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THE STATE OF HYPERTENSION GUIDELINES: 2012

For most clinicians, one of the most anticipated guideline updates is the Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8). The JNC 8 has been in development for some time and is expected to be released by the end of 2012. Suzanne Oparil, MD, University of Alabama, Birmingham, Alabama, USA, provided an update on the process and timing for these eagerly awaited guidelines.

A fundamental change, and part of the reason for the delay in issuing the guidelines, noted Dr. Oparil, is the adoption of a rigorous nine-step systematic review and development process (Figure 1). Previous versions of the guidelines have received criticism for relying too heavily on low-level evidence and consensus [Tricoci P et al. JAMA2009], and this new, more rigorous approach will result in guidelines that are strictly evidence-based. The recommendations will draw from the results of randomized controlled trials (RCTs) that assess important health outcomes rather than intermediate or surrogate endpoints. The new approach also involves an expanded group of experts on the guideline committee, which now includes expertise in hypertension, primary care, cardiology, nephrology, clinical trials, research methodology, evidence-based medicine, epidemiology, guideline development and implementation, nutrition/lifestyle, nursing, pharmacology, systems of care, and informatics. Senior scientists from the National Heart, Lung, and Blood Institute (NHBLI) and National Institute of Diabetes and Digestive and Kidney Diseases have also joined the panel as nonvoting members.

Figure 1. NHBLI Systematic Review and Guideline Development Process.

Reproduced with permission from S. Oparil, MD.

The JNC 8 is expected to focus on three major areas: the threshold blood pressure (BP) for drug therapy initiation, the target BP for drug therapy, and the most appropriate drugs to achieve the target BP. Prespecified subgroups of interest include patients with diabetes, chronic kidney disease (CKD), coronary artery disease, peripheral artery disease, or heart failure (HF); older patients; men and women; and racial and ethnic groups. Outcomes will focus on overall, cardiovascular (CV), and CKD mortality, myocardial infarction, HF, hospitalization for HF and stroke, coronary and peripheral revascularization, and end-stage renal disease.

Using the JNC 7 as a backdrop, Kenneth A. Jamerson, MD, University of Michigan, Ann Arbor, Michigan, USA, discussed the initial choice of therapy for hypertensive patients who are at low and high risk for CV events. In general, Dr. Jamerson stressed the importance of combination therapy, noting that nearly all monotherapy trials for BP control were "in essence combination therapy trials anyway” (Figure 2). As an example of risk-stratified recommendations, he reviewed the 2010 Updated Consensus on the Management of Blood Pressure in Blacks, issued by the International Society for Hypertension in Blacks [Flack JM et al. Hypertension2010]. For primary prevention in low-risk patients with BP ≥135/85 mm Hg but without target-organ damage or overt or preclinical cardiovascular disease (CVD), this consensus document recommends a modest lowering of target BP to <135/85 mm Hg using lifestyle modification and drug therapy. For patients in this group whose BP is consistently <145/90 mm Hg, the recommendations encourage the use of comprehensive lifestyle modification for up to 3 months without concurrent drug therapy. For high-risk patients with BP ≥130/80 mm Hg and target-organ damage, preclinical CVD, or the presence or history of CVD, these consensus guidelines recommend a lower BP target of <130/80 mm Hg using both lifestyle modification and drug therapy. As to the choice of drug therapy, Dr. Jamerson sees no advantage to using diuretics as initial therapy, suggesting that both high- and low-risk patients benefit more from combination therapy (preferably with an ACE inhibitor and amlodipine), as it provides prompt and efficient BP control. Given the importance and proven efficacy of lifestyle modification in reducing BP, Dr. Jamerson suggested an article by Scisney-Matlock M. et al. in Postgrad Med 2009 as a good resource for those who are interested in strategies to overcome the barriers to patient compliance.

Figure 2. Multiple Medications Are Required to Achieve BP Control in Clinical Trials.

Reproduced with permission from WC Cushman, MD.

Current target BP guidelines are not drawn from RCTs; rather, they are based on a general acceptance of the concept that "lower is better,” particularly so for patients who are at higher risk. One of the major unknowns with the JNC 8 is whether there will be changes to BP targets. William C. Cushman, MD, Veterans Affairs Medical Center and University of Tennessee College of Medicine, Memphis, Tennessee, USA, discussed why he believes that there are good reasons for the guidelines not to go below BPs that have been proven in RCTs, although he emphasized that this was his opinion and not to be assumed what JNC 8 will recommend. These include:

• A much larger proportion of the population of the United States will be classified as having hypertension that presumably needs drug therapy [Greenlund KJ et al. Arch Intern Med 2004]
• Patients who were previously classified as having hypertension will require more drugs to achieve lower BP goals [Cushman WC et al. N Engl J Med 2010]
• Treating to lower BP targets at a population level may be harmful, in that some patients may achieve BP levels that are too low (a concept known as the J-curve) [Messerli FH et. al. Ann Intern Med 2006]
• If neither beneficial nor harmful, resources would be wasted and, importantly, patient adherence may suffer

 

"If we are to use RCTs to set BP targets, what is the evidence?” asked Dr. Cushman. For diastolic targets, he noted that several trials have demonstrated a consistent reduction in CV events using a diastolic goal <90 mm Hg. Examples includes the landmark VA Cooperative Morbidity Trial in Hypertension [Veterans Administration Cooperative Study Group on Antihypertensive Agents. JAMA 1967 and 1970] and the Hypertension Detection and Follow-up Program [HDFP Cooperative Group. JAMA 1979]. At least one trial, the Hypertension Optimal Treatment (HOT) study [Hansson L et al. Lancet 1998], did ask the question "Is lower better?” for diastolic BP, noted Dr. Cushman, and the results showed that for most patients, there is neither benefit nor harm with going below a diastolic BP of 90 mm Hg. As for systolic targets, there is good RCT evidence for a systolic BP target of <150 mm Hg (Table 1), but there is no strong support from RCTs for a target of 140 mm Hg or lower (Table 2).

Table 1. Systolic BP trials Testing SBP Goals and Showing CVD Benefit.1

*Integrated SBP goal Source: personal communication, Barry Davis; BP = blood pressure; ¹All showed significant reductions in primary and/or other CVD outcomes or mortality; ²Systolic Hypertension in the Elderly Program [JAMA 1991]; ³Systolic Hypertension in Europe Trial [Staessen JA et al. Lancet 1997]; ⁴Systolic Hypertension in China [Wang JG et al. Arch Int Med 2000]; ⁵Hypertension in the Very Elderly Trial [Beckett NS et al. N Engl J Med 2008].

Table 2. Trials Testing Systolic BP Goal <140 mm Hg.

BP=blood pressure; *32% reduction in stroke, but non-significant (p=0.237); ¹Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients [Hypertens Res 2008]; ²Valsartan in Elderly Isolated Systolic Hypertension [Ogihara T et al. Hypertension 2010].

RCT data support BP goals of <150/90 mm Hg in most hypertensive patients; however, a goal of <140/90 mm Hg may still be reasonable, especially for patients aged under 60 years or with CKD. In hypertensive patients with diabetes, RCTs support BP goals of 140–150/80–85 mm Hg or lower. The ACCORD BP Trial did not prove CVD benefit for a systolic goal <120 mm Hg compared with a goal of <140 mm Hg [Cushman WC et al. N Engl J Med 2010]. SPRINT and several other trials are testing lower BP goals that may provide more clarity regarding optimal BP targets. Regardless of the results, these important studies of lower BP targets will need to be incorporated into future guidelines.

COMPARISON OF BARIATRIC SURGICAL PROCEDURES AND IMT FOR THE TREATMENT OF T2DM IN PATIENTS WITH MODERATE OBESITY: ONE-YEAR STAMPEDE TRIAL RESULTS

Results from the 1-year Surgical Therapy And Medications Potentially Eradicate Diabetes Efficiently trial [STAMPEDE; NCT00432809], comparing bariatric surgery with intensive medical therapy (IMT) for the treatment of type 2 diabetes (T2DM) in patients with moderate obesity, concluded that bariatric surgery is more effective than IMT. Philip Raymond Schauer, MD, Cleveland Clinic, Cleveland, Ohio, USA, who reported the results, noted that many of the surgical patients achieved glycemic control without the use of diabetic medications. In addition, improvement in cardiovascular (CV) risk factors after surgery allowed many of these patients to reduce their use of CV medications.

This was the first study to compare IMT with IMT plus bariatric surgery to achieve resolution of T2DM in moderate to severely obese patients (body mass index [BMI] >30 kg/m²). IMT was based on 2011 American Diabetes Association clinical care guidelines but with an increased focus on reducing HbA1C to ≤6% through the use of diet and lifestyle counseling and potent diabetes medications (eg, insulin sensitizers, GLP-1 agonists, sulfonylureas, and insulin). All patients were evaluated and counseled by dieticians and psychologists in preparation for possible bariatric surgery and were instructed in frequent home glucose monitoring and self-titration of medications.

The primary endpoint was the success rate of achieving HbA1C ≤6% at 12 months. Secondary endpoints included changes in fasting plasma glucose (FPG), BMI, lipids, blood pressure, hsCRP, and the use of diabetic and CV medications, as well as safety and adverse events. Patients (n=150) were randomized to IMT alone, IMT plus gastric bypass, or IMT plus sleeve gastrectomy, a procedure that involves vertically stapling and excising the stomach to achieve approximately 75% to 80% stomach volume reduction, leaving a narrow tubular stomach. Both procedures are performed laparoscopically and require a very small abdominal incision, resulting in a hospital stay of about 2 days and recovery time of 2 to 4 weeks.

Eligible patients were aged 20 to 60 years with HbA1C >7% and BMI 27 to 43 kg/m². The average patient age was 49 years, average BMI was 37 kg/m², and average duration of diabetes was 8 years. Mean baseline HbA1C was 9.2+1.5%. Subjects were well treated at baseline, with the majority on at least 3 diabetes medications. Approximately half were on insulin; 80% were on a lipid-lowering agent, and 66% were on an ACEI/ARB.

The primary endpoint, HbA1C ≤6%, was achieved in 12% of IMT patients, compared with 42% of gastric bypass patients (p=0.002 relative to IMT) and 37% of sleeve gastrectomy patients (p=0.008 relative to IMT). All of the gastric bypass patients and 27% of the sleeve gastrectomy patients achieved the primary endpoint target without requiring an increase in their diabetes medications. Patients who were undergoing surgery had an average weight loss of 25 to 30 kg (55 to 65 lbs) compared with 4 to 5 kg (10 lbs) in patients who were receiving IMT. Changes in FPG, hsCRP, and triglycerides and increases in high-density lipoprotein cholesterol also favored surgery over IMT (Table 1). The average number of diabetes medications that were used was significantly reduced (p<0.001) in the surgery groups relative to IMT patients. At 12 months, insulin was withdrawn in 92% to 96% of the surgical patients compared with ~40% of the IMT patients.

Table 1. Secondary Efficacy Endpoints.

¹Gastric bypass vs IMT; ²Sleeve vs IMT; FPG=fasting plasma glucose; BMI=body mass index; HDL= high-density lipoprotein; TG=triglycerides; hsCRP=high-sensitivity C-reactive protein.

In addition, at 12 months, 94% of gastric bypass and 71% of sleeve gastrectomy patients were on only 0 to 1 CV medications, while 72% of the IMT patients were on 3 or more CV medications. There were no differences in final blood pressure between the 3 groups. There were no unexpected complications or deaths through 12 months. More serious adverse events (SAEs) that required hospitalization were seen in patients who were assigned to gastric bypass than sleeve gastrectomy or IMT (22% vs 9% vs 8%). Other SAEs that occurred more frequently in the surgery groups included reoperation (6% of gastric bypass patients and 2% of sleeve gastrectomy patients vs no patients in the IMT), intravenous treatment for dehydration (8% of gastric bypass and 4% of sleeve gastrectomy patients vs no IMT patients), and pneumonia, which occurred only in the gastric bypass group (4% of patients).

The investigators caution that the study is limited by its short duration but add that a 4-year extension is ongoing. This was also a single-center trial, and larger multicenter studies will be needed to determine whether observed improvements in glycemic control and CV risk factors and withdrawal of diabetes and CV medications
translate into reductions in CV events and/or end organ failure from microvascular disease [Schauer PJ et al. N Engl J Med 2012].

NEW MONOCLONAL ANTIBODY TO PCSK9 MARKEDLY LOWERS LDL-C IN PATIENTS ON ATORVASTATIN

Proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) binds to low-density lipoprotein receptors (LDLRs) and plays a pivotal role in LDLR degradation [McKenney JM et al. J Am Coll Cardiol 2012]. James M. McKenney, PharmD, National Clinical Research, Inc., Richmond, Virginia, USA, reported outcomes on the low-density lipoprotein cholesterol (LDL-C)-lowering effects of SAR236553/REGN727 (SAR236553), a highly specific, fully human monoclonal antibody to PCSK9 [Efficacy and Safety Evaluation of SAR236553 (REGN727) In Patients With Primary Hypercholesterolemia and LDL-Cholesterol on Stable Atorvastatin Therapy; NCT01288443].

Three prior Phase 1 studies of SAR236553 have shown that the monoclonal antibody to PCSK9 significantly reduces LDL-C levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia [Stein EA et al. N Engl J Med 2012].

The current Phase 2 dose-ranging study was a double-blind, parallel-group, placebo-controlled, multicenter trial. It included patients aged 18 to 75 years with LDL-C ≥100 mg/dL (2.59 mmol/L) who were on stable-dose atorvastatin at 10 mg, 20 mg, or 40 mg for ≥6 weeks. A total of 183 individuals were randomized to either subcutaneous placebo every 2 weeks (Q2W); SAR236553 at 50 mg, 100 mg, or 150 mg (Q2W); or SAR236553 at 200 mg and 300 mg once every 4 weeks (Q4W) with an alternating placebo injection at 2 weeks.

The primary objective of the study was to evaluate the safety and LDL-C-lowering effect of 12 weeks of treatment with SAR236553 versus placebo. The primary study endpoint was the percentage change in calculated LDL-C from baseline (mean of Week -1 and Week 0) to Week 12.

The addition of SAR236553 resulted in a significant decrease in LDL-C from baseline. A clear dose-response relationship with respect to percentage of LDL-C lowering for both Q2W and Q4W administration was demonstrated: 40%, 64%, and 72% with 50 mg, 100 mg, and 150 mg Q2W, respectively, and 43% and 48% with 200 and 300 mg Q4W. At Week 12, LDL-C reduction with placebo was 5.1% (Table 1). SAR236553 also increased the rate of achievement of LDL-C goals (<70 mg/dL) compared with placebo. Of note, LDL-C reductions were generally unaffected by the baseline atorvastatin dose.

Table 1. Changes in LDL-C from Baseline to Week 12 by Treatment Group (mITT Population).

p<0.0001 for percent change SAR236553 versus placebo; 1LS mean (SE), using LOCF method.

SAR236553 produced consistent and robust reductions in all other Apo B-containing lipoproteins (Table 2), with important decreases in lipoprotein(a)—a finding that is consistent with the prior Phase 1 studies [Stein EA et al. N Engl J Med 2012]. There was also a trend toward lower triglycerides and increases in high-density lipoprotein cholesterol (HDL-C) and Apo AI versus placebo—findings that were not entirely explained by the direct mechanism of action of PCSK9 inhibition. The biweekly injections appeared to deliver a more sustained LDL-C reduction over the Q4W dosing schedule.

Table 2. Changes in ApoB, Non-HDL-C, and Lp(a) from Baseline to Week 12 by Treatment Group (mITT Population).

*p<0.0001 for percent change SAR236553 versus placebo; †p=0.05 for percent change SAR236553 versus placebo; p values are not adjusted for multiplicity (descriptive only).

SAR236553 was well tolerated during the study, with no signs of persistent or prevalent clinical or laboratory adverse events, including those that were associated with hepatic and muscle assessments. One patient who was assigned to the 300-mg Q4W regimen developed a rare complication, leukocytoclastic vasculitis, an inflammatory immune complex-mediated vasculitis of small-caliber blood vessels, although no similar reactions have been reported. No antidrug antibodies were observed 2 weeks before or after the incident.

According to Dr. McKenney, these results support further evaluation of this novel biologic lipid-lowering therapy in large, multicenter, randomized, controlled trials. Plans are underway to evaluate if PCSK9 antibody therapy can reduce adverse cardiovascular outcomes among an internationally diverse patient population who are taking a variety of different background lipid-lowering therapies.

THERAPEUTIC UPDATES: THE COMPLEXITIES OF DUAL ANTIPLATELET THERAPY

Dual antiplatelet therapy (DAPT) in patients with acute coronary syndromes (ACS) is becoming more complex, making it difficult to select the optimal therapy, said Matthew J. Price MD, FACC, Scripps Clinic, La Jolla, California, USA. With several P2Y12 ADP receptor antagonists that have been approved at varying doses, as well as three different doses of aspirin that are commonly used, there are multiple different combinations of oral DAPT. The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines note the options for DAPT as clopidogrel, prasugrel, and ticagrelor but provide no guidance on the selection of a particular agent [Levine GN et al. Circulation 2011]. The optimal regimen; the potential risk for adverse events, bleeding in particular; and the role of genotyping are among the most important questions that remain unanswered.

Drug Options for DAPT

Clopidogrel, when combined with aspirin, leads to improved outcomes (compared with aspirin alone) for patients with ACS, regardless of whether they are undergoing percutaneous coronary intervention (PCI) or not. Despite better results, studies showed that inhibition of platelet aggregation with clopidogrel was "variable, unpredictable, and insufficient,” said Paul Gurbel, MD, FACC, Sinai Center for Thrombosis Research, Baltimore, Maryland, USA [Gurbel PA et al. Circulation 2003].

DAPT with prasugrel achieved more rapid, potent, and consistent inhibition of platelet function than clopidogrel + aspirin. In the TRITON-TIMI 38 trial, prasugrel substantially reduced rates of ischemic events (9.9% vs 12.1%; HR, 0.81; 95% CI, 0.73 to 0.90; p<0.001), including stent thrombosis (1.1% vs 2.4%; HR, 0.48; 95% CI, 0.36 to 0.64; p<0.001), compared with clopidogrel in patients with ACS treated with coronary stenting [Wiviott SD et al. N Engl J Med 2007]. However, prasugrel increased the rate of major bleeding (2.4% vs 1.8%; HR, 1.32; 95% CI, 1.03 to 1.68; p=0.03), including fatal bleeding (0.4% vs 0.1%; HR, 4.19; 95% CI, 1.58 to 11.11; p=0.002). Overall mortality was similar for the two drugs.

The most recently approved P2Y₁₂ antagonist, ticagrelor, has a rapid onset, consistent antiplatelet effect, and is reversible [Gurbel PA et al. Circulation 2009]. Ticagrelor was compared with clopidogrel in the PLATO trial and significantly reduced the rate of the primary composite endpoint (cardiovascular [CV]-related death, myocardial infarction [MI], and stroke) by 1.9% absolute (p=0.0003), including a significant reduction in CV mortality (4.0% vs 5.1%; HR, 0.79; 95% CI, 0.69 to 0.91; p=0.001) [Wallentin L et al. N Engl J Med 2009]. The results were consistent in many subgroups including patients who were planned for an invasive strategy; those with ST-elevation myocardial infarction (STEMI), renal dysfunction and, previous stroke; and those having coronary artery bypass grafting within 5 days of treatment. Ticagrelor was of benefit independently of the loading dose of clopidogrel (300 or 600 mg) [Cannon CP et al. Lancet 2010], and also regardless of the genetic CYP2C19 polymorphism that identifies low responders to clopidogrel [Wallentin L et al. Lancet 2010]. Ticagrelor achieves a greater pharmacodynamic effect than clopidogrel, irrespective of CYP2C19 genotype [Tantry US et al. Circ Cardiovasc Genet 2010], which likely explains the higher rate of bleeding with ticagrelor compared with clopidogrel that is seen outside of the operating room.

Comparisons across the trials of P2Y₁₂ antagonists are difficult due to differences in the study designs in which the efficacy and safety of the drugs are evaluated (Table 1). Dr. Price suggested that physicians look at the study designs to see where their patients "fit” in terms of the type of MI (NSTEMI or STEMI), management strategy, pretreatment with clopidogrel, start of treatment before coronary angiography, potential need for CABG, and clinical characteristics (eg, advanced age, low body weight, previous stroke – each of which increases the risk of major bleeding).

Table 1. Comparative Study Designs Testing the Safety and Efficacy of the P2Y12 Antagonists in ACS.

Pre-Tx=pre-therapeutics; PCI=percutaneous coronary intervention; CVD=cardiovascular disease; MI=myocardial infarction; CVA=cerebrovascular accident; V. Death=vascualr death; ARR=absolute risk reduction.

Risk of Bleeding

The risk of bleeding is the greatest safety concern with DAPT. "It’s been difficult, if not impossible, to disassociate a reduction in things like, stent thrombosis, from increases in bleeding,” said Deepak L. Bhatt MD, MPH, Brigham and Women’s Hospital, Boston, Massachusetts, USA. The potential for increased risk of bleeding must be an important factor in selecting an antiplatelet regimen. It is wise to factor gastrointestinal (GI) bleeding risk in particular, whether the patient is older, has a history of ulcers, has H. pylori, or is on an anticoagulant, corticosteroids, or an NSAID, advised Dr Bhatt.

Proton pump inhibitors (PPIs) have been used widely to reduce the risk of upper GI bleeding that is associated with clopidogrel, but studies have shown a pharmacodynamic interaction between PPIs and clopidogrel, potentially reducing its clinical effectiveness. However, the clinical significance of this interaction has not been substantiated in more recent data. An analysis from TRITON-TIMI 38 indicated no influence of PPIs on outcomes in patients who are treated with clopidogrel [O’Donoghue ML et al. Lancet 2009]. Likewise, recent analyses from PLATO showed no interaction of clopidogrel with PPI, with a consistent benefit of ticagrelor, regardless of PPI treatment [Goodman S et al. Circulation 2012].

The best clinical data that have evaluated the interaction of PPIs and clopidogrel are from the prospectively designed, randomized, double-blinded COGENT trial, in which prophylactic use of omeprazole reduced the rate of upper GI bleeding compared with placebo (HR, 0.13; 95% CI, 0.03 to 0.56; p=0.001) [Bhatt DL et al. N Engl J Med 2010]. There was no apparent CV interaction between clopidogrel and omeprazole (HR in patients who were randomized to omeprazole, 0.99; 95% CI, 0.68 to 1.44; p=0.96), but the study could not rule out a potentially clinically meaningful difference in CV events due to use of a PPI.

To help provide insight on the issue, the ACC and AHA worked with the American College of Gastroenterology to develop an Expert Consensus Document on the use of PPIs and thienopyridines [Abraham NS et al. Circulation2010]. The consensus document, recommends using a PPI to reduce GI bleeding among patients with a history of upper GI bleeding, stating that PPIs are appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy. The document also indicates that the routine use of a PPI is not recommended for patients who are at lower risk of upper GI bleeding.

The risk of bleeding with prasugrel is higher than it is with clopidogrel. In particular, prasugrel should not be used in patients who have had a prior stroke or transient ischemic attack, and is not recommended for patients aged >75 years, except in high-risk situations. "This recommendation is derived from the data evaluating the net clinical benefit. [If] patients have high ischemic risk, they will benefit overall from prasugrel because the ischemic benefit outweighs the risk of bleeding, and that was seen in elderly patients with diabetes or prior MI,” said Dr. Price. He also added that dose adjustment in lightweight patients should be considered.

Concerns were initially raised about using ticagrelor for patients who had prior stroke as there was nearly a doubling of intracranial hemorrhage (ICH; HR, 1.87; 95% CI, 0.98 to 3.58; p=0.06) that was associated with ticagrelor compared with clopidogrel among all patients in the PLATO trial. However, further analysis showed that patients who had a prior stroke actually fared substantially better with ticagrelor than with clopidogrel in terms of the primary endpoint (HR, 0.62; 95% CI, 0.42 to 0.91). This suggests any increased risk of ICH in patients who were treated with ticagrelor (compared with clopidogrel) was counterbalanced by a larger benefit in the reduction of ischemic events.

A higher rate of non-CABG bleeding was also more common with ticagrelor than clopidogrel (2.8% vs 2.2%; HR, 1.25; 95% CI, 1.03 to 1.53; p=0.03), similar to the excess that was seen with prasugrel versus clopidogrel. However there was no difference in perioperative CABG bleeding between ticagrelor and clopidogrel, and a study by Held et al. found that the mortality rate after CABG was significantly lower for patients who were treated with ticagrelor versus clopidogrel (4.7% vs 9.7%; p<0.01) [Held et al. JACC 2011]. Because ticagrelor reversibly binds the P2Y₁₂ receptor, the rate of recovery of platelet function is faster after ticagrelor than clopidogrel [Gurbel PA et al. Circulation 2009]. However, since ticagrelor achieves a higher steady-state level of platelet inhibition than clopidogrel, it is recommended that both be stopped for 5 days before CABG, compared with 7 days prior to CABG for prasugrel.

Genotyping

Some of the variability in platelet inhibition with clopidogrel can be explained by the presence of CYP2C19 polymorphisms [Shuldiner AR et al. JAMA2009]. Loss-of-function alleles are common, occurring in ~30% of white individuals, ~35% of African-Americans, and 55% of East Asians, said Malcolm R. Bell, MBBS, FRACP, FACC, Mayo Clinic, Rochester, Minnesota, USA. However, patients with these polymorphisms make up less than 20% of patients with a low response to clopidogrel, and other factors also contribute to the variability in platelet inhibition [Hochholzer et al. J Am Coll Cardiol 2010].

In 2011, the ACCF/AHA published an update to its unstable angina/NSTEMI guidelines, with two new class IIb recommendations, noting that platelet function testing or genotyping for CYP2C19 loss-of-function variants may be considered if the testing may alter management [Wright RS et al. JACC2011]. However, a benefit of altering management based on platelet function or genetic testing has never been demonstrated in a large-scale prospective trial.

European Society of Cardiology 2011 ACS Guideline

Unlike the ACCF/AHA guidelines, the European Society of Cardiology guidelines now recommend the newer P2Y₁₂ inhibitors (ticagrelor or prasugrel) over clopidogrel in patients with NSTE-ACS. Ticagrelor has a Class I, level B recommendation, with the guidelines stating that a 180-mg loading dose, followed by 90 mg given twice daily, is recommended for "all patients at moderate-to-high risk of ischemic events, regardless of initial treatment strategy, and including those pretreated with clopidogrel (which should be discontinued when ticagrelor is commenced)” [Hamm CW et al. Eur Heart J2011]. Ticagrelor is of benefit regardless of type of ACS, a noninvasive or invasive strategy (including CABG), renal function and diabetes, use of PPIs, or CYP2C19 polymorphism. Prasugrel also has a Class I, level B recommendation; a 60-mg loading dose, followed by a 10-mg daily dose, is recommended for "P2Y12-inhibitor-naïve patients (especially diabetics) in whom coronary anatomy is known and who are proceeding to PCI unless there is a high risk of life-threatening bleeding or other contraindications." In contrast, clopidogrel is recommended only if patients are not candidates for ticagrelor or prasugrel (Class I, level A). Prof. Wallentin concluded that compared with clopidogrel, one life would be saved for every 54 ACS patients who are treated with ticagrelor for one year.

Science Advisor's Note:
Whether the benefits of ticagrelor and prasugrel over clopidogrel that were observed in a rigorous randomized trials will hold up in routine practice, the side effect profile, and anticipated use in patients who would not have qualified for a clinical trial remains to be seen.

NEW ANTI-DIABETES AGENTS OFFER PROMISE IN THE FIGHT AGAINST CVD

Type 2 diabetes mellitus (T2DM) is a major risk factor for ischemic heart disease, and cardiovascular disease (CVD) is the leading cause of morbidity and mortality for individuals with T2DM [McEwen LN et al. Diabetes Care2012]. CVD is also the largest contributor to direct and indirect medical costs that are associated with T2DM. Common conditions that coexist with T2DM (eg, hypertension and dyslipidemia) are clear risk factors for CVD; however, a diagnosis of T2DM itself confers independent risk [Whittington HJ et al. Cardiol Res Pract 2012].

Numerous studies have demonstrated the efficacy of targeting and controlling individual CV risk factors (eg, blood pressure less than 130/80 mm Hg, low-density lipoprotein cholesterol less than 100 mg/dL, HbA1C <7%) in preventing or slowing the progression of microvascular and macrovascular disease in patients with T2DM [American Diabetes Association Standards of Medical Care in Diabetes—2012. Diabetes Care 2012] (Figure 1). Larger benefits are seen when multiple risk factors are globally addressed in patients with T2DM [Buse JB et al. Diabetes Care 2007; Gaede P et al. N Engl J Med 2008].

Figure 1. Metabolic Components of Diabetes: ADA Treatment Recommendations.

Reproduced with permission from EA Oral, MD.

However, randomized clinical trials have also suggested the limits of intensive CV risk factor control in T2DM [The ACCORD Study Group. N Engl J Med 2010; Duckworth W et al. N Engl J Med 2009; ADVANCE Collaborative Group. N Engl J Med 2008]. In particular, achieving intensive glucose control alone may be insufficient to reduce major CVD events. A new medication class that may reduce CVD in patients with T2DM uses molecules that activate the incretin system to raise or mimic glucagon-like peptide-1 (GLP-1). In a recent review, Motta et al. [Recent Pat Cardiovasc Drug Discov 2012] reported that incretin-based agents improve glycemic control by mechanisms that minimize hypoglycemia and that some agents also improve lipoprotein profiles, blood pressure control, and weight loss.

GLP-1 receptors have been discovered on cardiac myocytes and endothelial cells [Ban K et al. Circulation 2008; Bose AK. Diabetes2005], and intravenous GLP-1 acutely improves left ventricular ejection function (LVEF) and reduces BNP levels in heart failure patients [Sokos GG et al. Card Fail 2006]. A 72-hour GLP-1 infusion also improved left ventricular wall motion abnormalities and LVEF in patients with a history of myocardial infarction (MI) [Nikolaidis LA et al. Circulation 2004]. Given all of these favorable effects on surrogate outcomes, there are currently large ongoing trials of GLP-1 agonists in patients with T2DM that are studying their ability to reduce CV endpoints [LEADER, NCT01179048; EXSCEL, NCT01144338].

Dipeptidyl peptidase 4 (DPP-4) inhibitors are another form of incretin-based therapy that indirectly increase endogenous GLP-1. Evidence shows that GLP-1 receptor agonists and DPP-4 inhibitors are capable of preserving myocardial function and protecting cardiac myocytes from ischemic damage, independent of their glucose-lowering function [Mannucci E, Dicembrini I. Curr Med Res Opin 2012].

Mannucci and Dicembrini note that both classes of drugs enhance endothelial function. In addition, DPP-4 inhibitors increase the availability of endothelial progenitor cells via a GLP-1 receptor-independent pathway. Taken together, available experimental evidence, with a few pilot studies in humans, suggests that incretin-based therapies could prevent CVD [Monami M et al. Exp Diabetes Res 2011; Phung OJ et al. JAMA 2010; Frederich R et al. Postgrad Med 2010]. As a result, there are several large randomized clinical trials studying the effects of DPP-4 inhibitors in patients with T2DM to reduce incident and recurrent CV events [TECOS, NCT00790205; EXAMINE, NCT00968708; SAVOR-TIMI 53, NCT01107886].

Neuroendocrine-based therapies are another approach of interest for reducing CVD in patients with T2DM. Quick-release bromocriptine (bromocriptine-QR) is a D2 dopamine receptor agonist. The Cycloset Safety Trial, a 52-week, randomized, double-blind, multicenter trial demonstrated the potential CV safety and efficacy of this novel therapy for T2DM (Figure 2) [Gaziano JM et al. Diabetes Care 2010]. Fewer people reported a CVD end point (the composite of MI, stroke, coronary revascularization, and hospitalization for angina or congestive heart failure) in the bromocriptine-QR group (1.8%) versus placebo group (3.2%; HR, 0.60; 95% two-sided CI, 0.35 to 0.96; Figure 2). The frequency of serious adverse events (SAEs) was comparable between the groups (8.6% vs 9.6%; HR, 1.02; 96% one-sided CI, 1.27).

Figure 2. CV Endpoints – Reported SAEs.

Reproduced from Gaziano JM et al. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care 2010. Jul;33(7):1503-8. With permission from the American Diabetes Association.

Incretin- and neuroendocrine-based therapies for patients with T2DM are exciting new developments; with the potential to improve overall CVD risk based on experimental and early clinical data. Although these early developments are promising, we await the results of the ongoing large multicenter clinical trials that are designed to determine whether these therapies reduce CV events in patients with T2DM.

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