Introduction of IE and meeting participants Sign in, name, email Pretest
Hypertension is an important contributing risk factor for morbidity and mortality from both cardiovascular (CV) and renal disease. Hypertension is one of the most significant contributing factors to the development of CV and renal disease. Complications of hypertension include coronary artery disease, congestive heart failure, stroke, renal disease (including end-stage renal disease), and peripheral vascular disease. These diseases account for significant disability, loss of productivity, and decreased quality of life for many Americans. National High Blood Pressure Education Program Working Group. National High Blood Pressure Education Program Working Group report on primary prevention of hypertension. Arch Intern Med. 1993;153:186-208.
A recent analysis of National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2000 reported a 3.7% increase in the prevalence of hypertension compared with 1988 to 1994. 1 In a recent study, data from NHANES and the US Census Bureau were used to estimate hypertension burden, prevalence rates, and trends relative to 1988 to 1994 for US adults in 1999 to 2000. 2 The study found that at least 65 million US adults (nearly 1 in 3 adults, or 31.3%) had hypertension during that time period. 2 Assuming continuing trends, the figures would be even higher for 2004.
The Framingham Heart Study represents one of the major milestones in our understanding of the cardiovascular risks of hypertension. This study, for the first time, clearly demonstrated that patients with elevated blood pressure were at increased risk for cardiovascular events. Based on the findings of the Framingham Study, physicians were given evidence that patients with hypertension were at risk. 1,2 This long-term study provided epidemiologic data in which a cohort of subjects from the general population were followed biennially over 4 decades to observe the development of cardiovascular events in relation to their blood pressure and other suspected risk factors. The study found hypertension to be a major contributor to cardiovascular diseases. 1,2 Individuals with hypertension in this study were found to be at much greater risk for coronary disease, stroke, peripheral arterial disease, and heart failure compared with normotensive individuals. 1,2 Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA . 1996;275:1571-1576. Kannel WB. Fifty years of Framingham Study contributions to understanding hypertension. J Hum Hypertens . 2000;14:83-90.
MRFIT showed that SBP is a stronger predictor of CHD mortality than DBP in men of all age groups except those 35 to 39 years of age. This study examined the relative risk of CHD mortality as a function of SBP and DBP in 353,340 screened men who were followed for an average of 12 years. A strong, graded relationship was evident between SBP at every level >110 mm Hg and death due to CHD. Differences in CHD-related mortality at various DBP levels were relatively small. 24 Results from MRFIT strongly support the conclusion that SBP is a better indicator of increased CHD risk than DBP. This conclusion prompted the recent recommendation by the Coordinating Committee, National High Blood Pressure Education Program, National Heart, Lung, and Blood Institute, that SBP should “…become the principal clinical end point for the detection, evaluation, and treatment of hypertension, especially in middle-aged and older Americans.” 26
Numerous epidemiologic studies have shown that elevated SBP is an independent risk factor for cardiovascular morbidity and mortality and have supported the conclusion that, more than high DBP, elevated SBP increases those risks. 20-24 The Framingham Study indicated significantly increased risk of coronary disease, stroke, cardiac failure, and peripheral vascular disease in individuals 65 to 94 years old with elevated SBP. In all cases, the risks with elevated DBP were lower than those with elevated SBP. 20 A study of 11,912 hypertensive US veterans (5730 African American and 6182 nonblack; mean age, 52.5 years) showed significant and increasing risk of end-stage renal disease with rising SBP.21 The risk ratio (relative to that in the normotensive cohort) was 2.8 for SBP of 165 to 180 mm Hg and increased to 7.6 for SBP >180 mm Hg. In the Multiple Risk Factor Intervention Trial (MRFIT) of 332,554 screened men (35 to 57 years of age), the relative risks of end-stage renal disease were 6.0 for SBP of 160 to 179 mm Hg, 11.2 for SBP of 180 to 209 mm Hg, and 22.1 for SBP 210 mm Hg. 22 Elevated SBP also increases risk of stroke. A prospective, population-based study of 6621 individuals 50 years of age indicated relative risks of 2.7 for men and 3.0 for women versus normotensives. 23 Men with high SBP also had an increased risk of MI. MRFIT showed further that the risk of mortality from coronary heart disease (CHD) increases progressively with increased SBP. The adjusted relative risk rate was 1.8 for individuals with high-normal SBP (132–141 mm Hg) and 3.0 for hypertensive individuals (SBP 142 mm Hg). 24
HOT Study: Significant Benefit From Intensive Treatment in the Diabetic Subgroup The Hypertension Optimal Treatment (HOT) study was a Prospective Randomized Open Blinded End-point (PROBE) study comparing the effect of 3 different target DBP levels ( 90 mm Hg, n=6264; 85 mm Hg, n=6264; 80 mm Hg, n=6262) in 18,790 patients with hypertension and DBP between 100 mm Hg and 105 mm Hg. Antihypertensive therapy started with the long-acting calcium channel blocker felodipine, with the addition of other agents according to a five-step regimen. Patients were followed for an average period of 3.8 years [Hansson et al, 1998]. The primary objective of HOT was to assess: 1) major cardiovascular events (nonfatal MI, nonfatal stroke, and cardiovascular death) for each of the target DBP groups during treatment, and 2) major cardiovascular events for the DBP achieved during treatment. In the overall HOT study population, intensive lowering of BP substantially reduced the incidence of major cardiovascular events including fatal and nonfatal MI, fatal and nonfatal stroke, and cardiovascular death, although the differences among the 3 groups did not reach statistical significance. The greatest risk reduction (30%) was observed in those who achieved a DBP of 83 mm Hg. Additional lowering of BP did not produce further reduction in events, but was not harmful; there was no evidence of a J-shaped curve for the relation of cardiovascular events with the achieved BPs in the HOT study. Among the 1501 patients with diabetes at baseline, there was a 51% reduction in the risk of major cardiovascular events in the group randomized to a DBP target of 80 mm Hg compared with that of the 90 mm Hg target group ( p =0.005 for trend). Cardiovascular mortality was also significantly lower in the 80 mm Hg target group than in each of the other target groups. Thus, intensive BP-lowering is particularly beneficial to patients with hypertension and diabetes mellitus.
The risk reductions associated with BP treatment are well established. However, the relative benefits of BP treatment with different drugs have been studied only recently. The Blood Pressure Lowering Treatment Trialists’ Collaboration was established to undertake a series of prospectively designed, systematic overviews to analyze the effects of different BP-lowering regimens on mortality and major cardiovascular events. The first round of analyses was published in 2000. The second cycle analyzed data from 29 randomized trials (n=162,341) to gather estimates of the performance of treatment strategies based on different classes of antihypertensive drugs. 29 As seen in this slide of placebo-controlled trials, regimens using angiotensin-converting enzyme inhibitors (ACEIs) or calcium antagonists (CAs) produced significant reductions in risk versus placebo related to the BP differences for the end points of stroke, CHD, and major c a r d i o v a s c u l a r events. ACEI regimens significantly reduced heart failure (HF) events, whereas CAs did not. 29 Cardiovascular mortality and total mortality were significantly reduced by ACEI treatment. Trends toward fewer cardiovascular deaths and lower total mortality were observed with CAs. 29 Trials in the analysis are listed below. 29. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet . 2003;362:1527-1535. CA vs diuretic or -blocker AASK ALLHAT CONVINCE ELSA INSIGHT NICS-EH NORDIL SHELL STOP-2 VHAS ARBs vs control regimens IDNT RENAAL SCOPE LIFE Calcium antagonist vs placebo IDNT NICOLE PREVENT SYST-EUR More intensive vs less intensive regimens AASK ABCD (H) ABCD (N) HOT UKPDS-HDS ACEI vs calcium antagonist AASK ABCD (H) ABCD (N) ALLHAT JMIC-B STOP-2 Different drug classes ACEI vs diuretic or -blocker AASK ALLHAT ANBP2 CAPPP STOP-2 UKPDS-HDS Active treatment vs placebo ACEI vs placebo HOPE PART2 PROGRESS QUIET SCAT
Participants were men and women, age ≥ 55 years, who had Stage 1 or Stage 2 hypertension with at least one additional risk factor for CHD events . Randomized participants were assigned to receive amlodipine, chlorthalidone, doxazosin, or lisinopril as their initial study antihypertensive drug. Participants with LDL-cholesterol values in the eligible range and who were otherwise eligible for the lipid-lowering component were randomized to 40 mg/day of pravastatin or usual care. This presentation focuses on the antihypertensive component of ALLHAT.
The ALLHAT cohort had a mean baseline blood pressure of 146/84 mm Hg. The mean age was 67 years; 36% were Black, 47% were women, 22% were current cigarette smokers, 26% had a history of CHD, and 36% were diabetic. 92% were on antihypertensive medications at entry.
In January 2000, the doxazosin arm of the trial was terminated. There were two reasons for this: Futility of finding a significant difference for the primary outcome, and A statistically significant 20 percent higher rate of a major secondary endpoint, combined CVD outcomes. The rest of our discussion will focus on the other three treatment arms.
The blood pressure results show that: Chlorthalidone, amlodipine, and lisinopril all lowered BP from baseline levels. Chlorthalidone was best in lowering SBP. Amlodipine was best in lowering DBP.
No significant difference was observed between amlodipine (the red line) and chlorthalidone (the blue line) for the primary outcome. The relative risk for amlodipine compared to chlorthalidone was 0.98, with a 95% confidence interval of 0.90-1.07. Also, no significant difference was observed between lisinopril (the green line) and chlorthalidone for the primary outcome. The relative risk was 0.99, with a 95% confidence interval of 0.91-1.08.
The results were consistent across age, race, gender and baseline diabetes subgroups, except that the results were even more compelling for Black patients.
The results for the primary endpoint were consistent across the pre-defined subgroups, as shown here, as well as for participants with and without CHD at baseline.
The question on BP differences between ALLHAT’s treatment groups is an interesting one. The question is - Can at least some of the results be explained by differences in achieved SBP, especially between the lisinopril and chlorthalidone groups? What about adjustment of the primary outcome for these differences? Epidemiologic analyses indicate that a 2 mmHg difference in SBP can account for as much as a 7% difference in CHD and a 10% difference in stroke.
As you can see here on the primary endpoint of fatal CHD and nonfatal MI, these drugs did not differ from one another. Thus the older drug, diuretic, was unsurpassed by the newer classes. Similarly, in all secondary endpoints, chlorthalidone was unsurpassed, and, in fact when one looks at heart failure, chlorthalidone clearly bests the newer classes.
In response to your question about diabetes, here are the ALLHAT results on dysglycemia. The results of incident dysglycemia or diabetes in ALLHAT are consistent with other literature, which show that thiazide diuretics are associated with an increase in serum glucose. However, treatment-related differences in fasting serum glucose did not translate into more cardiovascular events or into higher all-cause mortality in the chlorthalidone group compared with the other two groups during the trial.
Also, treatment group comparison results were similar in diabetic and nondiabetic participants. Just as in the overall trial results, for both diabetic and nondiabetic participants, there were significant advantages for the diuretic arm.
In addition to ALLHAT, data from many other important trials also supports the JNC7 recommendations.
Analyses for major cardiovascular events, c a r d i o v a s c u l a r mortality, and total mortality did not show significant differences among diuretics/ -blockers, CAs, or ACEIs. 29 29. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet . 2003;362:1527-1535.
This slide shows the comparisons of different active treatments for the end points of stroke, CHD, and HF. As can be seen, there was a trend toward CAs being better for stroke reduction than diuretic/ -blockers or ACEI-based therapies. 29 In terms of CHD, analysis of the effects of different active treatment regimens revealed no significant differences among treatment with CAs, -blockers, ACEIs, or diuretics. 2 9 Analysis of HF showed no significant difference in risk between ACEI regimens and diuretic or -blocker treatment. In contrast, diuretic/ -blocker- or ACEI-based regimens were associated with greater risk reductions compared with CA treatment. 2 9 Overall, the study showed that BP reduction was more important than choice of an antihypertensive agent. 29. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet . 2003;362:1527-1535.
Do the favorable results for chlorthalidone apply to other thiazide diuretics? Large, controlled trials have shown similar mortality or morbidity reductions with many thiazide diuretics: Bendrofluazide (MRC) Chlorthalidone (SHEP, HDFP) Hydrochlorothiazide (VA, Oslo, Australian) Indapamide (PATS, PROGRESS) HCTZ/amiloride (MRC-O, STOP-H) HCTZ/triamterene (EWPHE) Independent trial findings support the view that all thiazide diuretics are beneficial.
SLIDE SUMMARY: ANGIOTENSIN-CONVERTING ENZYME INHIBITOR AND ANGIOTENSIN RECEPTOR BLOCKER THERAPIES ARE MINIMALLY EFFECTIVE — THERE IS ROOM FOR IMPROVEMENT Although clinical trial data indicate that angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapies do provide a significant benefit vs placebo — as measured by relative risk reduction for myocardial infarction, stroke, congestive heart failure, cardiovascular hospitalization, and cardiovascular-related mortality—the incidence of these events across all treatment groups remains substantial 1-5 For example, while treatment with ramipril in the Heart Outcomes Prevention Evaluation (HOPE) trial did reduce the number of high-risk patients experiencing cardiovascular-related mortality, myocardial infarction, or stroke, compared with placebo, 14% of the patients in the treatment group nevertheless experienced a cardiovascular-related event, compared with 17.8% of placebo patients 1 In the SOLVD (Studies of Left Ventricular Dysfunction) trial, which compared enalapril vs placebo in heart failure patients receiving conventional treatment, 35.2% (452) of the enalapril patients died, compared with 39.7% (510) of placebo patients. Although the treatment added benefit, a considerable number of treated patients did not survive 3 In the CHARM-Alternative trial, heart failure patients with ACEI intolerance were randomized to placebo or candesartan (target dose, 32 mg qd). During the median follow-up of 33.7 months, hospitalization or cardiovascular-related death was reported in 33% (n=334) of candesartan patients vs 40% (n=406) of placebo patients. Once again, the treatment offered benefit compared to placebo, but a considerable number of patients did not survive or experienced an unfavorable outcome 4 HOPE, Heart Outcomes Prevention Evaluation; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; SOLVD, Studies of Left Ventricular Dysfunction; CHARM, Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity; LIFE, Losartan Intervention for Endpoint Reduction in Hypertension trial. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G, and the HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med . 2000;342:145-153. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study. N Engl J Med . 1987;316:1429-1435. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med . 1991;325:293-302. Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: CHARM-Alternative trial. Lancet . 2003;362:772-776. Dahl o f B, Devereux RB, Kjelden SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE): a randomised trial against atenolol. Lancet . 2002;359:995-1003. Yusef/NEJM/p 9/Fig 1 CONSENSUS/NEJM/p 1429/Abst/ln 14-17 SOLVD/NEJM/p 293/Abst/ln 14-17 Granger/Lancet/p 774/Fig 2 Dahlof/Lancet/p999/C 1/P 3/ln 3-5 Yusef/p 8/P 2/ln 1-3; CONSENSUS/NEJM/p 1429/Abst/ln 14-17; SOLVD/p 295/C 1/P 1/ln 1-2; P 2/ln 2-6; Granger/p 774;C 1/P 3/ln 1; C 2/P 2/ln 1-9; Dahlof/p 998/Table 3; Granger/p772/C 1/P 3/ln 3-9
So, how does all of this apply to you and your hypertensive patients? First, it’s very important to treat to <140/90 mm Hg (even lower in patients with renal disease or diabetes). Maximum benefits can only be achieved by lowering both SBP and DBP to goal. Initial drug therapy for most should be either thiazide-type diuretic alone or combined with other drug classes. Most patients with uncontrolled Stage 1 or Stage 2 hypertension should experience better blood pressure control and better long term CVD risk when the medication regimen includes a thiazide-type diuretic. At this slide, PAUSE and probe audience for questions/skepticism. Tell a personal story, if you have not already. Address audience issues. Ask: In terms of drug treatment, how does what I’m telling you have implications for your practice? Are there any other aspects of JNC7 or ALLHAT that you’d like me to cover? What barriers to you see to changes in your practice? (Probe audience to get discussion going. Be sure to acknowledge & validate concerns expressed by your audience with statements such as, “I had to answer that question for myself”. In discussing questions, you may insert personal examples that support the core messages of the presentation.)
A key point of the JNC7 treatment algorithm is the promotion of patient lifestyle change.
For patients with compelling indications, there are many drug choices available, as this slide shows.
SLIDE SUMMARY: THE BINDING OF THE RENIN INHIBITOR ALISKIREN TO THE RENIN MOLECULE PREVENTS CLEAVAGE OF ANGIOTENSINOGEN figure shows the crystallized structure of the renin molecule, but with the binding pocket occupied by the renin inhibitor Aliskiren. Inhibited renin is no longer available to cleave its substrate, angiotensinogen. 1,2 Third-generation renin inhibitors, such as Aliskiren, have a high binding affinity for renin. This may be explained by the number of interactions with the renin molecule‘s active site. These inhibitors appear to bind to both the hydrophobic S1/S3-binding pocket and to a large, distinct, subpocket that extends from the S3-binding site towards the hydrophobic core of the molecule. Compared to a renin molecule not bound by an inhibitor, the bound molecule exhibits a “closed, inhibited“ conformation. 1,2 Rahuel J, Priestle JP, Grutter MG. The crystal structure of recombinant glycosylated human renin alone and in complex with a transition state analog inhibitor. J Struc Biol . 1991;107:227-236. Stanton A. Potential of renin inhibition in cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2003;4:6-10. Rahuel/p 232/Fig 4 Rahuel/p 227/C 2/P 2/ln3-9; Stanton/p 6/Abstract/ln 8-9 Rahuel/p 228/C 1/P 1/ln 1-6, 11-15; Stanton/7/C 1/P 1/ln 1-7; Rahuel/p 227/C1/P 1/ln 20-25
Slide Grade: A A new class of drugs, renin inhibitors (RIs) such as aliskiren, offer optimized RAAS suppression, either alone or in combination with other RAAS blocking agents. 1,2 The unique action of RIs in blocking the initial step in the RAAS means that, although renin release is stimulated via compensatory feedback mechanisms, plasma renin activity (PRA) is not increased. Renin inhibition also reduces activity of local tissue renin-angiotensin systems (RAS). At the local tissue level, aliskiren, by inducing a conformational change in the renin molecule, may also prevent renin binding to the (pro)renin receptor, blocking potentially harmful direct receptor-mediated effects. 3 Abbreviations ACE = angiotensin converting enzyme AT 1 = type 1 angiotensin II receptor ACEI = angiotensin converting enzyme inhibitor Ang I = angiotensin I ARB = angiotensin II receptor blocker Ang II = angiotensin II RAAS = renin-angiotensin-aldosterone system RI = renin inhibitor RAS = renin-angiotensin system PRA = plasma renin activity References 1. Nussberger J, Wuerzner G, Jensen C, et al . Angiotensin II suppression in humans by the orally active renin inhibitor aliskiren (SPP100): comparison with enalapril. Hypertension. 2002;39:e1 e8. 2. Azizi M, M é nard J, Bissery A, et al. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol 2004;15:3126–3133. 3. Nguyen G, Burckle C, Sraer JD. The renin receptor: the facts, the promise and the hope. Curr Opin Nephrol Hypertens 2003;12:51–55.
[The purpose of this slide is to lead in to lifestyle modifications and to commiserate with the difficulty of dealing with patients over this issue.] Now let’s turn to the difficult issue of lifestyle for a moment.
As you can see, lifestyle modification can be very effective in helping to reduce blood pressure, especially if these modifications are used in combination. However, these modifications have been difficult for us to implement in many patients. There are some more effective ways to approach these changes, which we’ll discuss in a few minutes.
Although this is a difficult issue, there is evidence that brief physician interventions can initiate lifestyle change. Here are the keys: Advice giving alone and follow-up monitoring are a minimum. I am trying this motivational interviewing in my practice, and at the very least it has netted fewer “yes, but” conversations with patients. Usually now a patient at least leaves having honestly considered their own readiness to take on these changes. I consider it a success if I can move the patient toward change and reinforce that movement.
In just a couple of minutes of interaction your goals must be limited. You want to move the patient along to change – not cause him to dig his heels in. So you can use the following sequence to assess the patient’s readiness to change, get the patient to talk about their personal reasons for change, and match a behavior change message to the patient’s communication. Ask the patient for p ermission to talk about lifestyle change Ask the patient about readiness to change – How i nterested are you on a scale of 1-10. Ask about a lower number, to elicit change statements Ask how c onfident they are that they can do the behavior M atch a message to interest and confidence To match a message, of course you have to hear what the patient is telling you. The first thing to do is to elicit change statements from the patient. If someone has just told you that they are a five on a scale from one to ten, ask “you are a five -- why are you not a three or a two? …… What would it take for you to be a 6 or a 7?” This is not a measurement technique – it is a technique for drawing out the patient’s own motivation.
These recommendations and results have influenced the way that I treat my hypertensive patients, and I’m pleased with the results. I’m very confident that with a renewed focus on blood pressure goals and a commitment to following the treatment guidelines, you will be pleased with the results in your practice, and your patients will experience even better blood pressure control, resulting in lower risk of cardiovascular disease.
In the packet, you have a number of items that are intended to aid you in remembering and implementing the JNC7 recommendations. Let’s take a quick look at them. Probably the most important things in the packet are these tools for use with your patients. Show pad. Show poster. We have also included a newsletter that explains a bit about what we are trying to do with this program, and explains the main messages. Several ALLHAT Investigators talk about their own experiences with regimens containing thiazide-type diuretics. You also have a copy of the DASH Eating Plan. If you believe that this will be useful with your patients, you can order them from NHLBI.ORG or print pages from the PDF file on the CD. You also have a summary of the lifestyle techniques that we talked about. You have a copy of the JNC7 reference card, as well as a reprint of the JNC7 recommendations. Some of the ALLHAT doctors find it handy to keep the article in a lab coat pocket for reference. Another handy item is a lab coat pocket version of the JNC7 recommendations, ALLHAT results, and lifestyle intervention techniques. You can see that it lists some commonly-used antihypertensive medications and doses. If you’d like this for your palm device, you can download it from ALLHAT.ORG, as it says at the very end of the card. You have a copy of the JNC7 reference card, as well as a reprint of the JNC7 recommendations. Some of the ALLHAT doctors find it handy to keep the article in a lab coat pocket for reference. The ALLHAT final results paper, and an article on ALLHAT entitled “Setting the Record Straight” are also included. The second article responds to issues about the ALLHAT results, some of which we talked about today. Thank you for allowing me to come and talk with you about this important topic. If you have any other questions or issues, please feel free to contact me. My business card is inserted on the inside front pocket of the packet.
Hypertension: Improving Treatment and Control
Improving Blood Pressure Treatment in the Community: Implications of the JNC7 Recommendations and ALLHAT Results Nathan D. Wong, PhD, FACC Professor and Director Heart Disease Prevention Program University of California, Irvine
Hypertension: A Significant CV and Renal Disease Risk Factor Peripheral vascular disease Morbidity Disability Renal disease CAD CHF LVH Stroke Hypertension National High Blood Pressure Education Program Working Group. Arch Intern Med. 1993;153:186-208.
At Least 65 Million Americans Require Treatment for Hypertension Nearly 1 in 3 adults (31%) in the US has hypertension Fields LE et al. Hypertension . 2004;44:398-404. Hypertension: How Big Is the Problem?
Risk of Cardiovascular Events by Hypertensive Status 36-Year Follow-up in Patients Aged 35-64 Years 9.5 3.3 2.4 5.0 2.0 3.5 2.1 45.4 21.3 12.4 6.2 9.9 7.3 13.9 6.3 22.7 0 10 20 30 40 50 Normotensive Hypertensive Coronary Disease Stroke Peripheral Arterial Disease Cardiac Failure Biennial Age-Adjusted Rate per 1,000 Reprinted with permission from Kannel WB. JAMA. 1996;275:1571-1576. Men Women Men Women Men Women Men Women
SBP-Associated Risks: MRFIT Adapted from Neaton JD et al. Arch Intern Med . 1992;152:56-64 . SBP versus DBP in Risk of CHD Mortality Diastolic BP (mm Hg) Systolic BP (mm Hg) CHD Death Rate 100+ 90–99 80–89 75–79 70–74 <70 <120 120–139 140–159 160+ 48.3 20.6 10.3 11.8 8.8 8.5 9.2 23.8 16.9 13.9 12.8 12.6 11.8 31.0 25.5 24.6 25.3 25.2 24.9 37.4 34.7 43.8 38.1 80.6
<40 40-49 50-59 60-69 70-79 80+ Age (y) 17% 16% 16% 20% 20% 11% Distribution of Hypertension Subtype in the untreated Hypertensive Population in NHANES III by Age Numbers at top of bars represent the overall percentage distribution of untreated hypertension by age. Franklin et al. Hypertension 2001;37: 869-874 . Frequency of hypertension subtypes in all untreated hypertensives (%) ISH (SBP 140 mm Hg and DBP <90 mm Hg) SDH (SBP 140 mm Hg and DBP 90 mm Hg) IDH (SBP <140 mm Hg and DBP 90 mm Hg) 0 20 40 60 80 100
<ul><li>Disease Relative Risk </li></ul><ul><li>Kidney failure (ESRD) 2.8 </li></ul><ul><li>Stroke 2.7 </li></ul><ul><li>Heart failure 1.5 </li></ul><ul><li>Peripheral vascular disease 1.8 </li></ul><ul><li>Myocardial infarction* =1.6 </li></ul><ul><li>Coronary artery disease 1.5 </li></ul>Elevated SBP Alone Is Associated With Increased Risk of Cardiovascular and Renal Disease ESRD = end-stage renal disease; SBP 165 mm Hg. *Men only. Adapted from Kannel WB. Am J Hypertens . 2000;13:3S-10S; Perry HM Jr et al. Hypertension. 1995;25(part 1):587-594; Klag MJ et al. N Engl J Med . 1996;334:13-18; Nielsen WB et al. Ugeskr Laeger . 1996;158:3779-3783; Neaton JD et al. Arch Intern Med . 1992;152:56-64.
Prevalence, Awareness, Treatment, and Control of Hypertension in US Adults 2003-2004 (Ong et al., Hypertension 2007; 49: 69-75)
Prevalence (%) of HTN in US Adults, by Disease Status (Wong et al, Arch Intern Med 2007, in press) **P <0.01 when compared to No-Disease Group ** ** ** ** ** ** ** Mean age (y): 53.5 59.3 54.8 60.5 76.1 65.9 68.2 69.3 67.2 **
Treatment (%) of HTN in US Adults, by Disease Status (Wong et al., Arch Intern Med 2007, in press) *P<0.05, **P <0.01 when compared to No-Disease group Treatment is in persons with HTN ** ** ** **
Control (all treated) (%) of HTN in US Adults, by Disease Status (Wong et al., Arch Intern Med 2007, in press) **P<0.05**P<0.01 when compared to No-Disease Group Control is in persons with HTN defined as BP < 140/90 If DM and CKD is based on BP<130/80 control is **35.3% and **23.2%, respectively. If MetS is based on BP<130/85 control is **46.7% * ** ** **
Minimum BP distance from goal of < 140/90 in parenthesis, even with DM & CKD *p<0.05 **p<0.01 compared to no disease Mean BP and Distance to Goal Among HTN Pts Not at Goal (Wong et al., Arch Intern Med 2007, in press) 90* (7) 154 (19) Dyslipidemia 90 (6) 155 (21*) CAD 89* (7) 157 (23** ) PAD 89** (6) 154 (22**) CHF 87** (6) 155 (22* ) Stroke 87** (7**) 155 (18 ) CKD 87** (6) 149* (14) DM 94 (5) 154 (16) MetS 93 (3) 154 (14) No Disease DBP mm Hg (Distance to Goal) SBP mm Hg (Distance to Goal)
Blood Pressure Classification <80 and <120 Normal 80–89 or 120–139 Prehypertension 90–99 or 140–159 Stage 1 HTN > 100 or > 160 Stage 2 HTN DBP mmHg SBP mmHg BP Classification
4-Year Progression To Hypertension: The Framingham Heart Study (<120/80 mm Hg) (130/85 mm Hg) (130-139/85-89 mm Hg) Vasan, et al. Lancet 2001;358:1682-86 Participants age 36 and older
HOT Study: Significant Benefit From Intensive Treatment in the Diabetic Subgroup Hansson L et al. Lancet. 1998;351:1755-1762. 0 5 10 15 20 25 90 85 80 Major cardiovascular events/1,000 patient-years p =0.005 for trend mm Hg Target Diastolic Blood Pressure
Benefits of Lowering BP Average Percent Reduction Stroke incidence 35–40% Myocardial infarction 20–25% Heart failure 50% TROPHY Study ACC 2006: Even lowering BP in those with pre-HTN appears to reduce incidence of new HTN by up to 60%
Preventable CHD Events from Control of Hypertension in US Adults (Wong et al., Am Heart J 2003; 145: 888-95) PAR% = population attributable risk (proportion of CHD events preventable), NNT = number needed to treat to prevent 1 CHD event ; <0.01 comparing men and women for PAR%
Randomized Design of ALLHAT High-risk hypertensive patients Consent / Randomize (42,418) Amlodipine Chlorthalidone Doxazosin Lisinopril Eligible for lipid-lowering Not eligible for lipid-lowering Consent / Randomize (10,355) Pravastatin Usual care Follow for CHD and other outcomes until death or end of study (up to 8 yr). ALLHAT
Baseline Characteristics and Follow-up 82% Known alive 42,418 N 36 Type 2 diabetes, % 92 On antihypertensive treatment, % Person-years (% obs/exp) Lost / refused Confirmed dead Follow-up 15% 146 / 84 Mean SBP/DBP 26 History of CHD, % 22 Current smoking % 47 Women, % 99% 36 Black, % 3% 67 Mean age, y Baseline ALLHAT
Doxazosin Arm Terminated Early <ul><li>Futility of finding a significant difference for primary CHD outcome </li></ul><ul><li>Statistically significant 20 percent higher rate of major secondary endpoint, combined CVD outcomes (80% higher rate of heart failure) </li></ul>Hypertension. 2003;42:239-246. ALLHAT
BP Results by Treatment Group Compared to chlorthalidone: SBP significantly higher in the amlodipine group ( ~ 1 mm Hg) and the lisinopril group ( ~ 2 mm Hg). Compared to chlorthalidone: DBP significantly lower in the amlodipine group ( ~ 1 mm Hg), similar in the lisinopril group. ALLHAT
Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril Years to CHD Event 0 1 2 3 4 5 6 7 Cumulative CHD Event Rate 0 .04 .08 .12 .16 .2 0.81 0.99 (0.91-1.08) L/C 0.65 0.98 (0.90-1.07) A/C p value RR (95% CI) ALLHAT
Fasting Glucose Results * p<.05 compared to chlorthalidone Serum fasting glucose – mmol/L, mean (sd) 11.6% 4 Years Diabetes Incidence (follow-up fasting glucose 126 mg/dL) 8.1%* 9.8%* 104.4 (28.5) 4 Years 93.1 (11.7) Baseline Among baseline nondiabetics with baseline <126 mg/dL – mean (SD) 93.3 (11.8) 93.0 (11.4) 100.5 (19.5)* 103.1 (27.7) Lisinopril Amlodipine Chlorthalidone ALLHAT
<ul><li>Outcome results were similar in diabetic and nondiabetic participants </li></ul><ul><li>For both diabetic and nondiabetic participants, there were significant advantages for the diuretic arm </li></ul>ALLHAT Results by Baseline Diabetic Status ALLHAT
Effect of 2-Year Changes in Fasting Glucose on ALLHAT Endpoints (Cox Regressions Beginning at 2 Years) 0.988 0.939 – 1.066 1.000 Heart failure 0.561 0.921 – 1.164 1.035 ESRD Per 10-Unit of Increase in Fasting Glucose (Baseline to 2 Years) 0.664 0.948 – 1.035 0.990 Total mortality 0.836 0.971 – 1.036 1.003 CCVD 0.727 0.909 – 1.069 0.986 Stroke 0.824 0.968 – 1.042 1.004 CCHD 0.327 0.979 – 1.066 1.022 CHD P 95% CI Hazard Ratio Endpoint ALLHAT
Diuretics, Potassium, and Glucose <ul><li>Based on 40+ years’ evidence, potassium depletion is a major factor relating thiazide treatment and abnormal glucose. </li></ul><ul><li>Both reduced insulin release and decreased insulin sensitivity have been demonstrated. </li></ul><ul><li>More attention than is often given to preventing or reversing hypokalemia is warranted, especially in patients at risk of diabetes. </li></ul><ul><li>Reference: Wilcox CS. Seminars in Nephrology, 1999;19:557-68. </li></ul>
Large Hypertension Trials Comparing Two or More Regimens: CVD or CV Mortality <ul><li>Trial n BP Δ Outcomes </li></ul><ul><li>CAPPP 10,985 +3/+1 captopril not superior to D/BB </li></ul><ul><li>NORDIL 10,881 +3/0 diltiazem not superior to D/BB </li></ul><ul><li>CONVINCE 16,602 0/+1 verapamil not superior to D/BB </li></ul><ul><li>STOP-2 6,628 0/-1 isradipine/felodipine & </li></ul><ul><li> 0/0 ACEIs not superior to D/BB </li></ul><ul><li>INSIGHT 6,592 0/0 nifed GITS not superior to diuretic </li></ul><ul><li>LIFE 9,193 +1/0 losartan superior to atenolol </li></ul><ul><li>ANBP-2 6,083 +1/0 ACEIs not superior to diuretics </li></ul><ul><li>ALLHAT 42,418 -3/-1 chlorthalidone superior to doxazosin , </li></ul><ul><li> -1/+1,-2/ 0 amlodipine (HF only), lisinopril </li></ul><ul><li>INVEST 22,576 0/ 0 verapamil ( + trandolapril) equivalent </li></ul><ul><li>to atenolol ( + HCTZ) </li></ul><ul><li>VALUE 15,313 +2/+2 valsartan not superior to amlodipine </li></ul>
Large, controlled trials have shown similar mortality or morbidity reductions with: Bendrofluazide (MRC) Chlorthalidone (SHEP, HDFP) Hydrochlorothiazide (VA, Oslo, Australian) Indapamide (PATS, PROGRESS) HCTZ/amiloride (MRC-O, STOP-H) HCTZ/triamterene (EWPHE) Conclusion Independent trial findings support the view that all thiazide diuretics are beneficial
ACEIs and ARBs Reduce Cardiovascular Morbidity and Mortality angiotensin-converting enzyme inhibitors (ACEI); angiotensin receptor blocker (ARB); myocardial infarction (MI); cardiovascular (CV); heart failure (HF); left ventricular hypertrophy (LVH). Yusuf S et al. N Engl J Med . 2000;342:145-153; The CONSENSUS Trial Study Group. N Engl J Med . 1987;316:1429-1435; The SOLVD Investigators. N Engl J Med. 1991;325:293-302; Granger CB et al. Lancet . 2003;362:772-776; Dahlof B et al. Lancet. 2002;359:995-1003; Cohn JN et al. N Eng J Med. 2001;345:1667-1675. HOPE CONSENSUS Placebo (n=4652) Ramipril (n=4645) Placebo (n=126) Enalapril (n=127) LIFE Atenolol (n=4588) Losartan (n=4605) CHARM-Added MI, stroke, or CV death in high-risk patients Total mortality in severe HF Death, MI, or stroke in patients aged 55–80 years with hypertension and LVH Relative Risk Reduction, % CV death or HF hospitalization in patients with chronic HF Placebo (n=1272) Candesartan (n=1276) ACEIs SOLVD Placebo (n=1284) Enalapril (n=1285) Mortality in chronic HF Val-Heft Valsartan (n=2511) Placebo (n=2499) All cause mortality and morbidity in patients with HF ARBs – 40 – 30 – 20 – 10 0
Implications for Your Practice and Your Patients <ul><li>The blood pressure goal for most patients with hypertension is <140/90 mm Hg. </li></ul><ul><li>Initial drug therapy for most should be either thiazide-type diuretic alone or combined with other drug classes. </li></ul><ul><li>Most patients with uncontrolled Stage 1 or Stage 2 hypertension should experience better blood pressure control and better long term CVD risk when the medication regimen includes a thiazide-type diuretic. </li></ul>
Algorithm for Treatment of Hypertension Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices Lifestyle Modifications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. With Compelling Indications Stage 2 Hypertension (SBP > 160 or DBP > 100 m mHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Stage 1 Hypertension (SBP 140 –159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Without Compelling Indications Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.
AHA Scientific Statement Recommendations: General CVD Prevention, High CAD Risk, Stable and Unstable Angina, NSTEMI, STEMI, LVD (Circulation 2007; 115: 2761-2788)
AHA 2007 Statement Recommendations <ul><li>A target BP of <130/80 mmHg is reasonable for individuals with any of the following (Class IIa, level of evidence B): </li></ul><ul><ul><li>Diabetes mellitus </li></ul></ul><ul><ul><li>Chronic renal disease </li></ul></ul><ul><ul><li>Coronary artery disease (CAD) </li></ul></ul><ul><ul><li>CAD risk equivalents </li></ul></ul><ul><ul><li>Carotid artery disease </li></ul></ul><ul><ul><li>Peripheral artery disease </li></ul></ul><ul><ul><li>Abdominal aortic aneurysms </li></ul></ul><ul><ul><li>High risk pts defined as >=10% 10-year risk from FRS </li></ul></ul>
Compelling Indications for Individual Drug Classes ACEI, ARB Chronic kidney disease THIAZ , ACEI Recurrent stroke prevention THIAZ , BB, ACEI, ARB, CCB Diabetes THIAZ , BB, ACEI, CCB High CAD Risk BB, ACEI, ALDO ANT Post myocardial infarction THIAZ , BB, ACEI, ARB, ALDO ANT Heart failure Initial Therapy Option Compelling Indication
Renin Inhibition With Aliskiren Binding of Angiotensinogen Prevented Rahuel J et al. J Struct Biol. 1991;107:227-236. <ul><li>Angiotensinogen </li></ul>Aliskiren binds to a pocket in the renin molecule, blocking angiotensinogen from being cleaved by renin
Aliskiren Suppresses the Entire System—Targets the Point of Activation <ul><li>(Pro)Renin Receptor </li></ul><ul><li>Actions: </li></ul><ul><li>Binding of (Pro)Renin </li></ul><ul><li>Increased renin catalytic activity </li></ul><ul><li>Activates VSMC ERK1/2 </li></ul>Renin Ang II Angiotensinogen ARBs AT 1 receptor Ang I Target cell renin-angiotensin-aldosterone system (RAAS); vascular smooth muscle cells (VSMC); extracellular singal-regulated kinases (ERK 1/2); angiotensin (Ang); angiotensin-converting enzyme (ACE); angiotensin-converting enzyme inhibitor (ACEI); angiotensin receptor blockers (ARB); type 1 angiotensin II receptor (AT 1 ) . Aliskiren <ul><li>Vasoconstriction </li></ul><ul><li>Remodelling </li></ul>Vessels Kidney Heart Aldosterone Ang III + IV ACE ACEIs Non-ACE pathways Aliskiren (Pro)Renin receptor
Lifestyle Modifications <ul><li>Most patients will experience better control if they modify diet and exercise. </li></ul><ul><li>Physician advice sometimes works and should always be given along with a follow-up visit appointment to monitor both blood pressure and lifestyle change efforts. </li></ul><ul><li>Most of us do not do lifestyle counseling beyond simple advice and admonishment – the time factor is a problem. </li></ul><ul><li>Nevertheless, lifestyle modification is at the top of the JNC7 algorithm. </li></ul>
Lifestyle Modification 2-4 mmHg Moderation of alcohol consumption 4-9 mmHg Physical activity 2-8 mmHg Dietary sodium reduction 8-14 mmHg Adopt DASH eating plan 5-20 mmHg / 10 kg weight loss Weight reduction Approximate SBP reduction (range) Modification
Keys to Physician Influence in Lifestyle Modification <ul><li>Advice giving and follow-up monitoring are a minimum (many pts are not adequately titrated to goal BP) </li></ul><ul><li>Some evidence that brief behavioral counseling aimed at matching messages to patient readiness to change and eliciting the patient’s own motivation to change can move the patient along a continuum of change </li></ul>
Physician Influence in Lifestyle Modification- What to Do PICM <ul><li>P ermission: Ask the patient for permission to talk about lifestyle change and get preference for beginning with diet or exercise </li></ul><ul><li>I nterest: Ask the patient about readiness to change – How interested are you on a scale of 1-10. Ask why they are not a lower number – to elicit a motivational statement from the patient. </li></ul><ul><li>C onfidence: Ask how sure they are that they can do the behavior – again ask why not a lower number </li></ul><ul><li>M atch a message to interest and confidence </li></ul>
Summary: For better long-term CVD risk for your patients <ul><li>Focus on blood pressure control for both SBP and DBP (<140/90 mm Hg - <130/80 for patients with diabetes or chronic renal disease) </li></ul><ul><li>Follow the JNC7 treatment guidelines: Use a thiazide-type diuretic as first line treatment and in combination for uncontrolled HTN </li></ul><ul><li>Do your part to disseminate these evidence-based guidelines </li></ul><ul><li>Make a renewed effort to encourage lifestyle change </li></ul>
Tools to Enhance BP Control <ul><li>For use with patients: </li></ul><ul><li>Physician-patient hypertension treatment planning pad for exam rooms </li></ul><ul><li>Poster for exam rooms </li></ul><ul><li>The DASH Eating Plan (also on CD & NHLBI.ORG) </li></ul><ul><li>Brief behavioral counseling steps and patient monitoring tools </li></ul><ul><li>For your reference: </li></ul><ul><li>Pocket card (palm format downloadable from ALLHAT.ORG) </li></ul><ul><li>ALLHAT results paper; Setting the Record Straight paper </li></ul><ul><li>Newsletter </li></ul><ul><li>JNC7 reference card (also on CD & NHLBI.ORG) </li></ul>