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Partial Adherence to Antihypertensive Therapy Fails to Achieve Full Cardiovascular Benefits in Hypertensive Rats
Partial Adherence to Antihypertensive Therapy Fails to Achieve Full Cardiovascular Benefits in Hypertensive Rats DINKO SUSIC, MD, PHD; MARIE KROUSEL-WOOD, MD, MSPH; XIAOYAN ZHOU, MD; EDWARD D. FROHLICH, MD
ABSTRACT: Background: Partial adherence to antihypertensive therapy remains a public health challenge and may be associated with increased cardiovascular risk. We quantitatively evaluated cardiovascular risk inherent in partial therapy adherence in spontaneously hypertensive rats with accelerated hypertension. Methods: Adult spontaneously hypertensive rats were divided into 5 groups; Group 1 (controls) did not receive any treatment, whereas all other rats (Groups 2–5) were given nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) to exacerbate hypertension. Group 2 (untreated/nonadherers) was given L-NAME but not antihypertensive medication; Group 3 (Perfect Adherers) was treated daily with candesartan (10 mg/kg); Group 4 was given candesartan 3 times a week, whereas Group 5 received candesartan only during the last 6 days of the 3-week experiment (Partial Adherers). At the end, indices of systemic and regional (kidneys, brain,
and heart) hemodynamics, and indices of left ventricular function were determined. Results: Treatment with LNAME aggravated hypertension, adversely affected target organ blood flows and resistances, and grossly impaired ventricular function. Perfect adherence with candesartan completely reversed the adverse cardiovascular effects of L-NAME intervention. In partial adherers (Groups 4 and 5), arterial pressure decreased and reached control values. However, target organ hemodynamics and heart function showed only slight improvements, if any. Conclusions: The results demonstrate that partial adherence to therapy reduces arterial pressure, but may not prevent target organ damage. If replicated in humans, these results may have important clinical implications in hypertensive patients. KEY INDEXING TERMS: Cardiovascular risk; Adherence; Hemodynamics; Hypertension; Medications. [Am J Med Sci 2008; 335(6):420–425.]
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protection against adverse cardiovascular events.6 –9 Yet, despite the availability of effective pharmacologic therapy, it is estimated that only about 37% of hypertensive patients have controlled arterial pressure10,11 Therefore, most of the hypertensive patients does not achieve effective pressure control and is still exposed to increased cardiovascular risk of unknown magnitude. Considering the fact that over 65 million adults in the United States and over 1 billion adults worldwide have hypertension, this chronic disease is a significant public health problem.10,12 One important factor contributing to poor arterial pressure control is patient nonadherence or partial adherence to prescribed therapy.10,11,13 It is generally accepted that patients who adhere only partially to antihypertensive therapy are exposed to increased cardiovascular risk.10,11,13 However, the exact magnitude of that risk is unknown. The objective of this study was to evaluate quantitatively the cardiovascular risk inherent in partial therapeutic adherence. Spontaneously hypertensive rats (SHRs) in whom hypertension was exacerbated
ardiovascular diseases, including stroke, coronary heart disease, heart failure, and sudden cardiac death, are leading causes of morbidity and mortality in the general population.1,2 Hypertension is, in turn, a major independent risk factor for the foregoing endpoints of cardiovascular morbidity and mortality.3–5 Evidence from the early as well as recent clinical trials clearly demonstrates that effective control of arterial pressure can be achieved and that treatment provides significant
From the Hypertension Research Laboratory (DS, XZ, EDF); Center for Health Research (MK-W), Division of Research, Ochsner Clinic Foundation, New Orleans, Louisiana; and Department of Epidemiology (MK-W), Tulane Health Sciences Center, New Orleans, Louisiana. Submitted June 29, 2007; accepted in revised form August 1, 2007. The first two authors contributed equally to this study. Presented at the Meeting of the Southern Society for Clinical Investigation, New Orleans, LA, February 8 –10, 2007. Correspondence: Dinko Susic, MD, PhD, Division of Research, Ochsner Clinic Foundation, 1520 Jefferson Highway, New Orleans, LA 70121 (E-mail: [email protected]).
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by compromising endothelial function with N-nitroL-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, were used as the experimental model.14 Because it was important to use an accelerated hypertensive model to quickly and accurately assess if differences in cardiovascular risk in partial adherers could be detected, we used this malignant phase of uncontrolled blood pressure and not the typical case of essential hypertension. To this end, a comparison of systemic hemodynamics, blood flows, and vascular resistances in the target organs of hypertension (brain, kidneys and heart), and ventricular function between L-NAME-treated SHR given regular antihypertensive therapy and rats with simulated partial therapeutic adherence or nontreated rats was made. The 2 most common clinical forms of partial adherence were simulated: intermittent and visit related. Intermittent adherers do not take prescribed therapies regularly skipping days or weeks at a time. Visit-related adherers take antihypertensive medication only a few days or weeks before visits with their physician or healthcare provider. Materials and Methods Animals Adult 20-week-old male SHRs, obtained from Harlan Laboratories (Indianapolis, IN), were housed in a temperature and humidity controlled facility with a 12 hours light/dark cycle. Standard rat chow (PMI Nutrition International, St Louis, MO) and tap water were provided ad libitum. The investigation conformed with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85 to 23, revised 1966); and the Institutional Animal Care and Use Committee approved the study. Experimental Protocol and Techniques The SHRs were divided randomly into 5 groups with 12 rats in each group. Rats in Group 1, controls, did not receive any treatment. All other rats (Groups 2–5) were given L-NAME in their drinking water for 3 weeks. Initial concentration of L-NAME in the drinking water was 60 mg/L. The concentration for each rat was then adjusted every second day (based on fluid intake) so that the rats ingested approximately 5 mg/kg/d of L-NAME throughout the study. Rats in Group 2 were given L-NAME, but did not receive any antihypertensive medication at all (Untreated or Nonadherers). The rats in Group 3 were given an angiotensin II type 1 receptor blocker, candesartan (10 mg/kg), daily by gastric gavage (perfect adherers). Animals from the Group 4 were given candesartan (10 mg/kg) only 3 times a week (intermittent adherers). Finally, the rats in Group 5 were given candesartan (10 mg/kg) during the last week of the study (visit-related adherers). Although there are many antihypertensive drugs, an angiotensin receptor blocker (ie, candesartan) was selected for this experimental model because perfect adherence to therapy with agents that block renin-angiotensin system restores all indexes of cardiovascular function in L-NAME treated rats. At the end of the 3-week course of therapy, studies of ventricular function and systemic and regional hemodynamics were performed for all study groups. All rats were evaluated 24 hours after the last dose of candesartan. Each rat was anesthetized with pentobarbital (40 mg/kg); and a catheter-tip transducer (Millar Instruments, Houston, TX) was introduced into the left ventricle via the right carotid artery. The catheter was connected to a preamplifier of a multichannel polygraph (Grass Instrument,
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Quincy, MA), and the signal was then fed to the data acquisition system (Emka Technologies, Paris, France). Several indices of cardiac function, including end-diastolic pressure, maximum rates of pressure rise and decline (⫹dP/dTmax and – dP/dTmax), and diastolic time constant (), were obtained from the ventricular pressure tracing. A femoral artery catheter (PE-50) was used for measurement of arterial pressure. After measurement of the ventricular functions, the catheter-tip transducer was removed and the rats were then instrumented for the determination of systemic and regional hemodynamics (using the reference standard radiomicrosphere method) as detailed elsewhere.15–17 In brief, a jugular vein, femoral artery, and the left ventricle (via right carotid artery) were cannulated with polyethylene catheters (PE-50) filled with heparinized saline. Approximately 100,000 radioactively labeled microspheres 15 ⫾ 1 m in diameter (NEN, Perkin Elmer, Boston, MA), suspended in saline containing Tween 80 (0.01%), were injected into the left ventricle and followed by an equal volume of warm saline. The reference blood sample was withdrawn from the femoral catheter connected to a Harvard infusion/withdrawal pump (Harvard Apparatus) at a rate of 0.45 mL/min for a period of 60 seconds. Baseline systemic, coronary, renal, and cerebral hemodynamics measurements were obtained by injecting the first bolus of radioactively labeled microspheres (85Sr). Maximal coronary vasodilation was then achieved by dipyridamole infusion (4 mg/kg/min intravenously for 10 minutes) and the hemodynamic studies were repeated using a second bolus of differently labeled (57Co) microspheres. At the end of the each hemodynamic study, each rat was killed with an overdose of pentobarbital and the heart, kidneys, and brain were immediately removed. Ventricles were separated and all organs weighed. Tissue samples, as well as blood reference samples, were placed in plastic scintillation vials and counted for 5 minute in a deep-well gamma scintillation spectrometer (Packard, Downer Grove, IL) with a multichannel analyzer. Spillover correction between channels was achieved by matrix inversion software (Compusphere, Packard, Downer Grove, IL). Organ blood flows were calculated by multiplying the fractional distribution of radioactivity to each organ by cardiac output. These data were normalized for the wet weight of the respective organ and expressed as mL/min/g. Regional vascular resistances were calculated by dividing the mean arterial pressure by organ blood flow and then normalized for organ weight (expressed as U/g). Blood flow reserve for the right and left ventricles was calculated as the difference between the dipyridamole and baseline flows. Minimal vascular resistance was defined as vascular resistance achieved by dipyridamole.15–18 Statistical Analysis All values are expressed as the mean ⫾ 1 SEM. One-way ANOVA and Bonferroni’s modification of the t test for multigroup comparisons were used to test the differences among groups.19 A probability value of less than 0.05 was considered as statistically significant.
Results Body Weight and Cardiovascular Mass Indices Body weight was decreased in rats given L-NAME; treatment with candesartan either daily or 3 times a week restored body weight to the level seen in controls (Table 1). However, in those rats given candesartan only during the last week of the experiment body weight remained lower. As compared with controls, left ventricular weight index was significantly increased in L-NAME treated rats (P ⬍ 0.05). In the rats given candesartan daily (Group 3) left ventricular weight index was similar to the controls; in Partial Adherers (Groups 4 and 5) it was not different from either controls or L-NAME 421
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Table 1. The Effects of a 3-wk Treatment with L-NAME (Group 2), L-NAME ⫹ Candesartan (10/mg/kg) (Group 3), L-NAME ⫹ Candesartan (10 mg/kg) 3 Times per Week (M, W, F) (Group 4), and L-NAME with Candesartan (10 mg/kg) during the Last Week of Therapy Only (Group 5) on Body Weight and Cardiovascular Mass Indexes
BW; g LVI; mg/g RVI; mg/g AWI; mg/mm
Group 1 (N ⫽ 12) Control
Group 2 (N ⫽ 11) Untreated
Group 3 (N ⫽ 10) Perfect Adherers
Group 4 (N ⫽ 12) Intermittent Adherers
Group 5 (N ⫽ 12) Visit-Related Adherers
403 ⫾ 3 3.14 ⫾ 0.06 0.45 ⫾ 0.01 1.43 ⫾ 0.04
364 ⫾ 11* 3.68 ⫾ 0.15* 0.46 ⫾ 0.12 1.62 ⫾ 0.21
391 ⫾ 6 3.18 ⫾ 0.12† 0.50 ⫾ 0.11 1.35 ⫾ 0.17
389 ⫾ 7 3.26 ⫾ 0.23 0.45 ⫾ 0.07 1.42 ⫾ 0.12
376 ⫾ 12 3.46 ⫾ 0.34 0.52 ⫾ 0.11 1.49 ⫾ 0.14
Group 1, untreated controls. Values are means ⫾ 1 SEM. * P ⬍ 0.05 when compared to Group 1. † P ⬍ 0.05 when compared to Group 2. BW, body weight; LVI, left ventricular weight index; RVI, right ventricular weight index; AWI, aortic weight index.
treated rats. Right ventricular and aortic weight indexes did not differ among groups. Systemic and Regional Hemodynamics Systolic and mean arterial pressures, as well as total peripheral resistance, were increased (P ⬍ 0.05), whereas cardiac index decreased (P ⬍ 0.05) in L-NAME treated rats (Figure 1 and Table 2). Arterial pressure returned to control values in both Perfect and Partial Adherers; however, cardiac index remained low in rats given candesartan only during the last week of therapy. Heart rate did not differ among the groups, being 401 ⫾ 7, 387 ⫾ 7, 406 ⫾ 9, 405 ⫾ 5, and 412 ⫾ 9 beats/min in Groups 1 to 5, respectively. Hepatic and renal blood flows were greatly decreased (P ⬍ 0.05) and organ vascular resistances were greatly increased (P ⬍ 0.05) by L-NAME treatment (Table 2). Every-day therapy with candesartan (Group 3) returned these values toward control; but partial adherence to candesar-
tan therapy (Groups 4 and 5) failed to restore organ flows and resistances to control values (Table 2). Brain hemodynamics were not affected by either LNAME or subsequent candesartan therapy (Table 2). Coronary Hemodynamics Basal coronary blood flow as well as coronary flow reserve were significantly decreased (P ⬍ 0.05), and, conversely, basal and minimal vascular resistance were increased (P ⬍ 0.05) in L-NAME treated rats as compared with control rats (Figure 2). In those given daily candesartan, indices of coronary hemodynamics returned to control values; however, partial adherence to candesartan therapy failed to restore coronary hemodynamics (Groups 4 and 5). Ventricular Function In rats given L-NAME, both systolic and diastolic function were impaired, as indicated by significant increases in left ventricular end-diastolic pressure
Figure 1. Systolic arterial pressure (SAP), mean arterial pressure (MAP), cardiac index (CI), and total peripheral resistance (TPRI) in rats given no treatment (Group 1, control) and rats given L-NAME (⬃5/mg/kg/d) in drinking water for 3 weeks (Groups 2–5). Rats in Group 2 were given L-NAME but did not receive any antihypertensive medication (untreated/nonadherers). Group 3 was given candesartan (10 mg/kg) daily (perfect adherers). Animals from Group 4 were given candesartan (10 mg/kg) 3 times a week (intermittent adherers). Rats in Group 5 were given candesartan (10 mg/kg) during the last week of the study (visit-related adherers). *P ⬍ 0.05 when compared with Group 1. †P ⬍ 0.05 when compared with Group 2.
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Table 2. Effects of Varying Levels of Adherence on Regional Hemodynamics
Liver BF; mL/min/g VR; U Kidneys BF; mL/min/g VR; U Brain BF; mL/min/g VR; U
Group 1 (N ⫽ 12) Control
Group 2 (N ⫽ 11) Untreated
Group 3 (N ⫽ 10) Perfect Adherers
Group 4 (N ⫽ 12) Intermittent Adherers
Group 5 (N ⫽ 12) Visit-Related Adherers
2.56 ⫾ 0.07 69 ⫾ 6
0.85 ⫾ 0.11* 207 ⫾ 15*
2.11 ⫾ 0.13† 81 ⫾ 11†
1.79 ⫾ 0.22*† 102 ⫾ 17†
1.43 ⫾ 0.15*† 125 ⫾ 13*†
5.84 ⫾ 0.41 30.0 ⫾ 2.3
2.33 ⫾ 0.37* 87.4 ⫾ 5.4*
5.94 ⫾ 0.51† 27.3 ⫾ 3.0†
4.72 ⫾ 0.41† 39.1 ⫾ 3.1†
4.18 ⫾ 0.42† 42.5 ⫾ 3.0*†
0.99 ⫾ 0.05 175 ⫾ 12
0.88 ⫾ 0.10 228 ⫾ 17
1.03 ⫾ 0.09 162 ⫾ 13
0.97 ⫾ 0.04 186 ⫾ 13
0.96 ⫾ 0.07 191 ⫾ 11
Values are means ⫾ 1 SEM. Group 1, untreated controls; Group 2, rats given only L-NAME; L-NAME ⫹ Candesartan (10/mg/kg) (Group 3); L-NAME ⫹ Candesartan (10 mg/kg) 3 times per week (M, W, F) (Group 4), and L-NAME with Candesartan (10 mg/kg) during the last week of therapy only (Group 5). * P ⬍ 0.05 when compared to Group 1. † P ⬍ 0.05 when compared to Group 2. BF, blood flow; VR, vascular resistance.
and diastolic time constant (Tau index) (P ⬍ 0.01) and significant decreases in maximal rates of pressure rise and decline (P ⬍ 0.05) (Figure 3). Daily candesartan therapy returned all indices of ventricular function to control levels but partial adherence to candesartan therapy failed to normalize cardiac functions. There was also a difference between the 2 groups of Partial Adherers. That is, in those rats given candesartan 3 times a week, indices of ventricular function were near control level, whereas in rats given candesartan only during the last week of therapy, there were only slight improvements, if any. Discussion The results of this study clearly demonstrate that in those SHRs, in whom hypertension, systemic and
regional hemodynamics as well as ventricular function were seriously aggravated by inducing endothelial dysfunction, partial adherence to antihypertensive treatment failed to rectify cardiovascular impairments. In this study, it is important to recognize that “perfect” adherence to antihypertensive therapy completely restored all measured hemodynamic and functional indices. Perhaps even more important was the finding that even though both forms of partial adherence reduced arterial pressure to control levels, they failed to improve the several measured indices of systemic and regional hemodynamics and ventricular function. Furthermore, the data clearly showed that in partial adherers, the extent of cardiovascular damage may depend on the type of partial adherence. Thus, in visit-related adherers (Group 5) cardiovascular damage appeared to be
Figure 2. Coronary hemodynamics including blood flow (BF), vascular resistance (VR), minimal vascular resistance (VRmin), and flow reserve (FR), in rats given no treatment (Group 1-control) and rats given L-NAME (⬃ 5/mg/kg/d) in drinking water for 3 weeks (Groups 2–5). Rats in Group 2 were given L-NAME but did not receive any antihypertensive medication (untreated/nonadherers). Group 3 was given candesartan (10 mg/kg) daily (perfect adherers). Animals from Group 4 were given candesartan (10 mg/kg) 3 times a week (intermittent adherers). Rats in Group 5 were given candesartan (10 mg/kg) during the last week of the study (visit-related adherers). *P ⬍ 0.05 when compared with Group 1. †P ⬍ 0.05 when compared with Group 2.
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Medication Adherence and Cardiovascular Outcomes
Figure 3. Indices of left ventricular function including end-diastolic pressure (LVEDP), maximal rate of pressure rise (dP/dT max) and decline (dP/dT min), and diastolic time constant (Tau) in rats given no treatment (Group 1, control) and rats given L-NAME (⬃5/ mg/kg/d) in drinking water for 3 weeks (Groups 2–5). Rats in Group 2 were given L-NAME but did not receive any antihypertensive medication (untreated/nonadherers). Group 3 was given candesartan (10 mg/ kg) daily (perfect adherers). Animals from Group 4 were given candesartan (10 mg/kg) 3 times a week (intermittent adherers). Rats in Group 5 were given candesartan (10 mg/kg) during the last week of the study (visit-related adherers). *P ⬍ 0.05 when compared with Group 1. †P ⬍ 0.05 when compared with Group 2.
more pronounced as indicated by the persistence of adverse effects on indices of systemic and regional hemodynamics and ventricular function even though arterial pressure achieved control level. In the Intermittent Adherers (Group 4) cardiovascular damage appeared to be less pronounced. From a clinical standpoint, these data may have several implications. First, they indicate in quantitative terms that cardiovascular risk in patients who partially adhere to antihypertensive therapy may remain significantly increased. Furthermore, they suggest that reliance on arterial pressure measurement alone for assessment of blood pressure control and cardiovascular risk during office visits can be misleading. Specifically, in the visit-related adherers, arterial pressure appeared completely controlled but they had evidence of extensive cardiovascular damage and functional impairment. It also appears that the type of Partial Adherence may be important in determining the risk of adverse effects, namely Intermittent Adherers may be at lower risk than visit-related adherers. Finally, accepting the notion that partial adherence to antihypertensive therapy confers significant cardiovascular risk, our data emphasize the necessity of a simple, cost-effective tool or test to determine adherence in outpatient settings.20 As one of the authors (EDF) recalled, in the first clinical trials determining the effectiveness of antihypertensive therapy (Veterans Cooperative Studies), an inert agent (riboflavin), excreted in urine, was added to all medications (both those containing active drug as well as placebo). Study subjects were required to provide urine samples at each visit, and simple urine analysis was used to determine adherence. Other less intrusive tools to 424
measure medication adherence in the outpatient setting have been developed (eg, self-report surveys, electronic monitors, pill counts, pharmacy fill data) and are currently undergoing validity and reliability testing in diverse populations.11,21,22 A potential limitation of this study might be the choice of the experimental model. We used SHRs in which endothelial function had been compromised by chronic inhibition of nitric oxide synthesis with L-NAME. This model of accelerated hypertension has been used widely.23–26 The SHR, given L-NAME, develops over 3 to 4 weeks severe hypertension with increased left ventricular and aortic masses, reduced cardiac output, greatly increased peripheral resistance, severely reduced blood flow, and with increased vascular resistances in most vascular territories (except for brain), and ventricular dysfunction. Therapy with agents that block renin-angiotensin system (eg, candesartan) restores all indexes of cardiovascular function.25,26 Our results in “perfect” adherers further confirm these findings. However, questions may exist as to whether this form of cardiovascular damage is analogous to the slowly progressive damage in clinical essential hypertension. Further study in this and other animal models is warranted to confirm these findings. Of great (and timely) interest was a very recent dialogue dealing with the clear-cut merits of blood pressure control in contrast with other target organ benefit or impairment in response to antihypertensive therapy.27,28 The results of our report provide important evidence strongly suggesting that control of arterial pressure is not sine qua non of therapy. Partial adherence to antihypertensive therapy that controls arterial pressure can be misleading and can June 2008 Volume 335 Number 6
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provide “false security” that intermittent blood pressure control prevents damage to target organ structure and function. In conclusion, the present study indicates that partial adherence to antihypertensive therapy confers in quantitative terms significant risk for cardiovascular morbidity, and ultimately, mortality. Furthermore, intermittent restitution of arterial pressure in partial adherers may be deceiving for both patients and physicians seeking to decrease cardiovascular risk through blood pressure control.
13. 14. 15.
16. 17.
References 1. Murray CJL, Lopez AD. Mortality by cause for eight regions of the world: global burden of disease study. Lancet 1997;349:1269 –76. 2. Bonow RO, Smaha LA, Smith SC Jr, et al. World heart day 2002: the international burden of cardiovascular disease: responding to the emerging global epidemic. Circulation 2002;106:1602–5. 3. Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA 1996;275:1571– 6. 4. Frohlich ED. Fibrosis and ischemia: the real risks in hypertensive heart disease. Am J Hypertens 2001;14(6 Pt 2):194S– 9S. 5. Frohlich ED. Recent advances in hypertension, stroke, and cardiorenal disease. Curr Opin Cardiol 2005;20:258 – 63. 6. Veterans administration study group on antihypertensive agents. Effects of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA 1967;202:1028 –34. 7. Veterans administration study group on antihypertensive agents. Effects of treatment on morbidity in hypertension: II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970;213:1143–52. 8. Cushman WC, Ford CE, Cutler JA. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens 2002;4:393– 404. 9. Chobanian AV, Bakris GL, Black HR, et al; and the National High Blood Pressure Education Program Coordinating Committee. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42:1206 –52. 10. Ong KL, Cheung BM, Man YB, et al. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999 –2004. Hypertension 2007;49:69 –75. 11. Krousel-Wood M, Thomas S, Muntner P, et al. Medication adherence: a key factor in achieving blood pressure control and good clinical outcomes in hypertensive patients. Curr Opin Cardiol 2004;19:357– 62. 12. Fields LE, Burt VL, Cutler JA, et al. The burden of adult
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hypertension in the United States 1999 to 2000: a rising tide. Hypertension 2004;44:398 – 404. Turnbull F. Managing cardiovascular risk factors: the gap between evidence and practice. PloS Med 2005;2:e131–2. Ono H, Ono Y, Frohlich ED. ACE inhibition prevents and reverses L-NAME-exacerbated nephrosclerosis in spontaneously hypertensive rats. Hypertension 1996;27:176 – 83. Ishise S, Pegram B, Yamamoto Y, et al. Reference sample microsphere method: cardiac output and blood flows in conscious rat. Am J Physiol Heart Circ Physiol 1980;239: H443–9. Kaneko K, Susic D, Nunez E, et al. Losartan reduces cardiac mass independent of pressure and hemodynamic changes. J Hypertens 1996;14:645–53. Susic D, Nunez E, Hosoya K, et al. Coronary hemodynamics in aging spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. J Hypertens 1998;16: 231–7. Susic D, Varagic J, Frohlich ED. Pharmacologic agents on cardiovascular mass, coronary dynamics, and collagen in aged spontaneously hypertensive rats. J Hypertens 1999;17: 1209 –15. Armitage P, Berry G. Statistical methods in medical research, 3rd ed. Oxford: Blackwell Scientific; 1994. Harmon G, Lefante J, Krousel-Wood MA. Overcoming barriers: the role of providers in improving patient adherence to antihypertensive medications. Curr Opin Cardiol 2006;21: 310 –5. Krousel-Wood MA, Muntner P, Jannu A, et al. Reliability of a medication adherence measure in an outpatient setting. Am J Med Sci 2005;330:128 –33. Hawkshead J, Krousel-Wood MA. Techniques for measuring medication adherence in hypertensive patients in outpatient settings: advantages and limitations. Dis Manag Health Outcomes 2007;15:109 –18. Vaskonen T, Mervala E, Krogerus L, et al. Cardiovascular effects of chronic inhibition of nitric oxide synthesis and dietary salt in spontaneously hypertensive rats. Hypertens Res 1997;20:183–92. Varagic J, Jerkic M, Jovovic D, et al. Regional hemodynamics after chronic nitric oxide inhibition in spontaneously hypertensive rats. Am J Med Sci 2000;320:171– 6. Li JS, Deng LY, Grove K, et al. Comparison of effects of endothelin antagonism and angiotensin-converting enzyme inhibition on blood pressure and vascular structure in spontaneously hypertensive rats treated with N omega-nitro-L-arginine methyl ester. Correlation with topography of vascular endothelin-1 gene expression. Hypertension 1996;28:188 –95. Zhou X, Frohlich ED. Differential effects of antihypertensive drugs on renal and glomerular hemodynamics and injury in the chronic nitric-oxide-suppressed rat. Am J Nephrol 2005;25:138 –52. Sever PS, Poulter NR. Blood pressure reduction is not the only determinant of outcome. Circulation 2006;111:2754 – 63. Elliott WJ, Jonsson MC, Black HR. It is not beyond the blood pressure; It is the blood pressure. Circulation 2006;111: 2763–72.
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ABSTRACT: Background: Partial adherence to antihypertensive therapy remains a public health challenge and may be associated with increased cardiovascular risk. We quantitatively evaluated cardiovascular risk inherent in partial therapy adherence in spontaneously hypertensive rats with accelerated hypertension. Methods: Adult spontaneously hypertensive rats were divided into 5 groups; Group 1 (controls) did not receive any treatment, whereas all other rats (Groups 2–5) were given nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) to exacerbate hypertension. Group 2 (untreated/nonadherers) was given L-NAME but not antihypertensive medication; Group 3 (Perfect Adherers) was treated daily with candesartan (10 mg/kg); Group 4 was given candesartan 3 times a week, whereas Group 5 received candesartan only during the last 6 days of the 3-week experiment (Partial Adherers). At the end, indices of systemic and regional (kidneys, brain,
and heart) hemodynamics, and indices of left ventricular function were determined. Results: Treatment with LNAME aggravated hypertension, adversely affected target organ blood flows and resistances, and grossly impaired ventricular function. Perfect adherence with candesartan completely reversed the adverse cardiovascular effects of L-NAME intervention. In partial adherers (Groups 4 and 5), arterial pressure decreased and reached control values. However, target organ hemodynamics and heart function showed only slight improvements, if any. Conclusions: The results demonstrate that partial adherence to therapy reduces arterial pressure, but may not prevent target organ damage. If replicated in humans, these results may have important clinical implications in hypertensive patients. KEY INDEXING TERMS: Cardiovascular risk; Adherence; Hemodynamics; Hypertension; Medications. [Am J Med Sci 2008; 335(6):420–425.]
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protection against adverse cardiovascular events.6 –9 Yet, despite the availability of effective pharmacologic therapy, it is estimated that only about 37% of hypertensive patients have controlled arterial pressure10,11 Therefore, most of the hypertensive patients does not achieve effective pressure control and is still exposed to increased cardiovascular risk of unknown magnitude. Considering the fact that over 65 million adults in the United States and over 1 billion adults worldwide have hypertension, this chronic disease is a significant public health problem.10,12 One important factor contributing to poor arterial pressure control is patient nonadherence or partial adherence to prescribed therapy.10,11,13 It is generally accepted that patients who adhere only partially to antihypertensive therapy are exposed to increased cardiovascular risk.10,11,13 However, the exact magnitude of that risk is unknown. The objective of this study was to evaluate quantitatively the cardiovascular risk inherent in partial therapeutic adherence. Spontaneously hypertensive rats (SHRs) in whom hypertension was exacerbated
ardiovascular diseases, including stroke, coronary heart disease, heart failure, and sudden cardiac death, are leading causes of morbidity and mortality in the general population.1,2 Hypertension is, in turn, a major independent risk factor for the foregoing endpoints of cardiovascular morbidity and mortality.3–5 Evidence from the early as well as recent clinical trials clearly demonstrates that effective control of arterial pressure can be achieved and that treatment provides significant
From the Hypertension Research Laboratory (DS, XZ, EDF); Center for Health Research (MK-W), Division of Research, Ochsner Clinic Foundation, New Orleans, Louisiana; and Department of Epidemiology (MK-W), Tulane Health Sciences Center, New Orleans, Louisiana. Submitted June 29, 2007; accepted in revised form August 1, 2007. The first two authors contributed equally to this study. Presented at the Meeting of the Southern Society for Clinical Investigation, New Orleans, LA, February 8 –10, 2007. Correspondence: Dinko Susic, MD, PhD, Division of Research, Ochsner Clinic Foundation, 1520 Jefferson Highway, New Orleans, LA 70121 (E-mail: [email protected]).
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by compromising endothelial function with N-nitroL-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, were used as the experimental model.14 Because it was important to use an accelerated hypertensive model to quickly and accurately assess if differences in cardiovascular risk in partial adherers could be detected, we used this malignant phase of uncontrolled blood pressure and not the typical case of essential hypertension. To this end, a comparison of systemic hemodynamics, blood flows, and vascular resistances in the target organs of hypertension (brain, kidneys and heart), and ventricular function between L-NAME-treated SHR given regular antihypertensive therapy and rats with simulated partial therapeutic adherence or nontreated rats was made. The 2 most common clinical forms of partial adherence were simulated: intermittent and visit related. Intermittent adherers do not take prescribed therapies regularly skipping days or weeks at a time. Visit-related adherers take antihypertensive medication only a few days or weeks before visits with their physician or healthcare provider. Materials and Methods Animals Adult 20-week-old male SHRs, obtained from Harlan Laboratories (Indianapolis, IN), were housed in a temperature and humidity controlled facility with a 12 hours light/dark cycle. Standard rat chow (PMI Nutrition International, St Louis, MO) and tap water were provided ad libitum. The investigation conformed with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85 to 23, revised 1966); and the Institutional Animal Care and Use Committee approved the study. Experimental Protocol and Techniques The SHRs were divided randomly into 5 groups with 12 rats in each group. Rats in Group 1, controls, did not receive any treatment. All other rats (Groups 2–5) were given L-NAME in their drinking water for 3 weeks. Initial concentration of L-NAME in the drinking water was 60 mg/L. The concentration for each rat was then adjusted every second day (based on fluid intake) so that the rats ingested approximately 5 mg/kg/d of L-NAME throughout the study. Rats in Group 2 were given L-NAME, but did not receive any antihypertensive medication at all (Untreated or Nonadherers). The rats in Group 3 were given an angiotensin II type 1 receptor blocker, candesartan (10 mg/kg), daily by gastric gavage (perfect adherers). Animals from the Group 4 were given candesartan (10 mg/kg) only 3 times a week (intermittent adherers). Finally, the rats in Group 5 were given candesartan (10 mg/kg) during the last week of the study (visit-related adherers). Although there are many antihypertensive drugs, an angiotensin receptor blocker (ie, candesartan) was selected for this experimental model because perfect adherence to therapy with agents that block renin-angiotensin system restores all indexes of cardiovascular function in L-NAME treated rats. At the end of the 3-week course of therapy, studies of ventricular function and systemic and regional hemodynamics were performed for all study groups. All rats were evaluated 24 hours after the last dose of candesartan. Each rat was anesthetized with pentobarbital (40 mg/kg); and a catheter-tip transducer (Millar Instruments, Houston, TX) was introduced into the left ventricle via the right carotid artery. The catheter was connected to a preamplifier of a multichannel polygraph (Grass Instrument,
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Quincy, MA), and the signal was then fed to the data acquisition system (Emka Technologies, Paris, France). Several indices of cardiac function, including end-diastolic pressure, maximum rates of pressure rise and decline (⫹dP/dTmax and – dP/dTmax), and diastolic time constant (), were obtained from the ventricular pressure tracing. A femoral artery catheter (PE-50) was used for measurement of arterial pressure. After measurement of the ventricular functions, the catheter-tip transducer was removed and the rats were then instrumented for the determination of systemic and regional hemodynamics (using the reference standard radiomicrosphere method) as detailed elsewhere.15–17 In brief, a jugular vein, femoral artery, and the left ventricle (via right carotid artery) were cannulated with polyethylene catheters (PE-50) filled with heparinized saline. Approximately 100,000 radioactively labeled microspheres 15 ⫾ 1 m in diameter (NEN, Perkin Elmer, Boston, MA), suspended in saline containing Tween 80 (0.01%), were injected into the left ventricle and followed by an equal volume of warm saline. The reference blood sample was withdrawn from the femoral catheter connected to a Harvard infusion/withdrawal pump (Harvard Apparatus) at a rate of 0.45 mL/min for a period of 60 seconds. Baseline systemic, coronary, renal, and cerebral hemodynamics measurements were obtained by injecting the first bolus of radioactively labeled microspheres (85Sr). Maximal coronary vasodilation was then achieved by dipyridamole infusion (4 mg/kg/min intravenously for 10 minutes) and the hemodynamic studies were repeated using a second bolus of differently labeled (57Co) microspheres. At the end of the each hemodynamic study, each rat was killed with an overdose of pentobarbital and the heart, kidneys, and brain were immediately removed. Ventricles were separated and all organs weighed. Tissue samples, as well as blood reference samples, were placed in plastic scintillation vials and counted for 5 minute in a deep-well gamma scintillation spectrometer (Packard, Downer Grove, IL) with a multichannel analyzer. Spillover correction between channels was achieved by matrix inversion software (Compusphere, Packard, Downer Grove, IL). Organ blood flows were calculated by multiplying the fractional distribution of radioactivity to each organ by cardiac output. These data were normalized for the wet weight of the respective organ and expressed as mL/min/g. Regional vascular resistances were calculated by dividing the mean arterial pressure by organ blood flow and then normalized for organ weight (expressed as U/g). Blood flow reserve for the right and left ventricles was calculated as the difference between the dipyridamole and baseline flows. Minimal vascular resistance was defined as vascular resistance achieved by dipyridamole.15–18 Statistical Analysis All values are expressed as the mean ⫾ 1 SEM. One-way ANOVA and Bonferroni’s modification of the t test for multigroup comparisons were used to test the differences among groups.19 A probability value of less than 0.05 was considered as statistically significant.
Results Body Weight and Cardiovascular Mass Indices Body weight was decreased in rats given L-NAME; treatment with candesartan either daily or 3 times a week restored body weight to the level seen in controls (Table 1). However, in those rats given candesartan only during the last week of the experiment body weight remained lower. As compared with controls, left ventricular weight index was significantly increased in L-NAME treated rats (P ⬍ 0.05). In the rats given candesartan daily (Group 3) left ventricular weight index was similar to the controls; in Partial Adherers (Groups 4 and 5) it was not different from either controls or L-NAME 421
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Table 1. The Effects of a 3-wk Treatment with L-NAME (Group 2), L-NAME ⫹ Candesartan (10/mg/kg) (Group 3), L-NAME ⫹ Candesartan (10 mg/kg) 3 Times per Week (M, W, F) (Group 4), and L-NAME with Candesartan (10 mg/kg) during the Last Week of Therapy Only (Group 5) on Body Weight and Cardiovascular Mass Indexes
BW; g LVI; mg/g RVI; mg/g AWI; mg/mm
Group 1 (N ⫽ 12) Control
Group 2 (N ⫽ 11) Untreated
Group 3 (N ⫽ 10) Perfect Adherers
Group 4 (N ⫽ 12) Intermittent Adherers
Group 5 (N ⫽ 12) Visit-Related Adherers
403 ⫾ 3 3.14 ⫾ 0.06 0.45 ⫾ 0.01 1.43 ⫾ 0.04
364 ⫾ 11* 3.68 ⫾ 0.15* 0.46 ⫾ 0.12 1.62 ⫾ 0.21
391 ⫾ 6 3.18 ⫾ 0.12† 0.50 ⫾ 0.11 1.35 ⫾ 0.17
389 ⫾ 7 3.26 ⫾ 0.23 0.45 ⫾ 0.07 1.42 ⫾ 0.12
376 ⫾ 12 3.46 ⫾ 0.34 0.52 ⫾ 0.11 1.49 ⫾ 0.14
Group 1, untreated controls. Values are means ⫾ 1 SEM. * P ⬍ 0.05 when compared to Group 1. † P ⬍ 0.05 when compared to Group 2. BW, body weight; LVI, left ventricular weight index; RVI, right ventricular weight index; AWI, aortic weight index.
treated rats. Right ventricular and aortic weight indexes did not differ among groups. Systemic and Regional Hemodynamics Systolic and mean arterial pressures, as well as total peripheral resistance, were increased (P ⬍ 0.05), whereas cardiac index decreased (P ⬍ 0.05) in L-NAME treated rats (Figure 1 and Table 2). Arterial pressure returned to control values in both Perfect and Partial Adherers; however, cardiac index remained low in rats given candesartan only during the last week of therapy. Heart rate did not differ among the groups, being 401 ⫾ 7, 387 ⫾ 7, 406 ⫾ 9, 405 ⫾ 5, and 412 ⫾ 9 beats/min in Groups 1 to 5, respectively. Hepatic and renal blood flows were greatly decreased (P ⬍ 0.05) and organ vascular resistances were greatly increased (P ⬍ 0.05) by L-NAME treatment (Table 2). Every-day therapy with candesartan (Group 3) returned these values toward control; but partial adherence to candesar-
tan therapy (Groups 4 and 5) failed to restore organ flows and resistances to control values (Table 2). Brain hemodynamics were not affected by either LNAME or subsequent candesartan therapy (Table 2). Coronary Hemodynamics Basal coronary blood flow as well as coronary flow reserve were significantly decreased (P ⬍ 0.05), and, conversely, basal and minimal vascular resistance were increased (P ⬍ 0.05) in L-NAME treated rats as compared with control rats (Figure 2). In those given daily candesartan, indices of coronary hemodynamics returned to control values; however, partial adherence to candesartan therapy failed to restore coronary hemodynamics (Groups 4 and 5). Ventricular Function In rats given L-NAME, both systolic and diastolic function were impaired, as indicated by significant increases in left ventricular end-diastolic pressure
Figure 1. Systolic arterial pressure (SAP), mean arterial pressure (MAP), cardiac index (CI), and total peripheral resistance (TPRI) in rats given no treatment (Group 1, control) and rats given L-NAME (⬃5/mg/kg/d) in drinking water for 3 weeks (Groups 2–5). Rats in Group 2 were given L-NAME but did not receive any antihypertensive medication (untreated/nonadherers). Group 3 was given candesartan (10 mg/kg) daily (perfect adherers). Animals from Group 4 were given candesartan (10 mg/kg) 3 times a week (intermittent adherers). Rats in Group 5 were given candesartan (10 mg/kg) during the last week of the study (visit-related adherers). *P ⬍ 0.05 when compared with Group 1. †P ⬍ 0.05 when compared with Group 2.
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Table 2. Effects of Varying Levels of Adherence on Regional Hemodynamics
Liver BF; mL/min/g VR; U Kidneys BF; mL/min/g VR; U Brain BF; mL/min/g VR; U
Group 1 (N ⫽ 12) Control
Group 2 (N ⫽ 11) Untreated
Group 3 (N ⫽ 10) Perfect Adherers
Group 4 (N ⫽ 12) Intermittent Adherers
Group 5 (N ⫽ 12) Visit-Related Adherers
2.56 ⫾ 0.07 69 ⫾ 6
0.85 ⫾ 0.11* 207 ⫾ 15*
2.11 ⫾ 0.13† 81 ⫾ 11†
1.79 ⫾ 0.22*† 102 ⫾ 17†
1.43 ⫾ 0.15*† 125 ⫾ 13*†
5.84 ⫾ 0.41 30.0 ⫾ 2.3
2.33 ⫾ 0.37* 87.4 ⫾ 5.4*
5.94 ⫾ 0.51† 27.3 ⫾ 3.0†
4.72 ⫾ 0.41† 39.1 ⫾ 3.1†
4.18 ⫾ 0.42† 42.5 ⫾ 3.0*†
0.99 ⫾ 0.05 175 ⫾ 12
0.88 ⫾ 0.10 228 ⫾ 17
1.03 ⫾ 0.09 162 ⫾ 13
0.97 ⫾ 0.04 186 ⫾ 13
0.96 ⫾ 0.07 191 ⫾ 11
Values are means ⫾ 1 SEM. Group 1, untreated controls; Group 2, rats given only L-NAME; L-NAME ⫹ Candesartan (10/mg/kg) (Group 3); L-NAME ⫹ Candesartan (10 mg/kg) 3 times per week (M, W, F) (Group 4), and L-NAME with Candesartan (10 mg/kg) during the last week of therapy only (Group 5). * P ⬍ 0.05 when compared to Group 1. † P ⬍ 0.05 when compared to Group 2. BF, blood flow; VR, vascular resistance.
and diastolic time constant (Tau index) (P ⬍ 0.01) and significant decreases in maximal rates of pressure rise and decline (P ⬍ 0.05) (Figure 3). Daily candesartan therapy returned all indices of ventricular function to control levels but partial adherence to candesartan therapy failed to normalize cardiac functions. There was also a difference between the 2 groups of Partial Adherers. That is, in those rats given candesartan 3 times a week, indices of ventricular function were near control level, whereas in rats given candesartan only during the last week of therapy, there were only slight improvements, if any. Discussion The results of this study clearly demonstrate that in those SHRs, in whom hypertension, systemic and
regional hemodynamics as well as ventricular function were seriously aggravated by inducing endothelial dysfunction, partial adherence to antihypertensive treatment failed to rectify cardiovascular impairments. In this study, it is important to recognize that “perfect” adherence to antihypertensive therapy completely restored all measured hemodynamic and functional indices. Perhaps even more important was the finding that even though both forms of partial adherence reduced arterial pressure to control levels, they failed to improve the several measured indices of systemic and regional hemodynamics and ventricular function. Furthermore, the data clearly showed that in partial adherers, the extent of cardiovascular damage may depend on the type of partial adherence. Thus, in visit-related adherers (Group 5) cardiovascular damage appeared to be
Figure 2. Coronary hemodynamics including blood flow (BF), vascular resistance (VR), minimal vascular resistance (VRmin), and flow reserve (FR), in rats given no treatment (Group 1-control) and rats given L-NAME (⬃ 5/mg/kg/d) in drinking water for 3 weeks (Groups 2–5). Rats in Group 2 were given L-NAME but did not receive any antihypertensive medication (untreated/nonadherers). Group 3 was given candesartan (10 mg/kg) daily (perfect adherers). Animals from Group 4 were given candesartan (10 mg/kg) 3 times a week (intermittent adherers). Rats in Group 5 were given candesartan (10 mg/kg) during the last week of the study (visit-related adherers). *P ⬍ 0.05 when compared with Group 1. †P ⬍ 0.05 when compared with Group 2.
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Medication Adherence and Cardiovascular Outcomes
Figure 3. Indices of left ventricular function including end-diastolic pressure (LVEDP), maximal rate of pressure rise (dP/dT max) and decline (dP/dT min), and diastolic time constant (Tau) in rats given no treatment (Group 1, control) and rats given L-NAME (⬃5/ mg/kg/d) in drinking water for 3 weeks (Groups 2–5). Rats in Group 2 were given L-NAME but did not receive any antihypertensive medication (untreated/nonadherers). Group 3 was given candesartan (10 mg/ kg) daily (perfect adherers). Animals from Group 4 were given candesartan (10 mg/kg) 3 times a week (intermittent adherers). Rats in Group 5 were given candesartan (10 mg/kg) during the last week of the study (visit-related adherers). *P ⬍ 0.05 when compared with Group 1. †P ⬍ 0.05 when compared with Group 2.
more pronounced as indicated by the persistence of adverse effects on indices of systemic and regional hemodynamics and ventricular function even though arterial pressure achieved control level. In the Intermittent Adherers (Group 4) cardiovascular damage appeared to be less pronounced. From a clinical standpoint, these data may have several implications. First, they indicate in quantitative terms that cardiovascular risk in patients who partially adhere to antihypertensive therapy may remain significantly increased. Furthermore, they suggest that reliance on arterial pressure measurement alone for assessment of blood pressure control and cardiovascular risk during office visits can be misleading. Specifically, in the visit-related adherers, arterial pressure appeared completely controlled but they had evidence of extensive cardiovascular damage and functional impairment. It also appears that the type of Partial Adherence may be important in determining the risk of adverse effects, namely Intermittent Adherers may be at lower risk than visit-related adherers. Finally, accepting the notion that partial adherence to antihypertensive therapy confers significant cardiovascular risk, our data emphasize the necessity of a simple, cost-effective tool or test to determine adherence in outpatient settings.20 As one of the authors (EDF) recalled, in the first clinical trials determining the effectiveness of antihypertensive therapy (Veterans Cooperative Studies), an inert agent (riboflavin), excreted in urine, was added to all medications (both those containing active drug as well as placebo). Study subjects were required to provide urine samples at each visit, and simple urine analysis was used to determine adherence. Other less intrusive tools to 424
measure medication adherence in the outpatient setting have been developed (eg, self-report surveys, electronic monitors, pill counts, pharmacy fill data) and are currently undergoing validity and reliability testing in diverse populations.11,21,22 A potential limitation of this study might be the choice of the experimental model. We used SHRs in which endothelial function had been compromised by chronic inhibition of nitric oxide synthesis with L-NAME. This model of accelerated hypertension has been used widely.23–26 The SHR, given L-NAME, develops over 3 to 4 weeks severe hypertension with increased left ventricular and aortic masses, reduced cardiac output, greatly increased peripheral resistance, severely reduced blood flow, and with increased vascular resistances in most vascular territories (except for brain), and ventricular dysfunction. Therapy with agents that block renin-angiotensin system (eg, candesartan) restores all indexes of cardiovascular function.25,26 Our results in “perfect” adherers further confirm these findings. However, questions may exist as to whether this form of cardiovascular damage is analogous to the slowly progressive damage in clinical essential hypertension. Further study in this and other animal models is warranted to confirm these findings. Of great (and timely) interest was a very recent dialogue dealing with the clear-cut merits of blood pressure control in contrast with other target organ benefit or impairment in response to antihypertensive therapy.27,28 The results of our report provide important evidence strongly suggesting that control of arterial pressure is not sine qua non of therapy. Partial adherence to antihypertensive therapy that controls arterial pressure can be misleading and can June 2008 Volume 335 Number 6
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provide “false security” that intermittent blood pressure control prevents damage to target organ structure and function. In conclusion, the present study indicates that partial adherence to antihypertensive therapy confers in quantitative terms significant risk for cardiovascular morbidity, and ultimately, mortality. Furthermore, intermittent restitution of arterial pressure in partial adherers may be deceiving for both patients and physicians seeking to decrease cardiovascular risk through blood pressure control.
13. 14. 15.
16. 17.
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