When and How to Implement Basal-Bolus Therapy: Treating to Success

by Russell D. White, MD

Technorati Tags: Diabetes,Insulin,Hyperglicemia,A1C

Type 2 Diabetes Is a Progressive Disease

Because of the progressive nature of type 2 diabetes, the majority of patients with longstanding disease are likely to be candidates for insulin therapy.^[1]

• This is due to the fact that a large fraction of β-cell function has been lost by the time the disease is diagnosed and this decline continues over time.^[2]
• During the early stages of type 2 diabetes, lifestyle interventions may be successful for improving glycemic control for some patients,^[3] but as β-cell function continues to decline, pharmacologic treatment is likely to be necessary:
  • Oral therapy may progress from treatment with a single agent to combination therapy with 2 or 3 drugs.^[4]
  • When oral agents are not effective in reaching A1C targets, addition of insulin therapy is required.^[5]
  • There is an emerging awareness that using insulin earlier in the course of the disease is physiologically sound and should be an integral part of adequate diabetes management.^[6]

  Progressive Disease Requires Progressive Treatment

  Insulin treatment for patients with diabetes should be aimed at treating to target, using information gained from careful blood glucose (BG) monitoring.^[7]

  • As the disease progresses, so should therapy.
  • Treatment should be aimed at a specific A1C goal and adjusted as needed to reach it.
  • This approach is in contrast to a slower stepwise approach likely to result in repeated failure and loss of glycemic control.

  Basal Insulin

  There are multiple approaches to the initiation of insulin therapy in a patient with type 2 diabetes who can no longer maintain glycemic control on oral agents.

  • Addition of basal insulin therapy to oral drugs:
    • This approach is consistent with results from clinical trials that have shown that adding basal insulin to ongoing oral therapy can improve glycemic control.^[8]
    • Addition of basal insulin is thought to improve control over BG by suppression of overnight hepatic glucose production, both through direct effects on the liver and indirect effects due to inhibition of free fatty acid release by adipose tissue.^[9] Decreasing elevated fasting plasma glucose may decrease the risk for long-term complications of diabetes.^[10]
    • Main options for basal insulin therapy^[11]:
      • Intermediate-acting neutral protamine Hagedorn (NPH) insulin
      • Long-acting insulin analog (insulin glargine or insulin detemir)
      • The pharmacokinetic/pharmacodynamic profiles for NPH insulin and long-acting insulin analogs are substantially different. Those for the long-acting insulin analogs are relatively flat, whereas those for NPH insulin have a distinct peak at approximately 4 hours. This difference results in different dosing requirements for these insulins^[9]:
        • NPH insulin must be given in the evening or at bedtime and often requires twice daily administration, with a second dose in the morning.
        • Long-acting insulin analogs can be administered at bedtime, before dinner, or in the morning, due to their longer durations of action and lower peak effects.
      • There are other important differences between NPH insulin and long-acting insulin analogs:
        • The pharmacokinetic effects of NPH insulin are more variable than those of insulin glargine or insulin detemir. This variability is a result of the manner in which NPH insulin is structured^[12]:
          • Protamine is added to regular insulin to extend its duration of action. Addition of protamine increases the tendency of insulin molecules to remain in a hexameric structure at the injection site, resulting in a longer duration of action and longer time to peak. However, the resulting poor solubility of this insulin preparation increases the variability in its pharmacokinetic profile.
          • The requirement for resuspension of NPH before injection may also contribute to inter- and intrapatient variability in the action of this insulin because the actual amount of insulin administered may vary from one injection to the next.^[12]
          • Long-acting insulin analogs have much less variability than NPH. The coefficient of variation for a glucose infusion in patients given 0.4 U/kg NPH insulin is 68%, that for insulin glargine is 48%, and that for insulin detemir is 27%.^[13]
          • This may contribute to the lower risk for hypoglycemia with these agents versus NPH insulin.^[7]
          • Clinical studies have demonstrated the effectiveness of adding a long-acting basal insulin analog to oral therapy in patients with type 2 diabetes.^[7,14–16]
          • Insulin detemir appears to be associated with less weight gain than either insulin glargine or NPH insulin.^[17,18]
    • How to dose basal insulin:
      • The initial dose for insulin detemir is usually 10 U or 0.1-0.2 U/kg.^[19]
      • In the PREDICTIVE 303 study patients self-adjusted their insulin detemir dose every 3 days based on the average of three self-monitored BG (SMBG) values. Insulin detemir doses were adjusted as follows^[20]:
        • If the mean fasting plasma glucose (FPG) is <80 mg/dL, the dose is reduced by 3 U.
        • If the mean FPG is 80 to 110 mg/dL, there is no change in dosing.
        • If the mean FPG is >110 mg/dL, the dose is increased by 3 U.
      • One recent study has demonstrated that patients can safely self-titrate insulin detemir to an FPG target of 70-90 mg/dL with low rates of hypoglycemia.^[21]
      • The typical initial dose for insulin glargine is 10 U.^[22] In one study, doses for insulin glargine were adjusted as follows^[23]:
        • No change is required if FPG remains between 70 and 94 mg/dL.
        • If FPG is <70 mg/dL for 3 days, the dose should be decreased by up to 10% of the total dose.
        • If FPG is 95 to 119, 120 to 139, 140 to 180, or >180 mg/dL for 3 days, the dose should be increased by 2, 4, 6, or 8 U, respectively.

  Adding Prandial Insulin

  While addition of basal therapy is highly effective in many patients, the progressive nature of diabetes may require further intensification of treatment. Rapid-acting insulin analogs are a suitable first choice for intensification of therapy:

  • Rapid-acting insulin analogs have lower variability in absorption and more consistent pharmacodynamic profiles than regular human insulin.^[24,25]
  • Rapid-acting insulin analogs provide higher 1- and 2-hour insulin values, reduced risk for late postprandial hypoglycemia due to a shorter duration of action than regular human insulin, and may provide quality of life benefits due to greater flexibility in timing and meal-time dosing.^[26]
  • These insulin analogs provide a more physiologic action which coincides with meal patterns.

  Adding prandial insulin to basal insulin may be the best way to restore postprandial and overall glycemic control when the combination of basal insulin and oral therapies is no longer effective. Prandial insulin may be added to basal insulin in a step-wise manner^[9]:

  • Adding prandial insulin to decrease postprandial glucose (PPG) may be most beneficial in patients with FPG that is at or near goal, but who still have modestly elevated A1C. Results from Monnier and colleagues have shown that PPG makes the greatest contribution to A1C at values below approximately 8.5%.^[27] Addition of prandial insulin should also be considered when the basal insulin dose is very high (>0.6 U/kg).
  • A single mealtime prandial injection of a rapid-acting insulin analog that controls the highest postprandial glucose (PPG) may be sufficient to restore glycemic control^[28]:
    • The basal insulin dose should be lowered by the amount of prandial insulin to decrease the risk for nocturnal hypoglycemia.^[29]
    • The prandial insulin dose can then be titrated in accordance with SMBG measured 2 hours after the start of the meal, before the next meal, or at bedtime if the injection is administered before the evening meal:
      • The American Diabetes Association goal for peak PPG is <180 mg/dL.^[30]
      • The American College of Endocrinology recommends a 2-hour postprandial BG level <140 mg/dL.^[31]
    • It has also been shown that prandial insulin doses can be effectively adjusted based on premeal BG patterns from the previous week.^[23]
    • The prandial insulin dose can be adjusted independently to limit postprandial hyperglycemia without affecting basal insulin action.^[9,27]

  Basal-Bolus Therapy

  Basal-bolus therapy may be an appropriate treatment progression for patients who have had prandial insulin added to the treatment regimen^[32]:

  • In these regimens, basal and bolus insulin requirements are each approximately 50% of the total daily insulin needed.
  • Results from the PREFER study indicated that one-third of the total prandial insulin dose can be delivered with each meal with the majority of patients achieving A1C ≤7%.^[33]
  • It has also been suggested that the total dose of rapid-acting insulin analog may be divided with 38% delivered at breakfast, 28% at lunch, and 33% at dinner (White RD, et al., unpublished data). The highest prandial dose is delivered at breakfast for two reasons:  
    • High carbohydrate content for this meal
    • The “dawn phenomenon,” a morning surge in plasma glucose that occurs secondary to a physiologic morning rise in cortisol and growth hormone levels.^[34]

  There are several considerations for titration of prandial insulin:

  • Rapid-acting insulin analogs have accelerated pharmacokinetics compared with long-acting insulins, and they require different adjustments that can be made at shorter intervals.
  • SMBG should be carried out at least three times per day for patients using multiple insulin injections.^[30]
  • Exercise improves insulin sensitivity, and it is often necessary to reduce the prandial insulin before exercise occurring within 3 hours in patients who engage in moderate or strenuous exercise.^[35] Carbohydrate counting is an alternative to dosage algorithms for determining prandial insulin dose, and it provides for more flexibility in meal planning,^[23] but this is not absolutely necessary.
  • Concern about hypoglycemia is a significant psychological barrier to intensive insulin therapy^[36]:  
    • This risk is reduced by the use of long- and rapid-acting insulin analogs versus human insulins.
    • In one study, switching patients from the combination of regular human insulin and NPH insulin to insulin lispro and insulin glargine resulted in a 44% reduction in the occurrence of hypoglycemia.^[37]
    • A second study indicated a 43% reduction in the occurrence of nighttime hypoglycemia with the insulins lispro and glargine versus regular human and NPH insulin.^[38]
    • The combination of insulins detemir and aspart has also been shown to be associated with 38% lower risk for nighttime hypoglycemia than NPH plus regular human insulin in patients receiving basal-bolus treatment.^[39]

  Simplifying Basal-Bolus Therapy

  Advances in therapy may help to simplify basal-bolus therapy:

  • Rapid-acting insulin analogues that can be administered shortly before or even after meals^[40] have the potential to improve adherence.
  • Adherence to treatment in difficult-to-manage patients may also be improved with intensive home- and community-based family therapy.^[41]
  • Patient referral to specialists for intensive diabetes care may be necessary to reach treatment targets in some patients.^[42]
  • Use of an insulin pen may improve adherence to treatment and thus glycemic control. It has been shown that patients with type 2 diabetes prefer insulin pen devices over syringe and vial; and these devices improve adherence to therapy and decrease the risk for hypoglycemia.^[43]
  • Additional steps that may increase the probability of reaching treatment goals include^[44]:
    • Monitoring A1C every 3 months in addition to SMBG
    • Aggressively managing hyperglycemia, dyslipidemia, and hypertension with the same intensity to obtain the best patient outcome
    • Implementing a multi- and interdisciplinary team approach to diabetes management both to encourage patient education and self-care and to share responsibility for patients achieving glucose goals

  References

  1. Wright A, Burden AC, Paisey RB, Cull CA, Holman RR, for the U.K. Prospective Diabetes Study Group. Sulfonylurea inadequacy. Efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care. 2002;25:330-336.
  2. DeFronzo RA. From the triumvirate to the ominous octet – a new paradigm for the treatment of T2DM. The Banting Lecture. Programs and abstracts of the American Diabetes Association 68th Scientific Sessions; June 6-10, 2008; San Francisco, California.
  3. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes. 2005;54:603-608.
  4. Bell DS. Type 2 diabetes mellitus: what is the optimal treatment regimen? Am J Med. 2004;116(suppl 5A):23S-29S.
  5. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193-203.
  6. Eldor R, Stern E, Milicevic Z, Raz I. Early use of insulin in type 2 diabetes. Diabetes Res Clin Pract. 2005;68(suppl 1):S30-S35.
  7. Riddle MC, Rosenstock J, Gerich J; on behalf of the Insulin Glargine 4002 Study Investigators. The treat-to-target trial. Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080-3086.
  8. Davies M, Evans R, Storms F, Gomis R, Khunti K; on behalf of the AT.LANTUS Study Group. Initiation of insulin glargine in suboptimally controlled patients with type 2 diabetes: sub-analysis of the AT.LANTUS trial comparing treatment outcomes in subjects from primary and secondary care in the UK. Diabetes Obes Metab. 2007;9:706-713.
  9. Raccah D, Bretzel RG, Owens D, Riddle M. When basal insulin therapy in type 2 diabetes mellitus is not enough–what next? Diabetes Metab Res Rev. 2007;23:257-264.
  10. Gimeno-Orna JA, Castro-Alonso FJ, Boned-Juliani B, Lou-Arnal LM. Fasting plasma glucose variability as a risk factor of retinopathy in Type 2 diabetic patients. J Diabetes Complications. 2003;17:78-81.
  11. Scholtz HE, Pretorius SG, Wessels DH, Becker RH. Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique. Diabetologia. 2005;48:1988-1995.
  12. Takiya L, Dougherty T. Pharmacist’s guide to insulin preparations: a comprehensive review. Pharmacy Times CE. 2005. Available at: https://secure.pharmacytimes.com/lessons/200510-03.asp.
  13. Heise T, Nosek L, Rønn BB, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53:1614-1620.
  14. Garber AJ, Clauson P, Pedersen CB, Kølendorf K. Lower risk of hypoglycemia with insulin detemir than with neutral protamine Hagedorn insulin in older persons with type 2 diabetes: a pooled analysis of phase III trials. J Am Geriatr Soc. 2007;55:1735-1740.
  15. Fritsche A, Schweitzer MA, Häring HU; and the 4001 Study Group. Glimepiride combined with morning insulin glargine, bedtime neutral protamine Hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med. 2003;138:952-959.
  16. Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P; on behalf of the Levemir Treat-to-Target Study Group. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care. 2006;29:1269-1274.
  17. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia. 2008;51:408-416.
  18. Fakhoury W, Lockhart I, Kotchie RW, Aagren M, LeReun C. Indirect comparison of once daily insulin detemir and glargine in reducing weight gain and hypoglycaemic episodes when administered in addition to conventional oral anti-diabetic therapy in patients with type-2 diabetes. Pharmacology. 2008;82:156-163.
  19. Levemir. [prescribing information]. 2007. Available at: http://www.levemir-us.com/prescribing_information.pdf. Accessed May 21, 2009.
  20. Selam JL, Koenen C, Weng W, Meneghini L. Improving glycemic control with insulin detemir using the 303 algorithm in insulin naïve patients with type 2 diabetes: a subgroup analysis of the US PREDICTIVE 303 study. Curr Med Res Opin. 2008;24:11-20.
  21. Blonde L, Merilainen M, Karwe V, Raskin P; TITRATE Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets - the TITRATE study. Diabetes Obes Metab. 2009;11:623-631.
  22. Lantus. [prescribing information]. 2007. Available at: http://products.sanofi-aventis.us/lantus/lantus.html. Accessed May 21, 2009.
  23. Bergenstal RM, Johnson M, Powers MA, et al. Adjust to target in type 2 diabetes: comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine. Diabetes Care. 2008;31:1305-1310.
  24. Becker RH, Frick AD. Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. Clin Pharmacokinet. 2008;47:7-20.
  25. Guerci B, Sauvanet JP. Subcutaneous insulin: pharmacokinetic variability and glycemic variability. Diabetes Metab. 2005;31:4S7-4S24.
  26. Rossetti P, Porcellati F, Bolli GB, Fanelli CG. Prevention of hypoglycemia while achieving good glycemic control in type 1 diabetes. The role of insulin analogs. Diabetes Care. 2008;31(suppl 2):S113-S120.
  27. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients Variations with increasing levels of HbA(1c). Diabetes Care. 2003;26:881-885.
  28. Monnier L, Colette C. Addition of rapid-acting insulin to basal insulin therapy in type 2 diabetes: indications and modalities. Diabetes Metab. 2006;32:7-13.
  29. Meneghini L. Why and how to use insulin therapy earlier in the management of type 2 diabetes. South Med J. 2007;100:164-174.
  30. American Diabetes Association. Standards of medical care in diabetes–2009.Diabetes Care. 2009;32(suppl 1):S13-S61.
  31. American College of Endocrinology. American College of Endocrinology Consensus Statement on Guidelines for Glycemic Control. Endocrinology. 2002;8(suppl 1):6-11.
  32. Mayfield JA, White RD. Insulin therapy for type 2 diabetes: rescue, augmentation, and replacement of beta-cell function. Am Fam Physician. 2004;70:489-500.
  33. Liebl A, Prager R, Binz K, Kaiser M, Bergenstal R, Gallwitz B; PREFER Study Group. Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: a randomized controlled trial. Diabetes Obes Metab. 2009;11:45-52.
  34. Carroll MF, Schade DS. The dawn phenomenon revisited: implications for diabetes therapy. Endocr Pract. 2005;11:55-64.
  35. Banting and Best Diabetes Centre. Approach to the Management of Diabetes Mellitus. 6th ed. Developed by the Diabetes Care and Education Committee, Banting and Best Diabetes Centre. Toronto: Faculty of Medicine, University of Toronto; 2005.
  36. Hartman I. Insulin analogs: impact on treatment success, satisfaction, quality of life, and adherence. Clin Med Res. 2008;6:54-67.
  37. Ashwell SG, Amiel SA, Bilous RW, et al. Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetes. Diabet Med. 2006;23:285-292.
  38. Murphy NP, Keane SM, Ong KK, et al. Randomized cross-over trial of insulin glargine plus lispro or NPH insulin plus regular human insulin in adolescents with type 1 diabetes on intensive insulin regimens. Diabetes Care. 2003;26:799-804.
  39. Raslová K, Bogoev M, Raz I, Leth G, Gall MA, Hâncu N. Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes. Diabetes Res Clin Pract. 2004;66:193-201.
  40. Garg SK, Rosenstock J, Ways K. Optimized basal-bolus insulin regimens in type 1 diabetes: insulin glulisine versus regular human insulin in combination with basal insulin glargine. Endocr Pract. 2005;11:11-17.
  41. Ellis DA, Frey MA, Naar-King S, Templin T, Cunningham P, Cakan N. Use of multisystemic therapy to improve regimen adherence among adolescents with type 1 diabetes in chronic poor metabolic control. A randomized controlled trial. Diabetes Care. 2005;28:1604-1610.
  42. Graber AL, Elasy TA, Quinn D, Wolff K, Brown A. Improving glycemic control in adults with diabetes mellitus: shared responsibility in primary care practices. South Med J. 2002;95:684-690.
  43. Goldstein HH. Pen devices to improve patient adherence with insulin therapy in type 2 diabetes. Postgrad Med. 2008;120:172-179.
  44. Del Prato S, Felton AM, Munro N, et al; on behalf of the Global Partnership for Effective Diabetes Management. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Int J Clin Pract. 2005;59:1345-1355.

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Rethinking Hypertension in the 21st Century: An Overview of the Expanded Definition and Classification of Hypertension

by Thomas D. Giles, MD

Technorati Tags: hipertension,cardiovascular disease,chest pain,angina

Introduction

As epidemiologic and clinical data regarding the relationship between blood pressure (BP) and the risk for cardiovascular disease (CVD) have accumulated, a pronounced shift has taken place in how the disease of hypertension is viewed and defined. Cardiovascular (CV) risk has been found to be elevated at BP levels previously considered normal; in some cases, sporadic elevations in BP levels may be physiologically benign and not associated with additional CVD risk.^[1-3] As a consequence, many hypertension experts consider elevated BP at its core a disease marker, rather than a cause of hypertension. Moreover, elevated BP, as 1 marker of CVD, frequently coexists with other equally compelling disease markers.^[2] Elevated BP should not, therefore, be viewed or treated in isolation, but considered in the context of whole patient care, which takes into account the presence of other risk factors and disease markers for CVD to achieve a more comprehensive, or global, assessment of CV risk.

With these points in mind, in 2005, the Hypertension Writing Group (HWG), a national group of hypertension specialists, proposed a new definition of hypertension as "a progressive cardiovascular syndrome, the early markers of which may be present even before BP elevations are observed."^[4] The stated goal of the new definition was to identify individuals at risk for CVD at an earlier point in the disease process, as well as to avoid labeling persons as hypertensive who are at low risk for CVD.^[4] Viewed from this perspective, the HWG believed that threshold-based classification systems of hypertension, such as that endorsed in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),^[5] while serving as tools to identify patients across a broad range of CVD risk, may lead to underestimation or overestimation of clinical risk within individual patients. In either case, the presence or absence of other disease markers or risk factors, the coexistence of target-organ damage, or both can be used to risk-stratify patients with hypertension more accurately.

To simplify risk stratification and align it more closely with clinical practice, the HWG proposed classifying all patients as either normal or hypertensive (eliminating the prehypertension category proposed in JNC 7), with hypertension classified into stage 1, stage 2, or stage 3.^[4] Because the CV syndrome represented by hypertension may be present even when BP falls within the normal category by conventional standards, the risk categories created by the HWG focus not on BP levels per se, but on the presence of deleterious BP patterns or the presence of CVD. Stages of hypertension are further categorized based on the presence of risk factors for early, advanced, or progressive CVD, as well as by other CVD markers (classified as BP, cardiac, vascular, renal, and retinal changes) and target-organ damage (classified as cardiac, vascular, renal, and cerebrovascular).^[4]

Beyond the goal of providing a more clinically relevant assessment of global CV risk in clinical practice, this paradigm shift served to focus attention on the enormous unmet need regarding prevention and optimal treatment of hypertension across a spectrum of fields, from basic research and drug development to patient education and clinical management.^[4] Two critical areas of research in particular -- the development of specific and sensitive cost-effective tests that can detect early CVD markers in the clinical setting, and the development of strategies to slow or prevent the onset of target-organ damage or overt CVD by treating early vascular derangements -- may benefit from being examined within the context of the categories for hypertension.

Recently, the HWG further refined and updated the definition and classification of hypertension.^[6] This article reviews the revised definition and classification scheme and the implications for clinical practice. As the authors stressed, however, while definitions of disease are useful for detection, management, research, and education, definitions alone do not constitute recommendations for treatment. In the latter case, the initiation of treatment should be individualized and guided by CV risk, rather than BP thresholds.^[1]

Blood Pressure as a Biomarker for Hypertension

The concept of elevated BP as a disease marker for hypertension, rather than its cause, is supported by multiple lines of evidence suggesting that the risk for renovascular and CV sequelae may be higher than expected in the presence of normal or near-normal BP in some patients, or, conversely, lower than expected in the presence of above-normal BP in others. This view is based, in part, on the physiologically dynamic nature of BP, in which tissue perfusion is matched with metabolic demands in a complex, ever-changing manner that depends on the coordinated activity of numerous mechanisms involved in hemostasis, including the sympathetic nervous system, the renin-angiotensin system, and the vasodilatory system (eg, prostaglandins and nitric oxide).^[4] According to this perspective, optimal BP can vary among individuals and within the same person, depending on hemodynamic circumstances. Sporadic BP elevations may occur in individuals who have no evidence of early CVD.^[2] Conversely, because adverse CV and renal outcomes increase across all BP values, hypertension-related morbidity and mortality can occur even at BP levels considered normal by conventional standards. The significant proportions of myocardial infarctions and strokes that occur in patients who have only slight BP elevation, or even normal BP, adds weight to this argument.^[7]

Perhaps the most convincing evidence against using BP thresholds to define hypertension is that there is no threshold of BP above 115/70 mm Hg that identifies CV risk -- that is, risk is linear and doubles for each 20/10 mm Hg increase in BP.^[2] As a consequence of the dynamic nature of BP, it may be more clinically relevant to use BP patterns, rather than discrete BP thresholds as measured in the clinic, when assessing CV risk in an individual patient. Thus, the HWG places particular attention on ambulatory BP and the contribution of systolic BP (SBP) and pulse pressure (the difference between SBP and diastolic BP [DBP]) to risk, because these are widely considered to be more accurate markers of CV risk than is office DBP, particularly in older patients.^[5,8]

The Interrelationship of High Blood Pressure and Other Cardiovascular Risk Factors

Another key principle endorsed by the HWG is that of the interrelationship between elevated BP and other CV risk factors. Even in patients with frank elevations in BP, risk stratification based on BP levels alone often underestimates CV risk. This is because above-optimal BP levels rarely occur in isolation, and patients seen in clinical practice frequently have multiple CVD markers or risk factors (eg, overweight, insulin resistance, dyslipidemia) that point to greater overall risk.^[1,9-13] What is particularly significant, from the perspective of defining hypertension beyond BP thresholds, is that many of these disease processes are intimately interrelated and interact via common pathobiologic processes involving oxidative stress and endothelial dysfunction (Figure).^[14] Moreover, the presence of risk factors and disease markers defines the earliest stage in this CVD continuum, well before overt CVD and target-organ damage can be measured in the clinic.^[14] From this perspective, above-optimal BP (a risk factor) is not necessarily synonymous with hypertension (a disease representative of progressive CVD and tissue injury).^[6]

Figure. Cardiovascular and renal pathophysiologic continuum. CV = cardiovascular; MI = myocardial infarction; CHF = congestive heart failure; ESRD = end-stage renal disease. Adapted from Dzau VJ, et al.^[14]

Another consequence of the CV and renal pathophysiologic continuum is that the complex interplay of risk factors and disease markers frequently may manifest as a dramatically higher CV risk than would be expected, based on thresholds for each individual risk factor alone. This is highlighted by the particularly deleterious condition known as the cardiometabolic syndrome, in which individual risk factors combine to increase CV risk synergistically, rather than additively.^[12,15] Ultimately, a more clinically meaningful assessment of CV risk can be obtained by global assessment of a patient's risk, rather than focusing solely on whether a patient has crossed a particular BP threshold.

Taken together, this evidence suggests that it may be more useful to view BP as 1, but not the only, biomarker for the disease hypertension, and to view above-optimal levels of BP in an individual patient as those that, when sustained, cause damage to the vasculature.^[6] This forms the basis of the revised definition of hypertension, as shown in Table 1.

Table 1. Revised Definition of Hypertension From Hypertension Writing Group 2009

• Hypertension is a progressive CV syndrome arising from complex and interrelated etiologies

• Early markers of the syndrome are often present before BP elevation is sustained; therefore, hypertension cannot be classified solely by discreet BP thresholds

• Progression is strongly associated with functional and structural cardiac and vascular abnormalities that damage the heart, kidneys, brain, vasculature, and other organs, and lead to premature morbidity and death

• Reduction of elevated BP generally confers a reduction in the risk for CV events. Note that HWG separates elevated BP (one manifestation of the disease) from hypertension (the disease)

BP = blood pressure; CV = cardiovascular
From Giles T, et al.^[6]

Because hypertension is defined by as "a progressive cardiovascular syndrome," it is clinically helpful to categorize, or stage, patients (Table 2), with each stage characterized by the cumulative presence or absence of markers of hypertensive CVD and evidence of target-organ damage. This provides a snapshot of the extent to which the disease has advanced at a particular time.^[6]

Table 2. Revised Definition and Classification of Hypertension From Hypertension Writing Group 2009

Classification	Normal	Stage 1 Hypertension	Stage 2 Hypertension	Stage 3 Hypertension
Descriptive category	Normal BP or rare BP elevations AND no identifiable CVD	Occasional or intermittent BP elevations OR early CVD	Sustained BP elevations OR progressive CVD	Marked and sustained BP elevations OR advanced CVD
Cardiovascular risk factors (see Table 3)	None or few	Several risk factors present	Many risk factors present	Many risk factors present
Early disease markers (see Table 4)	None	Usually present	Overtly present	Overtly present with progression
Target-organ disease (see Table 5)	None	None	Early signs present	Overtly present with or without CVD events

BP = blood pressure; CVD = cardiovascular disease
From Giles T, et al.^[6]

In the broadest sense, individuals are classified as either normal or hypertensive based on their CV status (ie, the absence or presence of identifiable CVD), regardless of their BP pattern. The stages within the hypertension category are further refined, based on BP patterns or the extent of CVD (early, advanced, or progressive). Each hypertension stage is further characterized by the cumulative presence or absence of risk factors for CVD (Table 3);markers of hypertensive CVD, such as microalbuminuria or mild left ventricular hypertrophy (Table 4); and evidence of target-organ damage, such as frank albuminuria or moderate-to-severe left ventricular hypertrophy (Table 5).^[6] The occurrence of a major cardiac event clearly places the progression of hypertensive CVD at a more advanced stage.^[6]

Table 3. Cardiovascular Risk Factors

Increasing age

Elevated BPa

High heart rate

Overweight/obesity

− Increased BMI

− Central obesity

− Increased abdominal circumference

− Increased abdominal adiposity (waist-to-hip ratio)a

Dyslipidemia

− Elevated LDL or non-HDLb cholesterol

− Low HDL cholesterola

− Elevated triglyceridesa

Elevated blood glucose, insulin resistance, or diabetes mellitusa

Chronic kidney disease

Smoking

Family history of premature CVD (age < 50 yr in men, < 60 yr in women)

Sedentary lifestyle

Psychosocial stressors

Elevated hs-CRP

BMI = body mass index; BP = blood pressure; CVD = cardiovascular disease; HDL = high-density lipoprotein; hs-CRP = high-sensitivity C-reactive protein; LDL = low-density lipoprotein
^aComponents of the metabolic syndrome
^bNon-HDL cholesterol = total cholesterol minus HDL cholesterol

Table 4. Early Markers of Hypertensive Cardiovascular Disease

System	Physiologic Alteration
Blood pressure
	Loss of nocturnal BP dipping
	Exaggerated BP responses to exercise or mental stress
	Salt sensitivity
	Widened pulse pressure
Cardiac
	Left ventricular hypertrophy (mild)
	Increased atrial filling pressure
	Decreased diastolic relaxation
	Increased natriuretic peptide
Renal
	Microalbuminuria (urinary albumin excretion of 30-300 mg/day)a
	Reduced estimated GFR (60-90 mL/min)
Cerebrovascular
	Stroke
	Transient ischemic attack
	Decreased cognitive function
	Dementia
	Loss of vision

BP = blood pressure; GFR = glomerular filtration rate
^aAlso a marker of microcirculatory disease

Table 5. Hypertensive Target-Organ Damage and Overt Cardiovascular Disease

System	Evidence of Target-organ Damage and Cardiovascular Disease
Cardiac
	Left ventricular hypertrophy (moderate to severe)
	Systolic or diastolic cardiac dysfunction
	Symptomatic heart failure
	Myocardial infarction
	Angina pectoris
	Ischemic heart disease or prior revascularization
Vascular
	Peripheral arterial disease
	Carotid arterial disease
	Aortic aneurysm
Renal
	Albuminuria (urinary albumin excretion > 300 mg/day)
	Chronic kidney disease (estimated GFR < 60 mL/min) or ESRD
Cerebrovascular
	Stroke
	Transient ischemic attack
	Decreased cognitive function
	Dementia
	Loss of vision

ESRD = end-stage renal disease; GFR = glomerular filtration rate

Clinical Characteristics and Practical Implications of the Proposed Hypertension Categories

A practical clinical interpretation of the revised hypertension categories is shown in Table 6.

Table 6. Clinical Characterization, BP Patterns, and Practical Implications of the Hypertension Algorithm

Hypertension Category	Clinical Characterization	BP Pattern	Practical Implications
Normal	Optimal BP levels	Resting BP levels usually < 120/80 mm Hg	Includes some patients identified as having prehypertension (based on JNC 7 criteria)
	No identifiable early markers of CVD	Occasional BP elevations, even to ≥ 140/90 mm Hg, may occur
Stage 1	Early CVD markers present	BP levels > 115/75 mm Hg	Earliest identifiable stage of hypertensive disease
	Frequently 1 or more CVD risk factors present	BP may be frankly elevated, particularly with environmental stress	Includes individuals with prehypertension (based on JNC 7 criteria) who also have CVD risk factors or early disease markers
	No evidence of target-organ damage
Stage 2	Diffuse disease markers present OR evidence (limited) of early target-organ damage	Sustained resting BP frequently ≥ 140/90 mm Hg, with much higher elevations induced by physiologic or psychologic stressors	Equivalent to JNC 7 stage 1 hypertension
			Indicates progressive disease
			Risk factors, if not attenuated, continue to contribute to progressive target-organ disease
Stage 3	Overt CVD present	Sustained resting BP levels ≥ 140/90 mm Hg usual (untreated or inadequately treated)	Equivalent to JNC 7 stage 2 hypertension
		Marked BP elevations to levels > 160/100 mm Hg not uncommon (untreated or inadequately treated)	Includes all individuals with clinical evidence of overt target-organ damage or CVD, or who have sustained a CVD event, regardless of BP levels

BP = blood pressure; CVD = cardiovascular disease; JNC 7 = Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

In the algorithm, individuals with optimal levels of BP and no identifiable early markers of CVD are categorized as normal. These individuals usually have resting BP levels of 120/80 mm Hg or lower, but BP may be elevated occasionally, even to levels of 140/90 mm Hg or higher.^[6] Given the limits of clinic BP measurements, home BP determinations or 24-hour ambulatory BP recordings may be helpful in identifying patients with more than occasional BP elevations, who may be categorized more appropriately as having stage 1 hypertension.^[16]Because the HWG algorithm does not recognize a prehypertension category, some individuals designated as having prehypertension according to the JNC 7 classification may be considered normal in the paradigm.

The earliest identifiable stage of hypertensive disease, stage 1 hypertension, is characterized by the presence of early CVD markers. Although BP levels are higher than 115/75 mm Hg and may be frankly elevated in patients at this stage, abnormal BP patterns -- including loss of nocturnal dipping, exaggerated responses to exercise or mental stress, and widened pulse pressure -- may provide clearer evidence of the presence of early hypertensive disease.^[4] Although patients should have more than 1 CV risk factor to be included in this category, they should not have any evidence of target-organ damage.

In contrast to stage 1, stage 2 hypertension is characterized by diffuse disease markers and evidence of progressive disease as a consequence of persistent functional and structural changes in BP control mechanisms and in the heart and vasculature. Although patients at this stage frequently have sustained elevations in resting BP levels of 140/90 mm Hg or higher -- with much higher elevations induced by physiologic or psychologic stress -- it is important to recognize that any individual with numerous disease markers or limited evidence of early target-organ damage, such as left ventricular hypertrophy, fits into this category, regardless of BP levels. Methods of detecting or measuring some of the early target-organ damage characteristic of this stage of hypertension are currently limited to specialized or research settings, and further evaluation is needed to determine their potential utility and cost-effectiveness in clinical settings.^[6] Nonetheless, aggressive management of CV risk factors that are identified in patients at this stage may help attenuate the progression of target-organ damage.

Finally, stage 3 hypertension is an advanced stage of the hypertensive continuum, characterized by the presence of overt CVD. Overt hypertensive target-organ disease is often pervasive, and CVD events may have already occurred. If inadequately treated or left untreated, individuals at this stage usually have sustained resting BP levels of 140/90 mm Hg or higher, although marked elevations to levels higher than 160/100 mm Hg are not uncommon.^[6] Regardless of BP levels, however, all individuals with clinical evidence of overt target-organ damage or CVD, as well as those who have already sustained CVD events, are included in this category. Reaching this phase means that damage to target organs, as well as overt cardiorenal disease, has already occurred. As a consequence, CV risk factor modification and treatment of target-organ disease and all identified CVD should be vigorous and sustained.^[6]

Strategies for and the Clinical Implications of Treating Patients Along a Continuum of Global Cardiovascular Risk

The paradigm shift in viewing elevated BP as a marker for hypertension and hypertension as a progressive CVD syndrome has important implications for treating patients in the clinical setting. The risk-based approach proposed by the HWG will lead to reclassifying patients who were previously designated prehypertensive (based on JNC 7 criteria) to either HWG normal or stage 1 hypertension.^[4] In terms of treatment, lowering BP remains an important goal of antihypertensive therapy, yet ultimately the overarching objective is to prevent CV complications.^[9] Treatment of other CV risk factors is therefore equally important. Moreover, CV risk factors, including elevated BP, are not only precipitators, but also continuous pathogenic components at every stage of progression of CVD.^[9] Clinical strategies, therefore, need to focus on detecting and treating patients at risk at every stage along the continuum, from preventing target-organ damage and interrupting CVD progression in patients with early-stage hypertension, to making aggressive efforts to slow further disease progression and avoid CV events in patients with late-stage hypertension.

Evidence for the benefit of antihypertensive treatment in early-stage hypertension (HWG stage 1 or JNC 7 prehypertension category) has only recently become available. The Trial of Preventing Hypertension (TROPHY) study has shown that antihypertensive therapy may help prevent the development of elevated BP levels among individuals with BP lower than 140/90 mm Hg who are at high risk for frank hypertension (due to the presence of multiple CV risk factors).^[17] In line with the HWG paradigm, patients in this study had high-normal SBP/DBP levels of 130-139/85-89 mm Hg at baseline, yet had a strikingly high rate of CV risk factors other than elevated BP.^[17] Among the TROPHY patients, 96% had at least 1 additional CV risk factor, includingvarious measures of dyslipidemia, insulin resistance, and obesity, as well as elevatedhematocrit and heart rate; 81% had 2 or more additional risk factors; and33% had 4 or more additional risk factors. The most prevalent risk factor in thecohort as being overweight.^[2,17] Patients were randomized to receive treatment with the angiotensin receptor blocker candesartan or placebo for 2 years, followed by an additional 2 years of placebo-only therapy; all patients were instructed to make changes in lifestyle to reduce BP throughout the trial.^[17] After 2 years, hypertension haddeveloped in 154 patients in the placebo group and 53 patients in the angiotensin receptor blockergroup, representing a significant 63% relative risk reduction with pharmacotherapy (P < .001). After 4 years, hypertension had developed in 240 patients assigned to placeboand 208 patients assigned to active treatment (relative risk reduction, 15.6%;P < .007). Serious adverse events occurred in 3.5% of patients who received active treatment and in 5.9% of those who received placebo. As the authors noted, the absolute difference between active treatment and placebo at 2 years in TROPHY, 26.8%, is much higher than the 8% absolute difference observed in the Trials of Hypertension Prevention,^[18] the only trial of lifestyle modification with a similar duration, suggesting that drug therapy plus lifestyle modification is more effective than lifestyle modification alone in early hypertension.^[17]

The benefit of treatment with antihypertensive agents in patients classified as normotensive by conventional standards also is supported by the Perindopril Protection Against Recurrent Stroke Study (PROGRESS).^[19] In this study, antihypertensive treatment in subjects without elevated BP (mean BP, 136/79 mm Hg) but with a history of target-organ damage -- in this case, a history of transient ischemic attacks or stroke -- was associated with a significant 27% reduction in the relative risk for stroke compared with placebo (P < .01), similar to the 32% reduction observed in patients designated as hypertensive.^[19] Moreover, intensive BP reduction with combination therapy was associated with better outcomes than less-intensive BP reduction with single-agent therapy, regardless of hypertension status. Because individuals similar to those considered normotensive in PROGRESS would be classified as having stage 2 hypertension (based on the presence of target-organ damage) in the HWG paradigm, results of this study highlight the importance of considering comprehensive risk factor assessment, including the presence of target-organ damage, when defining and staging patients with hypertension.

Whether all individuals with early-stage hypertension, as defined by the HWG, should be treated with antihypertensive therapy requires further study. As the group emphasized in their 2005 report, characterizing hypertension as a complex CV disorder associated with, but not exclusively defined by, high BP is best viewed as a transitional strategy that is intended to generate further clinical research into improved strategies for detecting, treating, and possibly preventing the disease.^[4]

Summary

The key points advanced by the HWG in their updated hypertension position paper are that BP serves as a biomarker for the disease hypertension and, as such, elevated BP is not synonymous with hypertension. Some individuals may exhibit elevated BP in the absence of hypertension, whereas other individuals with the same levels of BP might be classified into different stages of hypertension.^[6] Therefore, for purposes of calculating total CV risk and staging patients as normal or hypertensive, BP should be evaluated in the context of other CV risk factors and disease markers. Ultimately, it is hoped that the risk-based approach to defining and staging hypertension, as proposed by the HWG, will lead to earlier identification of individuals with hypertensive CVD. Preliminary data, such as that described by the TROPHY Investigators, suggest that lowering BP with pharmacologic therapy can prevent or delay the progression of hypertensive CVD even at early stages (ie, HWG stage 1 hypertension/JNC 7 prehypertension). Additional research is necessary to confirm these findings and identify cost-effective methods to detect and measure early CVD markers in clinical practice.

This activity is supported by an independent educational grant from Pfizer.

This article is a CME certified activity. To earn credit for this activity visit:
http://cme.staging.medscape.com/viewarticle/708548

References

1. Weir MR. Risk-based classification of hypertension and the role of combination therapy. J Clin Hypertens (Greenwich). 2008;10:4-12.
2. Giles TD. Assessment of global risk: a foundation for a new, better definition of hypertension. J Clin Hypertens (Greenwich). 2006;8:5-14.
3. Khosia N, Black HR. Expanding the definition of hypertension to incorporate global cardiovascular risk. Curr Hypertens Rep. 2006;8:384-390.
4. Giles TD, Berk BC, Black HR, et al. Expanding the definition and classification of hypertension. J Clin Hypertens (Greenwich). 2005;7:505-512.
5. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
6. Giles TD, on behalf of the Hypertension Writing Group. Definition and classification of hypertension: an update. J Clin Hypertens (Greenwich). In press.
7. Sierra C, de la Sierra A. Early detection and management of the high-risk patient with elevated blood pressure. Vasc Health Risk Manag. 2008:4;289-296.
8. Franklin SS, Khan SA, Wong ND, et al. Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham Heart Study. Circulation. 1999;100:354-360.
9. Basile J. Management of global risk across the continuum of hypertensive heart disease. J Clin Hypertens (Greenwich). 2006;8:21-30.
10. Khot UN, Khot MB, Bajzer CT. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA. 2003;290:898-904.
11. Neaton JD, Wentworth D; the Multiple Risk Factor Intervention Trial Research Group. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: overall findings and differences by age for 316,099 white men. Arch Intern Med. 1992;152:56-64.
12. Meigs JB, D'Agostino RB Sr, Wilson PW, et al. Risk variable clustering in the insulin resistance syndrome: the Framingham Offspring Study. Diabetes. 1997;46:1594-1600.
13. Gregg EW, Cheng YJ, Cadwell BL, et al. Secular trends in cardiovascular disease risk factors according to body mass index in US adults. JAMA. 2005;293:1868-1874.
14. Dzau VJ, Antman EM, Black HR, et al. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: Part I: pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation. 2006;114:2850-2870.
15. Hoerger TJ, Ahmann AJ. The impact of diabetes and associated cardiometabolic risk factors on members: strategies for optimizing outcomes. J Manag Care Pharm. 2008;14:S2-S14.
16. Pickering TG, White WB; American Society of Hypertension Writing Group. ASH position paper: home and ambulatory blood pressure monitoring. When and how to use self (home) and ambulatory blood pressure monitoring. J Clin Hypertens (Greenwich). 2008;10:850-855.
17. Julius S, Nesbitt SD, Egan BM, et al; Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354:1685-1697.
18. The Trials of Hypertension Prevention Collaborative Research Group. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure: the Trials of Hypertension Prevention, phase II. Arch Intern Med. 1997;157:657-667.
19. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033-1041.

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Teachable software may help diagnose endocarditis, study shows

Technorati Tags: Arrhytmias,Cardio Diagnstic,Endocarditis

by Barbara Boughton

San Francisco, CA - Artificial neural networks—teachable software designed to mimic the human brain—could one day be used to diagnose endocarditis related to implanted cardiac rhythm devices.

In a proof-of-concept study, investigators from the Mayo Clinic in Rochester, MN devised a neural network that could correctly identify 72 of 73 generator pocket infections and 12 of 13 cardiac rhythm management device-related infective endocarditis (CRMD-IE), according to research presented here at the American Society for Microbiology 2009 Interscience Conference on Antimicrobial Agents and Chemotherapy.

If proven, the software could benefit some patients by helping them avoid the risk, discomfort, and expense of transesophageal echocardiography (TEE), according to lead author Dr M Rizwan Sohail (Mayo Clinic). "In some cases, it might enable us to correctly diagnose patients without performing TEE or to select patients who might benefit from additional testing," Sohail said. "The result would be reduced healthcare costs and improved outcomes."

The researchers used data from 189 patients admitted to the Mayo Clinic with a diagnosis of CRMD infection to "train" the software to recognize variables that signaled infection. Of the patients, 23% actually had CRMD-IE.

In testing the artificial neural network, the researchers used three configurations of clinical variables to test how accurate the software could be. They found that the most reliable variables were blood-culture results, presenting signs and symptoms, tenderness at the infection site, ejection fraction, and fever. By using these variables, they increased the overall sensitivity of the artificial neural network to 86.4%, Sohail said.

In developing their model, they focused primarily on clinical features of CRMD infection, rather than laboratory parameters, because these findings are readily available to clinicians. However, the inclusion of positive blood cultures and presenting signs and symptoms were the variables that most improved the sensitivity of their model, Sohail said.

The scientists used the final neural network on six cases with an "unknown" diagnosis. They found that the trained software correctly identified all four cases without CRMD-IE (pocket-only infections) but missed one of the two CRMD-IE cases.

The scientists are continuing to work with the artificial neural network and have already used more than 400 cases to continue "training" the software. They also plan to expose it to 200 cases with unknown diagnoses to see how reliable the software is. If the model proves reliable, the artificial neural network might eventually be used to diagnose other types of infection, such as pneumonia, Sohail said.

"In training the artificial neural network, you have to be very careful about what data you feed into it, and expose it gradually to different variables," he said. Like humans, too much extraneous data can cause the artificial neural network to "become distracted," he said.

"These results are very encouraging," commented Dr Vance G Fowler Jr (Duke University, Durham, NC). "If appropriately validated, it could help clinicians make a sometimes-difficult diagnosis."

Yet Fowler pointed out that the artificial neural network correctly identified only a handful of CRMD-IE cases, while it was more successful in pinpointing generator pocket infections, which are fairly easy for clinicians to recognize, he said. "But it's a novel and innovative approach, and it clearly warrants further investigation," he said.

Source

Sohail MR, Saadah LM, Uslan DZ, et al. Using artificial neural networks to predict cardiac rhythm management device-related infective endocarditis. American Society for Microbiology 2009 Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12, 2009; San Francisco, CA. Abstract K-268.

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How to shave 10 years off your life: Have high cholesterol, be hypertensive, and smoke

Technorati Tags: Hypertension,Prevention,Dyslipidemia,Statin,Aspirin

by Lisa Nainggolan

Oxford, UK - A new analysis from the British Whitehall study looking at male civil servants has found that a single measurement of three cardiovascular risk factors in middle age—smoking, high blood pressure, and high cholesterol—predicted a threefold higher rate of vascular mortality compared with none of the risk factors [1]. The researchers also showed a twofold higher rate of nonvascular mortality and an almost 10-year shorter life expectancy from age 50 in those with the risk factors.

Dr Robert Clarke (University of Oxford, UK) and colleagues report their findings online September 17, 2009 in BMJ. And when they used more extreme categorization of risk factors, including body-mass index (BMI), diabetes mellitus/glucose intolerance, and employment grade, life expectancy differed by up to 15 years.

Clarke says there has been uncertainty about the limits of life expectancy and the relevance of cardiovascular risk factors for its prediction. "What is unique about this study is the prolonged follow-up; it enables us to put a figure on the life-limiting effects of these risk factors," he told heartwire.

The study shows concordance with recent findings from the Physicians' Health Study in the US [2] and "provides a stark illustration of the importance of these risk factors to reduce life expectancy," he adds. The findings also provide support for public-health policies aimed at achieving modest changes in major risk factors throughout the population to achieve improvements, he notes.

"This is a metric that is readily understood by patients. It's repackaging these old risk factors to give them a bit more quantitative importance. We have all these new factors, like CRP, when in fact these old risk factors explain much of the difference in life expectancy," he stresses.

All three risk factors associated with 10 to 15 years lower life expectancy

Data were collected from 18 863 men aged 40 to 69 who were working in the civil service in London when they were first examined in 1967-1970. They completed questionnaires and had a medical exam, including measurement of blood pressure, cholesterol, glucose concentrations, and height and weight, and answered questions about medical history, smoking habits, employment grades, and marital status.

People were divided into two groups based on the three main CV risk factors: current smoker (yes/no); baseline BP ("high"=systolic BP >140 mm Hg or "low"; and baseline cholesterol ("high"=cholesterol >5.0 mmol/L or "low"). In addition, a risk score was computed from these factors. The men were followed for 38 years: 13 501 died, and 4811 were reexamined in 1997.

At entry, 42% of the men were current smokers, 39% had high blood pressure, and 51% had high cholesterol. At the reexamination, about two-thirds of the previously "current" smokers had quit smoking shortly after entry, and the mean differences in levels of those with high and low levels of BP and cholesterol were attenuated by two-thirds.

Despite this, compared with men without any baseline risk factors, the presence of all three risk factors at entry was associated with a 10-year shorter life expectancy from age 50 (23.7 vs 33.3 years). And compared with men in the lowest 5% of the risk score based on smoking, diabetes, employment grade, and continuous levels of BP, cholesterol concentration, and BMI, men in the highest 5% had a 15-year shorter life expectancy from age 50 (20.2 vs 35.4 years).

Prospective study, with large sample size and long follow-up

The study has several strengths in addition to the prolonged follow-up, say Clarke et al, including a prospective design, large sample size, availability of repeat measurements between middle and old age, a large number or deaths, and virtually complete mortality follow-up.

Limitations include the fact that total cholesterol concentrations were employed rather than cholesterol fractions or apolipoproteins, which are much stronger predictors of vascular mortality than total cholesterol, they note. Also, the effects of BP and cholesterol on mortality might have been slightly underestimated because of increased use of aspirin, statins, and BP-lowering drugs during follow-up (in 1997, around a third of survey participants were taking aspirin and/or antihypertensives, although only 2% were taking statins).

"Continued public-health strategies to lower mean levels of the three main cardiovascular risk factors, together with more intensive medical treatment for 'high-risk' subgroups, including use of medication to lower blood pressure and cholesterol concentration, which have proven efficacy, could result in further improvements in life expectancy," they conclude.

Sources

Clarke R, Emberson J, Fletcher A, et al. Life expectancy in relation to cardiovascular risk factors: 38-yar follow-up of 19 000 men in the Whitehall study. BMJ 2009; DOI:10.1136/bmj.b3513. Available at: http://www.bmj.com.

Yates LB, Djoussé L, Kurth T, et al. Exceptional longevity in men: modifiable risk factors associated with survival and function up to age 90 years. Arch Intern Med 2009; 168: 284-290.

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MADIT-CRT: Resynchronization therapy cuts heart-failure risk in patients with only mild disease

by Steve Stiles

Barcelona, Spain (updated) - The evidence base has another randomized trial supporting cardiac resynchronization therapy (CRT) in patients with systolic dysfunction, ventricular dyssynchrony by ECG, but only mild heart failure or LV systolic dysfunction without symptoms.

In such patients, for whom a primary-prevention implantable cardioverter defibrillator (ICD) was already indicated, the addition of resynchronization pacing (CRT-D) cut the risk of death or heart-failure events, the primary end point, by about a third over two and a half years in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) [1]. A 41% reduction in risk of heart-failure events accounted for most of the CRT-D benefit, which was independent of whether the cardiomyopathy was ischemic or nonischemic.

"This study provides evidence that preventive CRT-ICD therapy decreases the risk of heart-failure events in vulnerable patients with ischemic or nonischemic heart disease who have minimal heart-failure symptoms but a wide QRS complex," write the authors, led by Dr Arthur J Moss (University of Rochester Medical Center, NY).

The MADIT-CRT findings were published online today in the New England Journal of Medicine to coincide with their release at the European Society of Cardiology Congress 2009. The investigators had released the trial's primary results to the investment community in June, as heartwire reported at the time.

A prespecified subgroup analysis showed that the CRT-D benefit for the primary end point was driven by the 52% risk reduction (p=0.001) in patients with QRS duration of >150 ms vs shorter QRS. There was also a significant interaction by sex, with women showing greater benefit than men (p=0.01).

"The striking thing was that females did better [with CRT-D] irrespective of their QRS duration," Moss said when formally presenting the study at the meeting. "Men got a good result, but the women got twice as good a result."

The definition of heart-failure events in MADIT-CRT allowed for patients to have been treated for decompensation on an outpatient basis and so wasn't strictly limited to HF hospitalization, a much more widely used end point in CRT trials.

CRT was also associated with significant improvements in LV volumes and LVEF, indications of the reverse-remodeling effect long observed as a benefit of the device therapy, including in the REVERSE trial. The MADIT-CRT findings are in general consistent with REVERSE, which also entered patients with mild heart failure, specifically patients in NYHA 1 or 2 with a QRS duration >120 ms, an LVEF <40%, and echocardiographic evidence of LV dilatation, as previously reported by heartwire.

"I think it will very possibly change our indications in the future, to include also these patients," Dr Guenter Breithardt (University Hospital, Münster, Germany) said of MADIT-CRT as the discussant following Moss's presentation. He observed that patients in the trial had a lower LVEF and more dyssynchrony than those in REVERSE, but were otherwise very similar. "We of course have to be cautious about this conclusion, but both trials point in the same direction, that the greatest benefit is achieved in patients in class 2, and with longer QRS complexes."

But, he asked, "Do we have the same strong evidence for class 1 patients as we do for class 2? I don't think so." Class 2 patients were dominant in both trials, he said, so perhaps CRT should be aimed more at them.

Other views

The trial's eligibility criteria reflect an expanded population in terms of NYHA class and a tightening of criteria in terms of QRS duration, relative to class I indications for CRT in the current guidelines: LVEF <35 or less, QRS >120 ms or more, and sinus rhythm with NYHA class 3 or ambulatory class 4 heart failure on optimal medical therapy.

In an accompanying editorial [2], Dr Mariell Jessup (University of Pennsylvania, Philadelphia), points out that "it is not completely clear how the enrolled patients differ from those in earlier CRT trials, since no objective criteria were used to classify functional status at baseline," and functional status assessments thereafter weren't blinded.

"I think we don't understand the [MADIT-CRT] patient population very well," Jessup told heartwire, adding that it seems to be a weakness of the trial. She notes that the report says 10% of the patients had been in NYHA class 3 or 4 more than three months before study entry, as the protocol allowed. Therefore, not all patients in the trial had always been asymptomatic; some apparently had mild heart failure after having responded to medical therapy.

"Patients walk in the door, they have a wide QRS and a low LVEF, and what the guidelines tell us to do is put them on medical therapy and see if they get better. And if they get better and they're asymptomatic and they do well on their six-minute-walk test, we can put in an ICD, but we're not supposed to put in a CRT. This study suggests that you could, that you probably should," Jessup said.

"We have to understand which patients we should be doing this in, because it's an expensive therapy, and we probably need to start with the premise that the QRS must be really wide, not just a little wide. And we have to ask, is there a cheaper way to keep people out of the hospital than doing [CRT]?"

You're talking about a pretty significant healthcare expenditure that doesn't give you an absolute gain in each person who receives the technology.

Given the benefit primarily in patients with a QRS duration of >150 ms and cost-effectiveness concerns if CRT use is broadened based on MADIT-CRT, Jessup writes, it "appears prudent" that any expanded indications to include patients with milder heart failure be limited to those with such very wide QRS complexes and a history of "marked symptoms" that were under control with medical therapy.

As observed for heartwire by Dr Clyde W Yancy (Baylor University Medical Center, Dallas, TX), "a number of patients who undergo CRT don't derive a benefit. So you're talking about a pretty significant healthcare expenditure that doesn't give you an absolute gain in each person who receives the technology. So refining the candidacy and understanding more about the substrate we're targeting end up being pretty important."

Yancy, who is president of the American Heart Association, said he feels the MADIT-CRT results are most relevant in what they say about the current indications for CRT, "and I'm intrigued that there may be other patients who can benefit."

According to Dr Angelo Auricchio (Fondazione Cardiocentro Ticino, Lugano, Switzerland), MADIT-CRT represents a significant advance in heart-failure therapy. "The magnitude of the effect that we saw in this population is as big as what we had seen in past years with beta blockers, as big as what we saw with ACE inhibitors," he told heartwire.

Back then, no one really called for cost-effectiveness analyses before starting to use those drugs, he observed. But, "obviously we will come to a point where we will have to justify the use of devices in this very, very large group of patients. We will have to find the resources," he said.

Perhaps they will come from cost savings as CRT-D helps patients avoid heart-failure events. "This is a relatively healthy population, so it may take 10 years to see an effect on mortality, but now we see an immediate effect on hospitalization. This is really what is going to save money."

Both Auricchio and Dr Josep Brugada Terradellas (University of Barcelona, Spain) seem to agree on the probable impact of the study: not a broad expansion of the indications for CRT, but more physicians convinced of the value of CRT for existing indications. Both kinds of devices are underused in Europe, more so than in North America, they note.

"Every patient in MADIT-CRT has an indication for an ICD, but in real life many of them probably are not receiving one," Brugada said to heartwire. "Now probably they will. I expect an increase in the number of implantations [of both CRT-D and ICD-only devices] in patients who already have an indication for an ICD but are not implanted."

Dr Kenneth Dickstein (University of Bergen, Stavanger, Norway) foresees a huge expansion of the population getting CRT devices. "Now it's a whole new ball game with these mildly symptomatic patients, who obviously have a low mortality rate—think of all the patients who have ICDs who actually would now satisfy [CRT-D] criteria," he told heartwire.

Dickstein, who chairs the writing committee for the European CRT guidelines, observed that neither REVERSE nor MADIT-CRT was published when the last recommendations came out. "So now we'll have to update the guidelines."

Others have expressed caution about how tightly the findings should be embraced right now. "I think we need more data on this before [changing] the recommendations in the guidelines, because it's an invasive therapy," Prof Heinz Völler (Klinik am See, Rüdersdorf, Germany) said for heartwire. He observed that the MADIT-CRT report didn't alleviate all concern about the safety of CRT in its patient population. For example, it didn't say anything about the prevalence of appropriate and inappropriate ICD shocks. Also, he observed, the left-ventricular coronary-vein lead had to be repositioned within the first month in 4% of the CRT-D patients "for a variety of reasons," the report says.

How CRT made it

MADIT-CRT randomized 1820 patients at 110 centers in North America and Europe who were in NYHA class 1 or 2 and had an LVEF <30% and ventricular dyssynchrony as defined by an electrocardiographic QRS duration of at least 130 ms. Three patients received CRT-D devices for every two that got an ICD only. They were commercially available transvenous devices from Boston Scientific, the trial's sponsor. Optimal medical therapy was required in both groups.

The entry criteria specified that patients with ischemic cardiomyopathy could be in NYHA class 1 or 2 and that those with nonischemic disease had to be in NYHA class 2.

Over a follow-up averaging 2.4 years, the primary end point—death from any cause or nonfatal HF events—occurred in 17.2% of CRT-D patients and 25.3% of those getting an ICD (p=0.001). Heart-failure end points were identified by physicians who were aware of the patients' randomization group, but events were blindly adjudicated, according to Moss et al.

HR (95% CI) for the primary end point* and its components, CRT-D patients (n=1089) vs ICD-only patients (n=731)

End point	All patients	Patients with ischemic cardiomyopathy	Patients with nonischemic cardiomyopathy
Death or HF*	0.66 (0.52-0.84)a	0.67 (0.52-0.88)b	0.62 (0.44-0.89)c
HF only	0.59 (0.47-0.74)a	0.58 (0.44-0.78)a	0.59 (0.41-0.87)c
Death	1.00 (0.69-1.44)	1.06 (0.68-1.64)	0.87 (0.44-1.70)

a. p<0.001

b. p=0.003

c. p=0.01

CRT-D was associated with significantly improved LV volumes in a subgroup of 746 CRT-D patients and 620 ICD patients who underwent two-dimensional echocardiography at baseline and at one year. LVEF also rose significantly higher with resynchronization.

Change in left ventricular volumes by echocardiography over one year

Parameter	CRTD, n=746	ICD, n=620
LVEDV (mL)	-52	-15
LVESV (mL)	-57	-18

LVEDV=left ventricular end diastolic volume. LVESV=left ventricular end-systolic volume.

p<0.001 for all differences between CRT-D and ICD

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"It's an exciting study," Jessup said to heartwire, recalling her reaction when she learned of the results of the MADIT-2 trial. "I said, oh my God, that's a lot of devices. And that was my impression when I read this, that this is a lot of devices."

But MADIT-CRT should be far from the last word. Further trials should have narrower entry criteria. And "a really cool trial would be to say we're going to put [CRT devices] in a group of patients with a very wide QRS, 150 ms, and we're going to compare them to a nurse call center and see who stays out of the hospital more often for the least amount of money. That's the kind of question we have to ask now. Do we really need to be putting these expensive devices in, or is there another way to keep people out of the hospital?"

"We have a current patient population that is not reaping the full benefit of CRT, and if part of the reason is some trepidation regarding the real benefit, these data, along with REVERSE, really make the compelling argument that there are changes in ventricular size and function that are really quite striking," Yancy said.

"There's a totality of evidence accumulating that says that CRT is beneficial, and I'm hoping that totality of evidence will be especially effective for the patients who already have a well-established indication [for CRT]," he said. "I think for those physicians who have not accepted CRT, it's time."

Sources

1. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009; DOI: 10.1056.NEJMa0906431. Available at: http://www.nejm.org.
2. Jessup M. MADIT-CRT—Breathtaking or time to catch our breath? N Engl J Med 2009; DOI:10.1056.NEJMe0907335. Available at: http://www.nejm.org.

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