. The PDE-5Is (ie, sildenafil, tadalafil, and vardenafil) increase the amount of cyclic guanosine monophosphate in the smooth muscle of the corpus cavernosum, prostate, and bladder.

Alpha1-Adrenergic Blockers. The four older AABs (ie, alfuzosin, doxazosin, tamsulosin, and terazosin) have been extensively investigated in clinical trials and widely used in the management of BPH. A 2010 review by the AUA concluded that the minor efficacy differences reported among the 4 older AABs were not clinically significant.¹⁹ Although ejaculatory dysfunction may occur with the use of the AABs, these agents are generally well-tolerated, with dizziness the most common AE, occurring in 2% to 14% of men. Ejaculatory dysfunction may be a part of the disease process itself, as noted earlier.

The newest AAB, silodosin, at a dosage of 8 mg/d was reported to have efficacy similar to tamsulosin 0.2 to 0.4 mg/d in reducing storage and voiding LUTS in three 12-week trials.^25-27 Silodosin has also been associated with a significant improvement in patients’ quality of life. The most frequent AE related to silodosin use was abnormal ejaculation, occurring in 10% to 22% and causing discontinuation in 1% to 3%.^25-27 One 12-week study reported that systolic blood pressure (BP) decreased 0.1 and 4.2 mm Hg in the silodosin and tamsulosin groups, respectively.²⁵ The negligible reduction in BP observed with silodosin is likely due to the selectivity of silodosin for the alpha_1A-adrenergic receptor rather than the alpha_1B-adrenergic receptor, the blockade of which reduces BP.

5-Alpha-Reductase Inhibitors. The efficacy of 5-ARIs in preventing progression of LUTS secondary to BPH and their tolerability are well-established. Dutasteride was associated with a greater reduction in dihydrotestosterone in prostate tissues compared with finasteride (94% vs 80%, respectively) and has a longer elimination half-life.¹⁹ Finasteride was reported to be less effective than an AAB in improving LUTS. Dutasteride may have been more effective in reducing the relative risk for acute urinary retention and BPH-related surgery compared with tamsulosin over 4 years, but more research is needed.²⁸ The 5-ARIs should not be used in men with LUTS secondary to BPH without prostatic enlargement, but may be used to prevent the progression of LUTS secondary to BPH and to reduce the risk for urinary retention and future prostate-related surgery.¹⁹ Prostate size ≥30 mL or PSA level ≥1.5 ng/dL is usually used as the threshold for considering 5-ARI therapy.¹⁹ As expected, because of the effects on dihydrotestosterone, AEs are primarily sexually related and include decreased libido, ejaculation disorders, and erectile dysfunction.¹⁹

Phosphodiesterase-5 Inhibitors. Approved by the FDA for erectile dysfunction, several observations led to the investigation of PDE-5Is for LUTS related to BPH.^8,29 One was that the prevalences of BPH, LUTS, and erectile dysfunction increase as a man ages. Second was that LUTS have been identified as a risk factor for sexual dysfunction in aging men. Third was that limited evidence had suggested that PDE-5Is might be effective in treating LUTS and erectile dysfunction. Further investigation suggested beneficial effects on LUTS with each of the 3 PDE-5Is (ie, sildenafil, tadalafil, and vardenafil).^30-32 Subsequent extensive investigation with tadalafil demonstrated its efficacy in reducing the storage and voiding symptoms of BPH and led to the approval by the FDA of tadalafil for symptoms of BPH alone or with erectile dysfunction.^33-37

The clinical studies investigating the efficacy and tolerability of tadalafil for LUTS associated with BPH have included a 12-week study with a 1-year extension.³⁸ Patients with BPH-associated LUTS (N = 1058) were randomized to tadalafil 2.5, 5, 10, or 20 mg/d or placebo once daily for 12 weeks. The total IPSS score was significantly improved at 12 weeks compared with baseline in each of the tadalafil groups relative to placebo (2.5 mg/d: –3.9, P = .015; 5 mg/d: –4.9, P < .001; 10 mg/d: –5.2, P < .001; 20 mg/d: –5.2, P < .001; placebo: –2.3). The use of tadalafil 5, 10, or 20 mg once daily was associated with significant improvements in the IPSS irritative (eg, frequency, nocturia, and urgency) and obstructive (eg, incomplete emptying, intermittency, slow stream, and straining) subscores, as well as scores on the IPSS quality-of-life measure, the BPH Impact Index (except 10 mg), and the LUTS Global Assessment Question. In sexually active men with erectile dysfunction, all doses of tadalafil were associated with significant improvements in scores on the International Index of Erectile Function–Erectile Function domain compared with placebo. Peak flow rate was not improved at any dose of tadalafil compared with placebo.

In total, 427 men who completed the 12-week study elected to receive tadalafil 5 mg once daily for an additional year.³⁷ Patients who were switched from placebo or who had the dose increased from 2.5 mg/d had a significant reduction in total IPSS score from week 12 to week 16, and this change was maintained until the end of follow-up at week 64. Patients who had received tadalafil 5, 10, or 20 mg/d maintained the changes observed at the end of the 12-week study. Similarly, sexually active men with erectile dysfunction and who had a female partner maintained the improvements observed at the end of 12 weeks. The mean postvoid residual volume was decreased from 61 to 42 mL. At least 1 treatment-emergent AE (TEAE) was reported in 58% of patients, with 89% of events being either mild or moderate in severity. Treatment was discontinued in 5% due to a TEAE. The most common TEAEs were dyspepsia (4%), gastroesophageal reflux disease (4%), back pain (4%), headache (3%), sinusitis (3%), hypertension (3%), and cough (2%). In this study, the improvement in LUTS, sexual function, and quality of life observed after 12 weeks of tadalafil were maintained over the additional year with tadalafil 5 mg once daily.

Continue to complete the online evaluation and receive your certification of completion.

This article reviews screening tools for benign prostatic hyperplasia (BPH) and steps to be taken to confirm a diagnosis of BPH. Among the treatment options for BPH, emphasis is placed on pharmacologic treatment with alpha₁-adrenergic blockers (AABs), 5-alpha-reductase inhibitors (5-ARIs), and phosphodiesterase-5 inhibitors (PDE-5Is). The two newest agents silodosin and tadalafil are discussed in greater detail.